Ceacam5 and APLP2 binding agents and uses thereof

Abstract

The present disclosure relates to novel carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAMS)-binding agents (e.g., anti-CEACAM5 antibodies), amyloid precursor¬ like protein 2 (APLP2)-binding agents (e.g., anti-APLP2 antibodies), CEACAM5xAPLP2 binding agents (e.g., CEACAM5xAPLP2 multispecific antibodies) bind to both CEACAM5 and APLP2, and CEACAM5xAPLP2 binding agent-drug conjugates (e.g., CEACAM5xAPLP2 multispecific antibody-drug conjugate (ADC)) derived therefrom. The present disclosure further provides compositions (e.g., pharmaceutical compositions) comprising the presently disclosed binding agents and binding agent-drug conjugates, and methods of use thereof.

Description

Attorney Docket No. 13370-187-228CEACAM5 AND APLP2 BINDING AGENTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to United States Provisional Application No.63 / 791,214 filed April 18, 2025, the content of which is incorporated by reference in its entirety herein.SEQUENCE LISTING

[0002] This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “13370-187-228_SEQLISTING.xml”, was created on April 10, 2026, and is 266,790 bytes in size.1. FIELD

[0003] The present disclosure relates to novel carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-binding agents (e.g., anti-CEACAM5 antibodies), amyloid precursor-like protein 2 (APLP2)-binding agents (e.g, anti-APLP2 antibodies), CEACAM5xAPLP2 binding agents (e.g, CEACAM5*APLP2 multispecific antibodies) that bind to both CEACAM5 and APLP2, and CEACAM5*APLP2 binding agent-drug conjugates (e.g., CEACAM5* APLP2 multispecific antibody-drug conjugate (ADC)) derived therefrom. The present disclosure further provides compositions (e.g., pharmaceutical compositions) comprising the presently disclosed binding agents and binding agent-drug conjugates, and methods of use thereof.2. BACKGROUND

[0004] Antibody-drug conjugates (ADCs) can specifically target and kill cancer cells, thus improving the therapeutic window and reducing the off-targeted side effects. Once the antibody portion of an ADC is bound to the target antigens specifically expressed on cancer cells, the ADC is internalized by cells, and the drug payloads are released in the lysosomes. However, some target antigens are not efficiently internalized, and some can recycle back to the cell surface, thus limiting the efficacy of ADCs.

[0005] Thus, there remains a need in the art for improved ADCs for treating diseases or disorders, such as cancer.NAI-5011482438vl 13. SUMMARY

[0006] In one aspect, the present disclosure provides a carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-binding agent comprising: (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:201 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119; or (b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 200 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; (c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:87; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:88; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:99; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 12; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:23; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:34; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (k) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising theNAI-5011482438vl 2amino acid sequence of SEQ ID NO:54; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (1) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (m) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:76; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (n) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 109; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119.

[0007] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 220, 78, 221, and 222; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 104, 105, and 106; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 223 and 224; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0008] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv)NAI-5011482438vl 3the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0009] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, 26, and 27; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 29, 30, and 31; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0010] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.NAI-5011482438vl 4

[0011] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 89, 90, 91, and 92; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 93, 94, 95, and 96; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 97 and 98; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0012] In certain embodiments, the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0013] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 100, 78, 101, and 102; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 104, 105, and 106; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 107 and 108; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNAI-5011482438vl 5NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0014] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0015] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 3, 4, and 5; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 7, 8, and 9; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 and 11; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0016] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:2, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:6, the VH-CDR3 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 6NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 7, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:4, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:8, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:5, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0017] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, and 20; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 22; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0018] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the aminoNAI-5011482438vl 7acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:22, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:20, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0019] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, 26, and 27; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 29, 30, and 31; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0020] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv)NAI-5011482438vl 8the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0021] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 36, 37, and 38; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 18, 40, and 41; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 42 and 43; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0022] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:35, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:39, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:36, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:37, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:40, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:38, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:41, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.NAI-5011482438vl 9

[0023] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 47, and 48; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, 18, 50, 51; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0024] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:49, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:46, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:47, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:48, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:51, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0025] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 55, 56, 57, and 58; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 59, 60, 61, and 62; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 63 and 64; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 andNAI-5011482438vl 10128; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.

[0026] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:55, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:59, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:56, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:60, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:57, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:61, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:64, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:58, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:62, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

[0027] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 68, and 69; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 71, 72, and 73; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 75; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 and 128; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.

[0028] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:66, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:70, the VH-CDR3 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 11NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:67, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:71, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:68, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:72, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:75, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:69, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:73, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

[0029] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 77, 78, 79, and 80; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 81, 82, 83, and 84; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 and 86; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0030] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:77, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:81, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:82, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the aminoNAI-5011482438vl 12acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:79, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:83, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:86, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:80, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:84, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0031] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 110, 111, 112, and 113; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 114, 18, 115, and 116; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 117 and 118; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0032] In certain embodiments, the CE AC AM5 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:110, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:112, the VH-CDR2 comprising the amino acid sequence of SEQ IDNO:115, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv)NAI-5011482438vl 13the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:116, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0033] In certain embodiments, the CEACAM5 -binding agent comprises: (a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 12; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:23; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:34; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:44; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (k) the VH comprising an amino acidNAI-5011482438vl 14sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (1) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 65; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (m) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:76; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (n) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 109; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119.

[0034] In certain embodiments, the CEACAM5 -binding agent comprises: (a) the VH comprising the amino acid sequence of SEQ ID NO:201; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising the amino acid sequence of SEQ ID NO:200; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (e) the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (f) the VH comprising the amino acid sequence of SEQ ID NO: 1; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising the amino acid sequence of SEQ ID NO: 12; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising the amino acid sequence of SEQ ID NO:23; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising the amino acid sequence of SEQ ID NO:34; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising the amino acid sequence of SEQ ID NO:44; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (k) the VH comprising the amino acid sequence of SEQ ID NO:54; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (1) the VH comprising the amino acid sequence of SEQ ID NO:65; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (m) the VH comprising the amino acid sequence of SEQ ID NO:76; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (n) the VH comprising the amino acid sequence of SEQ ID NO: 109; and the VL comprising the amino acid sequence of SEQ ID NO: 119.NAI-5011482438vl 15

[0035] In certain embodiments, the CE AC AM5 -binding agent is (a) an antibody; (b) a monoclonal antibody; (c) an antibody fragment comprising at least one antigen-binding site; (d) a chimeric antibody; (e) a humanized antibody; or (f) a multispecific antibody.

[0036] In certain embodiments, the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (SCFV)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody.

[0037] In one aspect, the present disclosure provides a polynucleotide or polynucleotides encoding a CEACAM5 -binding agent or a portion thereof disclosed herein.In one aspect, the present disclosure provides a vector or vectors comprising a polynucleotide or polynucleotides disclosed herein or a complementary polynucleotide or polynucleotides thereto.

[0038] In certain embodiments, the present disclosure provides a cell comprising a CEACAM5-binding agent disclosed herein, a polynucleotide or polynucleotides disclosed herein, or a vector or vectors disclosed herein.

[0039] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a CE AC AM5 -binding agent disclosed herein and a pharmaceutically acceptable excipient.

[0040] In one aspect, the present disclosure provides an amyloid precursor-like protein 2 (APLP2)-binding agent comprising: (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:203; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 149; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 138; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119; or (d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 156; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 167; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (g) aNAI-5011482438vl 16VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:205; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:207; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119.

[0041] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 139, 140, 141, and 142; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0042] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acidNAI-5011482438vl 17sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0043] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 139, 140, 141, and 142; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0044] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.NAI-5011482438vl 18

[0045] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 226, 227, and 142; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0046] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0047] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 228, 229, 230, and 231; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNAI-5011482438vl 19NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0048] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0049] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 226, 227, and 142; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0050] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQNAI-5011482438vl 20ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0051] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 228, 229, 230, and 231; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0052] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising theNAI-5011482438vl 21amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0053] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 139, 140, 141, and 142; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0054] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv)NAI-5011482438vl 22the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0055] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 139, 140, 141, and 142; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0056] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.NAI-5011482438vl 23

[0057] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 157, 158, 159, and 160; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161, 162, 163, and 164; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 165 and 166; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 and 128; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.

[0058] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 158, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:159, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:163, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 164, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

[0059] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 168, 169, 170, and 171; and (ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 172, 173, 174, and 175; and (iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 176 and 177; and (iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNAI-5011482438vl 24NOs: 127 and 128; and (v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and (vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.

[0060] In certain embodiments, the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 168, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 169, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 173, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 170, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 174, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 177, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

[0061] In certain embodiments, the APLP2-binding agent comprises: (a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 156; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence ofNAI-5011482438vl 25SEQ ID NO: 126; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 167; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:205; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:206; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:207; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

[0062] In certain embodiments, the APLP2-binding agent comprises: (a) the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising the amino acid sequence of SEQ ID NO: 156; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (e) the VH comprising the amino acid sequence of SEQ ID NO: 167; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (f) the VH comprising the amino acid sequence of SEQ ID NO:202; and the VL comprising the amino acid sequence of SEQ ID NO:119; or (g) the VH comprising the amino acid sequence of SEQ ID NO:204; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising the amino acid sequence of SEQ ID NO:205; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising the amino acid sequence of SEQ ID NO:206; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising the amino acid sequence of SEQ ID NO:207; and the VL comprising the amino acid sequence of SEQ ID NO: 119.NAI-5011482438vl 26

[0063] In certain embodiments, the APLP2-binding agent is (a) an antibody; (b) a monoclonal antibody; (c) an antibody fragment comprising at least one antigen-binding site; (d) a chimeric antibody; (e) a humanized antibody; or (f) a multispecific antibody.

[0064] In certain embodiments, the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (SCFV)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody.

[0065] In one aspect, the present disclosure provides a polynucleotide or polynucleotides encoding the APLP2-binding agent or a portion thereof disclosed herein.

[0066] In one aspect, the present disclosure provides a vector or vectors comprising a polynucleotide or polynucleotides disclosed herein or a complementary polynucleotide or polynucleotides thereto.

[0067] In one aspect, the present disclosure provides a cell comprising an APLP2-binding agent disclosed herein, a polynucleotide or polynucleotides disclosed herein, or a vector or vectors disclosed herein.

[0068] In one aspect, the present disclosure provides a pharmaceutical composition comprising an APLP2-binding agent disclosed herein and a pharmaceutically acceptable excipient.

[0069] In one aspect, the present disclosure provides a multispecific binding agent comprising: (A) a carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-binding domain comprising: (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:201 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 200 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; (c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:87; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:88; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:99; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VLNAI-5011482438vl 27comprising the amino acid sequence of SEQ ID NO: 119; or (g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 12; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:23; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:34; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (k) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:54; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (1) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (m) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:76; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (n) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 109; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119; and (B) an amyloid precursor-like protein 2 (APLP2)-binding domain, the APLP2-binding domain comprising: (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:203; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 149; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 138; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) aNAI-5011482438vl 28VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 156; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 167; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or (f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:205; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:207; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119.

[0070] In certain embodiments, (i) (a) the CEACAM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:201 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:203 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or (ii) (a) theCE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:200 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:203 and the VL comprising the VL-NAI-5011482438vl 29CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119 (iii) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:87 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or (iv) (a) theCE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:88 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or (v) (a) the CEACAM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:99 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or (vi) (a) theCE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:87 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or (vii) (a) the CEACAM5-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:88 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ IDNAI-5011482438vl 30NO: 119, and (b) the APLP2 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO:119; or (viii) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119.

[0071] In certain embodiments, (A) the CEACAM5 -binding domain comprises: (a) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:201 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence ofNAI-5011482438vl 31SEQ ID NO: 124; or (b) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 200 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (c) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence ofNAI-5011482438vl 32SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (d) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (e) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) theNAI-5011482438vl 33VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (f) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 1; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:2, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:6, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:7, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:4, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:8, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the aminoNAI-5011482438vl 34acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:5, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (g) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 12; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:22, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:20, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (h) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:23; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQNAI-5011482438vl 35ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (i) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:34; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:35, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:39, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:36, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:37, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:40, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:38, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:41, the VH-CDR3 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 36NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (j) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:44; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:49, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:46, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:47, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:48, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:51, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (k) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:54; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:55, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:59, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:56, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:60, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-NAI-5011482438vl 37CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:57, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:61, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:64, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:58, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:62, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (1) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:65; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:66, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:70, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:67, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:71, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:68, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:72, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:75, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:69, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:73, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (m) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acidNAI-5011482438vl 38sequence of SEQ ID NO:76; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:77, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:81, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:82, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:79, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:83, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:86, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:80, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:84, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (n) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 109; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:114, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:111, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 112, the VH-CDR2 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 39NO: 115, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (B) the APLP2-binding domain comprises: (a) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (b) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, theNAI-5011482438vl 40VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (c) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprisingNAI-5011482438vl 41the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (d) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 156; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 158, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 159, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 163, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 164, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (e) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 167; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 168, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprisingNAI-5011482438vl 42the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 169, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 173, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 170, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 174, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 177, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (f) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:202; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprisingNAI-5011482438vl 43the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (g) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:204; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (h) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:205; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-NAI-5011482438vl 44CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (i) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:206; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (j) the VH comprising the VH-CDR1, the VH-CDR2, and theNAI-5011482438vl 45VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:207; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0072] In certain embodiments, (1) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprisingNAI-5011482438vl 46the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124, and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (2) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprisingNAI-5011482438vl 47the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124, and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (3) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprisingNAI-5011482438vl 48the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (4) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1NAI-5011482438vl 49comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 50NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (5) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQNAI-5011482438vl 51ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (6) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQNAI-5011482438vl 52ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (7) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQNAI-5011482438vl 53ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (8) (a) the CE AC AM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-bindingNAI-5011482438vl 54domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0073] In certain embodiments, (A) the CE AC AM5 -binding domain comprises: (a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID N0:200; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acidNAI-5011482438vl 55sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 12; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:23; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:34; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:44; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (k) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (1) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 65; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (m) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:76; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (n) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 109; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (B) the APLP2-binding domain comprises: (a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at leastNAI-5011482438vl 5680% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 156; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 167; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:205; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:206; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:207; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

[0074] In certain embodiments, (1) (a) the CE AC AM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (2) (a) the CE AC AM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ IDNAI-5011482438vl 57N0:200; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; or (3) (a) the CE AC AM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (4) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (5) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (6) (a) the CE AC AM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (7) (a) theCE AC AM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acidNAI-5011482438vl 58sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (8) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

[0075] In certain embodiments, (A) the CEACAM5 -binding domain comprises: (a) the VH comprising the amino acid sequence of SEQ ID NO:201; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising the amino acid sequence of SEQ ID NO:200; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (e) the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (f) the VH comprising the amino acid sequence of SEQ ID NO: 1; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising the amino acid sequence of SEQ ID NO: 12; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising the amino acid sequence of SEQ ID NO:23; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising the amino acid sequence of SEQ ID NO:34; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising the amino acid sequence of SEQ ID NO:44; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (k) the VH comprising the amino acid sequence of SEQ ID NO:54; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (1) the VH comprising the amino acid sequence of SEQ ID NO:65; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (m) the VH comprising the amino acid sequence of SEQ ID NO:76; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (n) the VH comprising the amino acid sequence of SEQ ID NO: 109; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (B) the APLP2-binding domain comprises: (a) the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (b) the VHNAI-5011482438vl 59comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising the amino acid sequence of SEQ ID NO: 156; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (e) the VH comprising the amino acid sequence of SEQ ID NO: 167; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or (f) the VH comprising the amino acid sequence of SEQ ID NO:202; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising the amino acid sequence of SEQ ID NO:204; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising the amino acid sequence of SEQ ID NO:205; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising the amino acid sequence of SEQ ID NO:206; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising the amino acid sequence of SEQ ID NO:207; and the VL comprising the amino acid sequence of SEQ ID NO: 119.

[0076] In certain embodiments, (1) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:201; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (2) (a) the CE AC AM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:200; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (3) (a) the CE AC AM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (4) (a) the CE AC AM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (5) (a) the CE AC AM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (6) (a) the CE AC AM5 -binding domain comprises the VH comprising the aminoNAI-5011482438vl 60acid sequence of SEQ ID NO: 87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (7) (a) the CE AC AM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or (8) (a) the CE AC AM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO:119.

[0077] In one aspect, the present disclosure provides a multispecific binding agent comprising: (i) a first polypeptide comprising from N-terminus to C-terminus: a first VL and a first CL;(ii) a second polypeptide comprising from N-terminus to C-terminus: a first VH, a first CHI, a first CH2, and a first CH3; (iii) a third polypeptide comprising from N-terminus to C-terminus: a second VH, a second CHI, a second CH2, and a second CH3; and (iv) a fourth polypeptide comprising from N-terminus to C-terminus: a second VL and a second CL, wherein the first polypeptide and the second polypeptide form the first CE AC AM5 -binding domain, and the third polypeptide and the fourth polypeptide form the APLP2-binding domain.

[0078] In certain embodiments, the second polypeptide further comprises a first hinge domain between the first CHI and first CH2, and the third polypeptide further comprises a second hinge domain between the second CHI and second CH2. In certain embodiments, the first hinge domain and / or the second hinge domain comprises amino acid mutations that reduce remediated effector functions. In certain embodiments, the first hinge domain and / or the second hinge domain comprises amino acid substitutions of L234A and L235A, numbering according to EU numbering by Kabat.

[0079] In certain embodiments, (i) the first CH3 comprises amino acid substitutions of T366W and E356K, and the second CH3 comprises amino acid substitution of T366S, L368A, Y407V, and K439E; (ii) the first CH3 comprises amino acid substitutions of T366S, L368A, Y407V, and K439E, and the second CH3 comprises amino acid substitution of T366W and E356K, (iii) the first CH3 comprises amino acid substitutions of T366S, L368A and Y407V, and the second CH3 comprises amino acid substitution of T366W; (iv) the first CH3 comprises amino acid substitution of T366W, and the second CH3 comprises amino acid substitution of T366S, L368A and Y407V; (v) the first CH3 comprises amino acid substitutions of T366W, E356K,NAI-5011482438vl 61and D399K, and the second CH3 comprises amino acid substitution of T366S, L368A, Y407V, K392D, and K409D; or (vi) the first CH3 comprises amino acid substitutions of T366S, L368A, Y407V, K392D, and K409D, and the second CH3 comprises amino acid substitution of T366W, E356K, and D399K, numbering according to EU numbering by Kabat.

[0080] In certain embodiments, the first polypeptide, and / or the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 137.

[0081] In certain embodiments, the second polypeptide and / or third polypeptide comprises the amino acid sequence of SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ IDNO:216, SEQ ID NO:217, SEQ IDNO:218, or SEQ ID NO:219.

[0082] In certain embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 192, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 193, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 187, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 188, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (iii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 189, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 188, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (iv) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 190, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 191, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (v) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 182, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 185, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (vi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 183, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 185, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (vii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 184, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 185, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (viii) the firstNAI-5011482438vl 62polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 182, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 186, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; (ix) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 183, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 186, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; or (x) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 184, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 186, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181.

[0083] In one aspect, the present disclosure provides a polynucleotide or polynucleotides encoding the multispecific binding agent or a portion thereof disclosed herein.

[0084] In one aspect, the present disclosure provides a vector or vectors comprising the polynucleotide or polynucleotides disclosed herein or a complementary polynucleotide or polynucleotides thereto.

[0085] In one aspect, the present disclosure provides a cell comprising a multispecific binding agent disclosed herein, a polynucleotide or polynucleotides disclosed herein, or a vector or vectors disclosed herein.

[0086] In one aspect, the present disclosure provides a pharmaceutical composition comprising a multispecific binding agent disclosed herein and a pharmaceutically acceptable excipient.

[0087] In one aspect, the present disclosure provides a binding agent-drug conjugate having the structure of Formula (I),A-(L-D)y(i);wherein, A is the multispecific binding agent disclosed herein; L is a linker; D is a therapeutic agent; y represents the number of (L-D) moi eties linked to A, which is an integer from 1-10.

[0088] In certain embodiments, the therapeutic agent is a cytotoxic agent.

[0089] In certain embodiments, the cytotoxic agent is selected from the group consisting of the cytotoxic agents listed in Table 25 disclosed herein. In certain embodiments, the cytotoxic agent is MM AE.

[0090] In certain embodiments, the linker is selected from the group consisting of the cytotoxic agents listed in Table 26. In certain embodiments, the linker isNAI-5011482438vl 631 owherein position 1 refers to the point of attachment of the linker to the multispecific binding agent, and position 2 refers to the point of attachment of the linker to the therapeutic agent.

[0091] In certain embodiments, y is two, four, six, eight, or ten. In certain embodiments, the multispecific binding agent is a multispecific antibody.

[0092] In certain embodiments, the binding agent-drug conjugate has a chemical formula as the followingwherein A is a multispecific binding agent disclosed herein.

[0093] In one aspect, the present disclosure provides a pharmaceutical composition comprising a binding agent-drug conjugate disclosed herein and a pharmaceutically acceptable excipient.

[0094] In one aspect, the present disclosure provides a pharmaceutical composition comprising: (i) a first means for binding to CEACAM5 expressed on a cell; (ii) a second means for binding to APLP2 expressed on the cell, (iii) a therapeutic agent, wherein the first means and second means act together to deliver and retain the therapeutic agent in the cell to exert its therapeutic effects; and (iv) a pharmaceutically acceptable carrier.

[0095] In one aspect, the present disclosure provides a method for treating a cancer or a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a binding agent-drug conjugate disclosed herein, or a pharmaceutical composition disclosed herein.

[0096] In one aspect, the present disclosure provides a method for alleviating one or more symptoms associated with a cancer or a tumor in a subject in need thereof, decreasing tumor size in a subject in need thereof comprising administering to the subject, or for enhancing tumor cell removal in a subject in need thereof, comprising administering to the subject a therapeuticallyNAI-5011482438vl 64effective amount of a binding agent-drug conjugate disclosed herein, or a pharmaceutical composition disclosed herein.

[0097] In certain embodiments, the cancer or tumor is selected from the group consisting of biliary tract cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, nonsmall cell lung cancer (NSCLC), ovarian cancer, prostate cancer, stomach cancer, liver cancer, melanoma, and pancreatic cancer.

[0098] In one aspect, the present disclosure provides use of a therapeutically effective amount of a binding agent-drug conjugate disclosed herein, or a pharmaceutical composition disclosed herein for treating a cancer or a tumor in a subject in need thereof.

[0099] In one aspect, the present disclosure provides use of a therapeutically effective amount of the binding agent-drug conjugate disclosed herein, or a pharmaceutical composition disclosed herein for alleviating one or more symptoms associated with a cancer or a tumor in a subject in need thereof, decreasing tumor size in a subject in need thereof comprising administering to the subject, or for enhancing tumor cell removal in a subject in need thereof.

[0100] In certain embodiments, the cancer or tumor is selected from the group consisting of biliary tract cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, stomach cancer, liver cancer, melanoma, and pancreatic cancer.

[0101] In one aspect, the present disclosure provides a binding agent-drug conjugate disclosed herein, or a pharmaceutical composition disclosed herein for use in the manufacture of a medicament for the treatment of a cancer or a tumor in a subject in need thereof.

[0102] In one aspect, the present disclosure provides a binding agent-drug conjugate disclosed herein, or a pharmaceutical composition disclosed herein for use in the manufacture of a medicament for alleviating one or more symptoms associated with a cancer or a tumor in a subject in need thereof, decreasing tumor size in a subject in need thereof comprising administering to the subject, or for enhancing tumor cell removal in a subject in need thereof.

[0103] In certain embodiments, the cancer or tumor is selected from the group consisting of biliary tract cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, stomach cancer, liver cancer, melanoma, and pancreatic cancer.4. BRIEF DESCRIPTION OF THE FIGURES

[0104] FIG. 1 depicts representative results of the protein expression levels of CEACAM5 in normal tissues (“non-cancerous”) or tumor tissues. KICH = kidney chromophobe renal cell carcinoma; KIRC = kidney renal clear cell carcinoma; KIRP = kidney renal papillaryNAI-5011482438vl 65cell carcinoma; LIHC = liver hepatocellular carcinoma; PRAD = prostate adenocarcinoma; SKCM = skin cutaneous melanoma; UCEC = uterine corpus endometrial carcinoma; UCS = uterine carcinosarcoma; BRCA = breast invasive carcinoma; LU AD = lung adenocarcinoma; LUSC = lung squamous cell carcinoma; PAAD = pancreatic adenocarcinoma; COAD = colon adenocarcinoma.

[0105] FIG. 2 depict representative results of the protein expression levels of APLP2 in normal tissues (“non-cancerous”) or tumor tissues. KICH = kidney chromophobe renal cell carcinoma; KIRC = kidney renal clear cell carcinoma; KIRP = kidney renal papillary cell carcinoma; LIHC = liver hepatocellular carcinoma; PRAD = prostate adenocarcinoma; SKCM = skin cutaneous melanoma; UCEC = uterine corpus endometrial carcinoma; UCS = uterine carcinosarcoma; BRCA = breast invasive carcinoma; LU AD = lung adenocarcinoma; LUSC = lung squamous cell carcinoma; PAAD = pancreatic adenocarcinoma; COAD = colon adenocarcinoma.

[0106] FIGS. 3A-3B depict exemplary formats of the presently disclosed bispecific antibodies. FIG. 3A shows an exemplary bispecific antibody disclosed herein, which comprises a CE AC AM5 -binding domain and an APLP2-binding domain, wherein the CE AC AM5 -binding domain and APLP2 -binding domain have different light chains. FIG. 3B shows an exemplary bispecific antibody disclosed herein, which comprises a CEACAM5 -binding domain and an APLP2-binding domain, wherein the CEACAM5 -binding domain and APLP2 -binding domain comprise the same light chain (e.g., same VL and CL).

[0107] FIG. 4 depicts representative results of cytotoxicity assays performed in a HPAF-II human cancer cell line where the percentage of cell viability was measured in response to the serially increased concentration of CEACAM5xAPLP2 bispecific antibody-drug conjugates (ADCs) (denoted as aCEA><aAPLP2 ADC), or a control ADCs (a monospecific anti-CEACAM5 (aCEA) ADC, a monospecific anti-KLH (aKLH) ADC, or a KLH / APLP2 bispecific (aKLHxaAPLP2) ADC).

[0108] FIGS. 5A & 5B depict representative results in a HPAF-II cell line derived tumor xenograft (CDX) mouse model of pancreatic ductal adenocarcinoma (PDAC). Mouse were intravenously injected with either aCEAxaAPLP2 ADC or a control ADC (aCEA ADC, aKLH ADC, or aKLHxaAPLP2 ADC) at a single dosage of 0.5 mg / kg. Tumor volume was assessed bi-weekly. FIG. 5A depicts the tumor growth curve in the treated mice, which shows mean ± SEM and the statistical method used was a t-test on last time point. FIG. 5B is a representative IHC image showing CEACAM5 expression in the PDAC tumor tissue harvested from the mice.NAI-5011482438vl 66

[0109] FIGS. 6A & 6B depict representative results in a NCIH2122 cell line derived tumor xenograft mouse model of non-small cell lung cancer (NSCLC). Mouse were intravenously injected with aCEA><aAPLP2 ADC at a single dosage of 3 mg / kg, a control ADC (aCEA ADC, aKLH ADC, or aKLHx aAPLP2 ADC) at a single dosage of 3 mg / kg. FIG. 6A depicts the tumor growth curve in the treated mice. FIG. 6B is a representative IHC image showing CEACAM5 expression in the tumor tissue harvested from the mice.

[0110] FIG. 7 depicts representative results of a receptor internalization assay performed in a HPAF-II human cancer cell line where the amount of internalization of antibodies, including CEA(150)xAPLP2(C4-05v7), aKLH, aCEA, aKLHx APLP2(C4-05v7), and Fab only, was determined as FabFluor intensity over time (hours).

[0111] FIG. 8 depicts representative results of a cytotoxicity assay performed in a NCIH510A human cancer cell line where the percentage of cell viability was measured in response to the serially increased concentration of CEA(150)xAPLP2(C4-05v7) ADC, or a control ADC (aKLH ADC, aCEA-2 ADC, or aKLHx APLP2(C4-05v7) ADC). The bottom panel of FIG. 8 presents the IC50 (nM) of the tested ADCs.

[0112] FIGS. 9A-9C depict in vitro cytotoxicity results of anti-CEACAM5 clone 150 variants ADC (aCEA(150) ADC, aCEA(150v8) ADC and aCEA(150v9) ADC), control aKLH ADC, and an additional anti-CEACAM 5 antibody ADC (aCEA-2 ADC) in three different cell lines. The cytotoxic agent conjugated with the bispecific antibodies was MMAE. FIG. 9A depicts the in vitro cytotoxicity assay performed in HPAF-II cells. FIG. 9B depicts the in vitro cytotoxicity assay performed in NCIH2122 cells. FIG. 9C depicts the in vitro cytotoxicity assay performed in BxPC3 cells.

[0113] FIGS. 10A & 10B depict in vitro cytotoxicity assay results of bispecific antibody ADC aCEA(150v8)xaAPLP2(C4-05v2) ADC and control ADCs (aKLHxaAPLP2(C4-05v2) ADC, aCEA(150v8)xaKLH ADC, aKLH ADC, and aCEA-2 ADC), performed in HPAF-II cells (FIG. 10A) and in NCIH510 cells (FIG. 10B). The cytotoxic agent conjugated with the bispecific antibodies was DXd (deruxtecan) as DARA

[0114] FIGS. HA & 11B depict in vivo efficacy study results of bispecific antibody ADC aCEA(150v8)xaAPLP2(C4-05v2) ADC and control ADCs (aKLHxaAPLP2(C4-05v2) ADC, aCEA(150v8)xaKLH ADC, aKLH ADC, and aCEA-2 ADC) in HPAFII (FIG. HA) and H510A (FIG. 11B) CDX mouse models. The cytotoxic agent conjugated with the bispecific antibodies was DXd (deruxtecan) as DARA

[0115] FIGS. 12A & 12B depict the receptor internalization assessment of bispecific antibody (aCEA(150v8)xaAPLP2(C4-05v2), aCEA(150v8)xaKLH), monospecific antibody (aKLH, aCEA-2, aCEA), Fab only control, and no treatment control in HPAFII cells (FIG.NAI-5011482438vl 6712A) and the receptor internalization assessment of bispecific antibody (aCEA(150v8)xaAPLP2(C4-05v2), aCEA(150v8)*aKLH), monospecific antibody (aKLH, aCEA-2), and FabFluor only control in H510A cells (FIG. 12B).

[0116] FIGS. 13A & 13B depict the pharmacokinetic assessment of bispecific antibodies aCEA(150)xaAPLP2(C4-05), aCEA(150)xaAPLP2(C4-05v2), and aCEA(150)xaAPLP2(C4-05v7) in mice (FIG. 13A) and in rats (FIG. 13B).5. DETAILED DESCRIPTION

[0117] The present disclosure provides novel CE AC AM5 -binding agents (e.g., anti-CEACAM5 antibodies) and APLP2-binding agents (e.g., anti-APLP2 antibodies), CEACAM5xAPLP2 binding agents (e.g., CEACAM5xAPLP2 multispecific antibodies) that bind to both CEACAM5 and APLP2, and CEACAM5xAPLP2 binding agent-drug conjugates (e.g., CEACAM5xAPLP2 multispecific antibody-drug conjugate (ADC)) derived therefrom. The present disclosure further provides compositions (e.g., pharmaceutical compositions) comprising the presently disclosed binding agents and binding agent-drug conjugates, and methods of use thereof.

[0118] CEACAM5 (also known as CD66e, CEA) is a cell surface glycoprotein and is a member of the carcinoembryonic antigen (CEA) family of proteins. CEACAM5 is overexpressed in a wide array of carcinomas, spanning gastrointestinal, respiratory, and genitourinary systems. CEACAM5 is a very specific tumor-associated antigen (TAA) but is poorly internalized upon binding to its antibodies. The in vitro uptake rate of anti-CEACAM5 antibodies is about 5-15 hours, whereas the in vitro uptake rate of antibodies targeting good ADC antigen targets (such as HER2 and EGFR) is in minutes. The poor internalization of CEACAM5 limits its use as a target for effective ADC therapeutics.

[0119] The present disclosure is based, in part, on the surprising findings that multispecific antibodies having one tumor-antigen binding domain (i.e., CE AC AM5 -binding domain) and one binding domain that targets the lysosomal compartment (i.e., APLP2-binding domain) had improved internalization as compared to monospecific anti-CEACAM5 antibodies. Furthermore, ADCs derived from such CEACAM5xAPLP2 multispecific antibodies (CEACAM5xAPLP2 multispecific ADCs) had increased cytotoxicity as compared to control ADCs, including monospecific anti-CEACAM5 ADCs.5.1 Definitions

[0120] Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. Whenever appropriate, terms used in the singular will also include the plural and vice versa.NAI-5011482438vl 68In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0121] The term “binding agent” as used herein refers to a molecule (e.g., an antibody) that binds an antigen (e.g., CEACAM5 and / or APLP2). In certain embodiments, a binding agent is an antibody (including an antibody fragment, such as an antigen-binding fragment or an epitopebinding fragment) or other peptide-based molecule as well as a conjugate of an antibody, antibody fragment, or peptide-based molecule (e.g., an antibody-drug conjugate) that binds to an antigen (e.g., CEACAM5 and / or APLP2). In certain embodiments, a binding agent is a fusion protein comprising an antigen-binding site. In certain embodiments, a binding agent is a bispecific or multispecific molecule comprising at least one antigen-binding site (e.g., CEACAM5*APLP2 multispecific antibodies).

[0122] The terms “antibody” “immunoglobulin,” and “Ig” are used interchangeably and in the broadest sense and encompasses, for example polyclonal antibodies, recombinant antibodies, monoclonal antibodies (including agonist antibodies, antagonist antibodies, neutralizing antibodies, or full-length monoclonal antibodies), chimeric antibodies, humanized antibodies, human antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), or single domain antibodies (e.g., VHH).

[0123] “ Antibodies” as used herein also include antibody fragments that retain antigen (e.g., CEACAM5 and / or APLP2) binding characteristics. Non-limiting examples of antibody fragments include antigen-binding regions with or without effector regions of the antibody, e.g., single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide-linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting non-covalently coupled VH and VL). Antibody variable region may include heavy and / or light variable regions in any suitable arrangement.

[0124] VHH refers to a domain antibody derived from a variable region of a heavy chain only antibody. Exemplary single domain antibodies include, but are not limited to, antibodies naturally devoid of light chains such as those from Camelidae species (e.g., llama), single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies can be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, and bovine. VHH can also be derived from other species besides Camelidae that may produce heavy chain antibodies naturally devoid of light chain.

[0125] In certain embodiments, antibodies comprising a VH and / or VL further contain a light chain and / or a heavy chain constant region, such as one or more constant regions, including oneNAI-5011482438vl 69or more IgGl, IgG2, IgG3 and / or IgG4 constant regions. The antibodies described herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2) of immunoglobulin molecule.

[0126] The term “monospecific” when used in reference to a binding agent (e.g., an antibody) means that the binding agent (e.g., an antibody) has one or more binding sites, each of which binds to the same epitope of the same antigen.

[0127] The term “multispecific” when used in reference to a binding agent (e.g., an antibody) means that the binding agent can specifically bind to two or more different epitopes, for example different epitopes on different antigens or different epitopes on the same antigen. A bispecific binding agent (e.g., an antibody) is a multiple specific binding agent that binds to two different epitope (on the same antigen or different antigens), or two different antigens (e.g. , CEAC AM5 and APLP2).

[0128] The term “monoclonal antibody” as used herein refers to a substantially homogenous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. Furthermore, “monoclonal antibody” refers to such antibodies made by any kind of techniques, including but not limited to, hybridoma production, phage library display, recombinant expression, and transgenic animals.

[0129] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a first source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0130] The term “humanized antibody” as used herein refers to an antibody that comprises a human heavy chain variable region and light chain variable region, wherein the native CDR amino acid residues are replaced by residues from corresponding CDRs from a non-human antibody (e.g, mouse, rat, rabbit, or non-human primate), and the non-human antibody has the desired specificity, affinity, and / or activity. In certain embodiments, one or more framework region amino acid residues of the human heavy chain or light chain variable regions are replaced by corresponding residues from the non-human antibody. Furthermore, humanized antibodies can comprise amino acid residues that are not found in the human antibody or non-human antibody. In certain embodiments, these modifications are made to further refine and / or optimize antibody characteristics. In certain embodiments, the humanized antibody comprises at least a portion of a human immunoglobulin constant region (e.g, CHI, CH2, CH3, Fc, and / or hinge region).

[0131] The term “human antibody” as used herein refers to an antibody that possesses an amino acid sequence that corresponds to an antibody produced by a human and / or an antibody that has been made using any of the techniques that are known to those of skill in the art forNAI-5011482438vl 70making human antibodies. These techniques include, but are not limited to, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology.

[0132] The terms “identical” or percent “identity” in the context of two or more polynucleotides or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof. In certain embodiments, identity exists over a region of the sequences that is at least about 10, at least about 20, at least about 20-40, at least about 40-60, at least about 60-80 nucleotides or amino acids in length, or any integral value there between. In certain embodiments, identity exists over a longer region than 60-80 nucleotides or amino acids, such as at least about 80-100 nucleotides or more, and in certain embodiments the sequences are substantially identical over the full length of the sequences being compared, for example, the coding region of a nucleotide sequence or an amino acid sequence.

[0133] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a side chain with similar chemical characteristics. Families of amino acid residues having similar side chains include acidic side chains (e.g., aspartic acid, glutamic acid), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), beta-branched side chains (e.g., threonine, valine, isoleucine), basic side chains (e.g., lysine, arginine, histidine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Generally, conservative substitutions do not abrogate the binding of the polypeptide, soluble protein, or antibody containing the amino acid sequence, to the target binding site. Methods of identifying amino acid conservative substitutions that do not eliminate binding are well-known in the art.

[0134] As used herein, an “antigen” is a moiety or molecule that contains an epitope to which a binding agent (e.g., an antibody) can bind. In certain embodiments, the antigen, to which a binding agent (e.g., an antibody) described herein binds, is CEACAM5 (e.g., human CEACAM5), or a fragment thereof, including a fragment that comprises at least one domain of CEACAM5. In certain embodiments, the antigen, to which a binding agent (e.g., an antibody)NAI-5011482438vl 71described herein binds, is APLP2 (e.g., human APLP2), or a fragment thereof, including a fragment that comprises at least one domain of APLP2.

[0135] As used herein, an “epitope” refers to a localized region of an antigen to which an antibody can bind. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous, epitope. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “nonlinear” or “discontinuous” epitope). It will be appreciated by one of skill in the art that a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. In certain embodiments, an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope. In certain embodiments, an antibody binds to a group of amino acids regardless of whether they are folded in a natural three-dimensional protein structure.

[0136] “Epitope binning” is the process of grouping antibodies based on the epitopes they recognize. Particularly, epitope binning comprises methods and systems for discriminating the epitope recognition properties of different antibodies, using competition assays combined with computational processes for clustering antibodies based on their epitope recognition properties and identifying antibodies having distinct binding specificities.

[0137] An antibody binds “an epitope” or “the same epitope” as a reference antibody, when the two antibodies recognize identical, overlapping or adjacent epitopes in a three-dimensional space. Competition assays can be used for determining whether two antibodies bind to identical, overlapping or adjacent epitopes in a three-dimensional space, using labeled antigen or labeled antibody. The antigen can be immobilized on a 96-well plate, or expressed on a cell surface, and the ability of unlabeled antibodies to block the binding of labeled antibodies is measured using radioactive, fluorescent or enzymatic labels.

[0138] As used herein, the terms “specifically binds,” “specifically recognizes,” “immunospecifically binds,” “selectively binds,” “immunospecifically recognizes” and “immunospecific” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope) as such binding is understood by one skilled in the art. In certain embodiments, “specifically binds” means, for instance that a polypeptide or molecule interacts more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the epitope, protein, or target molecule than with alternative substances, including related and unrelated proteins. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by immunoassays, BIACORE™, Carterra® LSA instrument, KINEXA 3000NAI-5011482438vl 72instrument, the OCTETQK384 system, or other assays known in the art. In certain embodiments, an antibody or antigen-binding domain binds to or specifically binds to an antigen when it binds to the antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIAs) and enzyme linked immunosorbent assays (ELISAs). Typically, a specific or selective reaction will be at least twice background signal or noise and can be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding binding specificity. In certain embodiments, the extent of binding of an antibody or antigen-binding domain to a “non-target” protein is less than about 10% of the binding of the antibody or antigen-binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIAs. In certain embodiments, molecules that specifically bind to an antigen bind to the antigen with a Kathat is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the Kawhen the molecules bind to another antigen. In certain embodiments, molecules that specifically bind to an antigen do not cross react with other proteins. In certain embodiments “specifically binds” means, for instance, that a polypeptide or molecule binds a protein or target with a KD of about 0.1 mM or less, but more usually less than about 1 pM. In certain embodiments, “specifically binds” means that a polypeptide or molecule binds a target with a KD of at least about 0.1 pM or less, at least about 0.01 pM or less, or at least about 1 nM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include a polypeptide or molecule that recognizes a protein or target in more than one species. Likewise, because of homology within certain regions of polypeptide sequences of different proteins, specific binding can include a polypeptide or molecule that recognizes more than one protein or target. It is understood that, in certain embodiments, a polypeptide or molecule that specifically binds a first target may or may not specifically bind a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target. Thus, a polypeptide or molecule can, in certain embodiments, specifically bind more than one target. In certain embodiments, multiple targets can be bound by the same antigen-binding site on the polypeptide or molecule. For example, an antibody can, in certain instances, comprise two identical antigenbinding sites, each of which specifically binds the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be bispecific and comprise at least two antigen-binding sites with differing specificities. Generally, but not necessarily, reference to “binding” means “specific binding”.

[0139] “Binding affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding agent such as an antibody) and itsNAI-5011482438vl 73binding partner e.g., an antigen such as CEACAM5 or APLP2). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (KD). Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. In certain embodiments, the KD can be measured in a radiolabeled antigen-binding assay (RIA), for example, performed with the Fab version of an antibody of interest and its antigen or using surface plasmon resonance (SPR) assays by BIACORE™, using, for example, a BIACORE™T200 or Carterra® LSA In certain embodiments, the “KD” or “KD value” can be measured by biolayer interferometry (BLI) using, for example, the OctetQK384 system. An “on-rate” or “rate of association” or “association rate” or “kon,” as well as an “off-rate” or “rate of dissociation” or “dissociation rate” or “koir,” can also be determined with the same SPR or BLI techniques described above using, for example, the OctetQK384 system or a BIACORE™T200 or a Carterra® LSA respectively.

[0140] The term “compete” when used in the context of antigen-binding agents (e.g., antibodies) means binding agents that compete for the same epitope or binding site on a target, which includes competition between such binding agents as determined by an assay in which the binding agent under study prevents or inhibits the specific binding of a reference molecule (e.g., a reference ligand, or reference antigen-binding protein, such as a reference antibody) to a common antigen. Examples of assays that can be used to determine if a test binding agent competes with a reference molecule for binding to the antigen include solid phase direct or indirect enzyme immunoassay (EIA); sandwich competition assay; solid phase direct biotinavidin EIA; solid phase direct labeled assay; solid phase direct or indirect radioimmunoassay (RIA); solid phase direct labeled sandwich assay; solid phase direct label RIA using 1-125 label; and direct labeled RIA.

[0141] In certain embodiments, an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs. The amino acid sequences of the H chains are identical or different and the amino acid sequences of the L chains are identical or different. In certain embodiments, an antibody is a 2-chain antibody unit comprising a VHH-VHH pair. In certain embodiments, the H and / or L chains comprise constant regions, for example, human constant regions. In certain embodiments, the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region. In certain embodiments, the H chain constant region of such antibodies comprises a gamma heavy chain constant region, for example, a human gamma heavy chain constant region.NAI-5011482438vl 74In certain embodiments, such antibodies comprise IgG constant regions, for example, human IgG constant regions (e.g, IgGl, IgG2, IgG3, and / or IgG4 constant regions).

[0142] As used herein, the term “heavy chain” refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy -terminal portion includes one or more constant regions. A heavy chain can refer to any distinct types, e.g, for example, alpha (a), delta (8), epsilon (a), gamma (y) and mu (p), based on the amino acid sequence of the constant region, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgGl, IgG2, IgG3 and IgG4.

[0143] As used herein, the term “light chain” refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy-terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. Light chains include kappa (K) or lambda (1) based on the amino acid sequence of the constant regions.

[0144] The term “variable region” or “variable domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain, has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and is used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain can be referred to as “VH.” The variable region of the light chain can be referred to as “VL.” The variable regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called hypervariable regions or alternatively called complementarity determining regions (CDRs). The variable regions of heavy and light chains each comprise four frameworks (FR1, FR2, FR3 and FR4), connected by three CDRs. The CDRs in each chain are held together in close proximity by the frameworks and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies. The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with its antigen.

[0145] The term “hypervariable region,” “HVR,” “complementarity determining region,” or “CDR” as used herein refers to the regions of an antibody variable region that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six hypervariable regions: three in the VH (VH-CDR1, VH-CDR2, and VH-CDR3), and three in the VL (VL-CDR1, VL-CDR2, and VL-CDR3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat etal., Sequences of Proteins of ImmunologicalNAI-5011482438vl 75Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35 A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol.2, Chapter 3, Springer Verlag). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions or CDRs are noted below.

[0146] A universal numbering system has been developed and widely adopted, ImMunoGeneTics (IMGT®) Information System (Lefranc etal., Dev. Comp. Immunol.27(l):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pliickthun, J. Mol. Biol. 309: 657-670 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lefranc etal., supra) and is also illustrated below. Various systems known in the art or described herein represent different ways of delineating CDRs, and when they are used to define the same antibody, they are often considered equivalent.

[0147] It will be understood that reference to a heavy chain variable region CDR or CDRs and / or a light chain variable region CDR or CDRs of a specific antibody will encompass all CDR definitions as known to those of skill in the art.Exemplary CDRs According to Various Numbering SystemsNAI-5011482438vl 76Exemplary IMGT Kabat AbM Chothia Contact VH-CDR1 26-35 27-38 31-35 26-35 26-32 30-35 VH-CDR2 50-65 56-65 50-65 50-58 53-55 47-58 VH-CDR3 95-102 105-117 95-102 95-102 96-101 93-101 VL-CDR1 24-34 27-38 24-34 24-34 26-32 30-36 VL-CDR2 50-56 56-65 50-56 50-56 50-52 46-55VL-CDR3 89-97 105-117 89-97 89-97 91-96 89-96

[0148] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 or 26-35A (Hl), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH.

[0149] The term “Fc region” as used herein is define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226 (according to the EU numbering system), or from Pro230 (according to the EU numbering system), to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region can be removed, for example, during production or purification of the antibody, or by recombinantly engineering the polynucleotide encoding a heavy chain of the antibody.

[0150] The term “constant region” or “constant domain” as understood in the art refers to an antibody portion, for example, a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to an antigen but can exhibit various effector functions, such as interaction with an Fc receptor. The term includes the portions of an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0151] Antibody “effector functions” refer to the biological activities attributable to the Fc region (e.g., a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0152] An “effective amount” is generally an amount sufficient to reduce the severity and / or frequency of symptoms, eliminate the symptoms and / or underlying cause, prevent or delay the occurrence of symptoms and / or their underlying cause, and / or improve or remediate the damage that results from or is associated with a disease, disorder, or condition. In certain embodiments, the effective amount is a therapeutically effective amount.NAI-5011482438vl 77

[0153] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., an antibody described herein or any other agent described herein) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto. In certain embodiments, the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations.

[0154] The term “treating” refers to reducing and / or ameliorating the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein).

[0155] The terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less variation of a given value or range.

[0156] As used herein, comparative terms as used herein, such as reduce, decrease, increase, or any grammatical variation thereof, can refer to certain variation from the reference. In certain embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 fold, or about 3 fold, or about 4 fold, or about 5 fold, or about 10 fold, or about 20 fold, or about 30 fold, or about 40 fold, or about 100 fold or higher than the reference. In certain embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 9%, or about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.

[0157] As used in the present disclosure and claims, the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise.

[0158] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodiments are described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.NAI-5011482438vl 78

[0159] The term “between” as used in a phrase as such “between A and B” or “between A-B” refers to a range including both A and B.

[0160] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0161] As used herein, numerical values are often presented in a range format throughout this document. The use of a range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention unless the context clearly indicates otherwise. Accordingly, the use of a range expressly includes all possible subranges, all individual numerical values within that range, and all numerical values or numerical ranges including integers within such ranges and fractions of the values or the integers within ranges unless the context clearly indicates otherwise. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, for example, reference to a range of 90-100% includes 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91-94%, 91-93%, and so forth. Reference to a range of 90-100% also includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.

[0162] In addition, reference to a range of 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc. In a further example, reference to a range of 25-250, 250-500, 500-1,000, 1,000-2,500, 2,500-5,000, 5,000-25,000, 25,000-50,000 includes any numerical value or range within or encompassing such values, e.g., 25, 26, 27, 28, 29...250, 251, 252, 253, 254...500, 501, 502, 503, 504..., etc.

[0163] As also used herein, a series of ranges are disclosed throughout this document. The use of a series of ranges includes combinations of the upper and lower ranges to provide another range. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, for example, reference to a series of ranges such as 5-10, 10-20, 20-30, 30-40, 40-50, 50-75, 75-100, 100-150, includes ranges such as 5-20, 5-30, 5-40, 5-50, 5-75, 5-100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, 20-150, and so forth.NAI-5011482438vl 795.2 CEACAM5-Binding Agents and Domains

[0164] Provided herein is a CE AC AM5 -binding agent that comprises at least one domain binding to carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (CE AC AM5 -binding domain). The present disclosure further provides a CE AC AM5 -binding domain derived from a CEACAM5 -binding agent (e.g., an anti-CEACAM5 antibody) disclosed herein.

[0165] Amino acid (aa) sequences for human CEACAM5 (UniProtKB No. P06731) are known. CEACAM5 (also known as CEA; CD66e) is a cell surface glycoprotein that plays a role in cell adhesion, intracellular signaling and tumor progression. Human CEACAM5 has a predicted molecular weight of approximately 76 kDa. CEACAM5 is significantly overexpressed in a wide array of carcinomas, spanning gastrointestinal, respiratory, and genitourinary systems. As characterized within UniProtKB, human CEACAM5 is a protein of 702 amino acids (aa) comprising one Ig-like V-type domain and six Ig-like C2-type domains.

[0166] In certain embodiments, the CEACAM5 -binding agent is a monospecific CE AC AM5 -binding agent (e.g., a monospecific anti-CEACAM5 antibody) comprising an CE AC AM5 -binding domain. In certain embodiments, the CE AC AM5 -binding agent is a multispecific binding agent (e.g., a multispecific antibody, e.g., a bispecific antibody) comprising one or more CE AC AM5 -binding domains. In certain embodiments, the multispecific binding agent (e.g., a multispecific antibody, e.g., a bispecific antibody) comprising one or more CE AC AM5 -binding domains further comprises one or more APLP2-binding domains (e.g., one or more APLP2 -binding domains of Section 5.3).

[0167] As used herein, CEACAM5 refers to a CEACAM5 polypeptide, a CEACAM5 polypeptide fragment, a CEACAM5 peptide, or a CEACAM5 epitope. In certain embodiments, a CE AC AM5 -binding domain is derived from a human or humanized antibody (e.g., comprising human framework regions) that binds CEACAM5, including a CEACAM5 polypeptide, a CEACAM5 polypeptide fragment, a CEACAM5 peptide, or a CEACAM5 epitope. In certain embodiments, the CEACAM5 -binding agent (e.g., an antibody or a multispecific antibody) can bind to CEACAM5 expressed on the surface of a mammalian (e.g., human) cell, including a CEACAM5 expressing cancer or tumor cell. In certain embodiments, the CE AC AM5 -binding agent (e.g., an antibody or a multispecific antibody) binds a CEACAM5 extracellular epitope exposed on a cell such as a cancer or tumor cell. In certain embodiments, the CEACAM5-binding agent (e.g., an antibody or a multispecific antibody) binds to CEACAM5, such as human CEACAM5, or a portion thereof.

[0168] A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure, including by RIA, for example,NAI-5011482438vl 80performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81); by biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by OCTET®, using, for example, an OCTET®Red96 system, or by a Biacore™-T200 or Carterra® LSA. An “on-rate” or “rate of association” or “association rate” or “kon” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the OCTET®Red96, the Carterra® LSA, the Biacore™-T200, the BIACORE®™-2000, the BIACORE®™-3000 system, the BIACORE®™-8K, or the BIAC0RE®™-8K+ system.

[0169] In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g., human CEACAM5) with a dissociation constant (KD) of 1 pM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, or 1 nM or less. In certain embodiments, the CE AC AM5 -binding agent binds to CEACAM5 (e.g., human CEACAM5) with a KD of between 1 nM and 100 nM, between 1 nM and 90 nM, between 1 nM and 80 nM, between 1 nM and 70 nM, between 1 nM and 60 nM, between 1 nM and 50 nM, between 1 nM and 40 nM, between 1 nM and 30 nM, between 1 nM and 20 nM, between 1 nM and 10 nM, between 1 nM and 5 nM, between 5 nM and 100 nM, between 5 nM and 90 nM, between 5 nM and 80 nM, between 5 nM and 70 nM, between 5 nM and 60 nM, between 5 nM and 50 nM, between 5 nM and 40 nM, between 5 nM and 30 nM, between 5 nM and 20 nM, between 5 nM and 10 nM, between 10 nM and 100 nM, between 10 nM and 90 nM, between 10 nM and 80 nM, between 10 nM and 70 nM, between 10 nM and 60 nM, between 10 nM and 50 nM, between 10 nM and 40 nM, between 10 nM and 30 nM, between 10 nM and 20 nM, between 20 nM and 100 nM, between 20 nM and 90 nM, between 20 nM and 80 nM, between 20 nM and 70 nM, between 20 nM and 60 nM, between 20 nM and 50 nM, between 20 nM and 40 nM, between 20 nM and 30 nM, between 30 nM and 100 nM, between 30 nM and 90 nM, between 30 nM and 80 nM, between 30 nM and 70 nM, between 30 nM and 60 nM, between 30 nM and 50 nM, between 30 nM and 40 nM, between 40 nM and 100 nM, between 40 nM and 90 nM, between 40 nM and 80 nM, between 40 nM and 70 nM, between 40 nM and 60 nM, between 40 nM and 50 nM, between 50 nM and 100 nM, between 50 nM and 90 nM, between 50 nM and 80 nM, between 50 nM and 70 nM, between 50 nM and 60 nM, between 60 nM and 100 nM, between 60 nM and 90 nM, between 60 nM and 80 nM, between 60 nM and 70 nM, between 70 nM and 100 nM, between 70 nM and 90 nM, between 70 nM and 80 nM, between 80 nM and 100 nM, between 80 nM and 90 nM, or between 90 nM and 100 nM. In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g., human CEACAM5) with a KD of between 800 nM to 1200 nM or between 950 nM to 970 nM. In certain embodiments, the CE AC AM5 -binding agent binds toNAI-5011482438vl 81CEACAM5 (e.g., human CEACAM5) with a KD of about 1 nM, about 3 nM, about 5 nM, about 10 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, about 35 nM, about 40 nM, about 45 nM, about 50 nM, about 55 nM, about 60 nM, about 65 nM, about 70 nM, about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 95 nM, or about 100 nM. In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g, human CEACAM5) with aKoof 1.1 nM, 3.1 nM, 4.9 nM, 5.4 nM, 11 nM, 15 nM, 17 nM, 18 nM, 20 nM, 23 nM, 24 nM, 26 nM, 28 nM, 55, nM, 73 nM, or 95 nM.

[0170] In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g, cynomolgus macaque CEACAM5) with a dissociation constant (KD) of 150 nM or less or 100 nM or less. In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g., cynomolgus macaque CEACAM5) with a KD of between 100 nM and 140 nM or between 40 nM and 80 nM. In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g., cynomolgus macaque CEACAM5) with a KD of about 100 nM or about 50 nM. In certain embodiments, the CEACAM5 -binding agent binds to CEACAM5 (e.g., cynomolgus macaque CEACAM5) with a KD of 110 nM or 54 nM.

[0171] In certain embodiments, the KD of the CE AC AM5 -binding agent is determined using an CEACAM5 (e.g., human CEACAM5) protein immobilized on a Biacore chip and the binding agent flowed over the chip. In certain embodiments, the KD of the CE AC AM5 -binding agent is determined using the binding agent captured by an anti-human IgG antibody on a Biacore chip and soluble CEACAM5 flowed over the chip.

[0172] In certain embodiments, the CEACAM5 -binding agent is an anti-CEACAM5 antibody. In certain embodiments, the anti-CEACAM5 antibody is a recombinant antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody. In certain embodiments, the anti-CEACAM5 antibody is an IgG antibody (e.g., an IgGl antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody). In certain embodiments, the anti-CEACAM5 antibody comprises an IgG heavy chain (e.g., an IgGl heavy chain, an IgG2 heavy chain, or an IgG4 heavy chain). In certain embodiments, the anti-CEACAM5 antibody comprises a human IgGl heavy chain, a human IgG2 heavy chain, or a human IgG4 heavy chain. In certain embodiments, the anti-CEACAM5 antibody comprises a kappa light chain. In certain embodiments, the anti-CEACAM5 antibody comprises a kappa light chain constant region. In certain embodiments, the anti-CEACAM5 antibody comprises a human kappa light chain constant region. In certain embodiments, the anti-CEACAM5 antibody comprises a lambda light chain. In certain embodiments, the anti-CEACAM5 antibody comprises a lambda light chain constant region. In certain embodiments, the anti-CEACAM5 antibody comprises a human lambda light chain constant region.NAI-5011482438vl 82

[0173] In certain embodiments, the anti-CEACAM5 antibody is a monospecific antibody. In certain embodiments, the anti-CEACAM5 antibody is a bispecific antibody. In certain embodiments, the anti-CEACAM5 antibody is a multispecific antibody. In certain embodiments, the anti-CEACAM5 antibody is a monovalent antibody. In certain embodiments, the anti-CEACAM5 antibody is a bivalent antibody. In certain embodiments, the anti-CEACAM5 antibody is a trivalent antibody. In certain embodiments, the anti-CEACAM5 antibody is a tetravalent antibody. In certain embodiments, the anti-CEACAM5 antibody is isolated. In certain embodiments, the anti-CEACAM5 antibody is substantially pure.

[0174] In certain embodiments, the CE AC AM5 -binding agent is a polyclonal antibody. Polyclonal antibodies can be prepared by any methods known to those of skill in the art. In certain embodiments, the polyclonal antibodies are produced by immunizing an animal (e.g., a rabbit, rat, mouse, goat, donkey) with an antigen of interest (e.g., a purified peptide fragment, a recombinant protein, or a fusion protein) using multiple subcutaneous or intraperitoneal injections. In certain embodiments, the antigen is conjugated to a carrier such as keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor. The antigen (with or without a carrier protein) is diluted in sterile saline and usually combined with an adjuvant (e.g, complete or incomplete Freund’s adjuvant) to form a stable emulsion. After a period of time, polyclonal antibodies are recovered from the immunized animal (e.g, from blood). In certain embodiments, the polyclonal antibodies are purified from serum according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and / or dialysis.

[0175] In certain embodiments, the CE AC AM5 -binding agent is a monoclonal antibody. Monoclonal antibodies can be prepared by any method known to those of skill in the art. In certain embodiments, monoclonal antibodies are prepared using hybridoma methods known to one of skill in the art. For example, using a hybridoma method, a mouse, rat, rabbit, hamster, or other appropriate host animal, is immunized as described above. In certain embodiments, lymphocytes are immunized in vitro. In certain embodiments, the immunizing antigen is a human protein or a fragment thereof. In certain embodiments, the immunizing antigen is a mouse protein or a fragment thereof. In certain embodiments, the immunizing antigen is a cyno protein or a fragment thereof. In certain embodiments, the immunizing antigen is an African green monkey protein or a fragment thereof. In certain embodiments, the immunizing antigen is a combination of two or more (e.g., 2, 3, 4) related proteins or fragments thereof.

[0176] Following immunization, lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol or electrofusion. The hybridoma cells are selected using specialized media as known in the art and unfused lymphocytes andNAI-5011482438vl 83myeloma cells do not survive the selection process. Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen can be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., Biacore), and radioimmunoassay). Once hybridoma cells that produce antibodies of the desired specificity, affinity, and / or activity are identified, the clones can be subcloned by limiting dilution techniques. In certain embodiments, high-throughput methods are used to distribute single cell hybridoma cells into plates. In certain embodiments, high-throughput methods are used to directly distribute single cells from original fusion into plates. The hybridomas can be propagated either in in vitro culture using standard methods. The monoclonal antibodies can be purified from the culture medium according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and dialysis.

[0177] In certain embodiments, monoclonal antibodies are made using recombinant DNA techniques as known to one skilled in the art. For example, the polynucleotides encoding an antibody are isolated from mature B-cells or hybridoma cells, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors which produce the monoclonal antibodies when transfected into host cells such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins.

[0178] In certain embodiments, recombinant monoclonal antibodies are isolated from phage display libraries expressing variable domains or CDRs of a desired species. Screening of phage libraries can be accomplished by various techniques known in the art.

[0179] In certain embodiments, a monoclonal antibody is modified by using recombinant DNA technology to generate alternative antibodies. In certain embodiments, the constant regions of the light chain and heavy chain of a mouse monoclonal antibody are substituted for constant regions of a human antibody to generate a chimeric antibody. In certain embodiments, the constant regions are truncated or removed to generate a desired antibody fragment of a monoclonal antibody. In certain embodiments, site-directed or high-density mutagenesis of the variable region(s) is used to optimize specificity and affinity of a monoclonal antibody.

[0180] In certain embodiments, the CE AC AM5 -binding agent is a humanized antibody. Various methods for generating humanized antibodies are known in the art. In certain embodiments, a humanized antibody comprises one or more amino acid residues that have beenNAI-5011482438vl 84introduced into it from a source that is non-human. In certain embodiments, humanization is performed by substituting one or more non-human CDR sequences for the corresponding CDR sequences of a human antibody. In certain embodiments, the humanized antibodies are constructed by substituting all six CDRs of a non-human antibody (e.g., a mouse antibody) for the corresponding CDRs of a human antibody.

[0181] The choice of which human heavy chain variable region and / or light chain variable region to use for generating humanized antibodies can be made based on a variety of factors and by a variety of methods known in the art. In certain embodiments, the “best-fit” method is used where the sequence of the variable region of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable region sequences. The human sequence that is most similar to that of the non-human sequence is selected as the human variable region framework for the humanized antibody. In certain embodiments, a particular variable region framework derived from a consensus sequence of all human antibodies of a particular subgroup of light or heavy chains is selected as the variable region framework. In certain embodiments, the variable region framework sequence is derived from the consensus sequences of the most abundant human subclasses. In certain embodiments, human germline genes are used as the source of the variable region framework sequences.

[0182] Other methods for humanization include, but not limited to, a method called “superhumanization” which is described as the direct transfer of CDRs to a human germline framework, a method termed Human String Content (HSC) which is based on a metric of “antibody humanness”, methods based on generation of large libraries of humanized variants (including phage, ribosomal, and yeast display libraries), and methods based on framework region shuffling.

[0183] In certain embodiments, the CEACAM5 -binding agent is a human antibody. Human antibodies can be prepared using various techniques known in the art. In certain embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro. In certain embodiments, human antibodies are generated from lymphocytes isolated from an immunized individual. In any case, cells that produce an antibody directed against a target antigen can be generated and isolated. In certain embodiments, a human antibody is selected from a phage library, where that phage library expresses human antibodies. Alternatively, phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene repertoires from unimmunized human donors. Techniques for the generation and use of antibody phage libraries are well known in the art. Once antibodies are identified, affinity maturation strategies known in the art, including but not limited to, chain shuffling and site-directed mutagenesis, can be employed toNAI-5011482438vl 85generate higher affinity human antibodies. In certain embodiments, human antibodies are produced in transgenic mice that contain human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.

[0184] In certain embodiments, the CEACAM5 -binding agent is an antibody fragment (also encompassed in “antibody”) comprising an antigen-binding site that bind to CEACAM5. In certain embodiments, the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (SCFV)2, a single chain antibody molecule, a dual variable domain antibody, a single variable domain, a linear antibody, a V region, a multispecific antibody formed from antibody fragments, a F(ab)2, a Fd, a Fc, a diabody, a di-diabody, a disulfide-linked Fvs (dsFv), a single-domain antibody (e.g., nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non-covalently coupled).

[0185] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody. In certain embodiments, the antibody fragment disclosed herein is produced using recombinant technologies known in the art (e.g., E.coli or phage expression).

[0186] In certain embodiments, the CE AC AM5 -binding agent is a variant of the anti-CEACAM5 antibody described herein. In certain embodiments, the anti-CEACAM5 antibody variant comprises from 1 to 30, from 1-25, from 1 to 20, from 1 to 15, from 1 to 10, from 1 to 5, or from 1 to 3 amino acid substitutions. In certain embodiments, the amino acid substitution(s) is in a CDR of the antibody. In certain embodiments, the amino acid substitution(s) is not in a CDR of the antibody. In certain embodiments, the amino acid substitution(s) is in a framework region of the antibody. In certain embodiments, the amino acid substitution(s) is a conservative amino acid substitution.

[0187] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises the six CDRs of antibody designated as clones 28A2, 28A5, 28B10, 28C2, 28C6, 30A1, 30A10, 7, 104, 146, 150, 13A01, 150v8, and 150v9 based on the Kabat definition as set forth in Tables 1-14. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises the six CDRs of antibody designated as clones 28A2, 28A5, 28B10, 28C2, 28C6, 30A1, 30A10, 7, 104, 146, 150, 13A01, 150v8, and 150v9 based on based on Chothia definition as set forth in Tables 1-14. In certain embodiments, theCE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises the six CDRs of antibody designated as clones 28 A2, 28 A5, 28B10, 28C2, 28C6, 30A1, 30A10, 7, 104, 146, 150, 13A01, 150v8, and 150v9 based on the AbM definitionNAI-5011482438vl 86as set forth in Tables 1-14. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises the six CDRs of antibody designated as clones 28A2, 28A5, 28B10, 28C2, 28C6, 30A1, 30A10, 7, 104, 146, 150, 13A01, 150v8, and 150v9 based on Contact definition as set forth in Tables 1-14.

[0188] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises one, two, three, four, five, and / or six CDRs of any one of the anti-CEACAM5 antibodies described herein. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 1, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 1. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 2, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 2. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 3, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 3. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 4, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 4. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 5, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 5. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a heavy chain variable region comprising one, two, and / or three VH-CDRs from Table 6, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 6. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 7, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 7. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 8, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 8. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 9, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 9. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody orNAI-5011482438vl 87multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 10, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 10. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 11, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 11. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 12, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 12. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 13, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 13. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (i) a VH comprising one, two, and / or three VH-CDRs from Table 14, and / or (ii) a VL comprising one, two, and / or three VL-CDRs from Table 14. .NAI-5011482438vl 88Table 1: CEACAM5 Antibody Clone 28A2AbM Chothia Contact Kabat VH- GLTFSYYGMH GLTFSYY SYYGMH YYGMH CDR1 (SEQ ID NOT) (SEQ ID NOT) (SEQ ID NON) (SEQ ID NOT)IISYDGSIKKYAD VH- IISYDGSIKK SYDGSI WVAIISYDGSIKKSVKG CDR2 (SEQ ID NO: 6) (SEQ ID NO: 7) (SEQ ID NO: 8)(SEQ ID NO:9) VH- PQVGVTAFDI PQVGVTAFDI AAPQVGVTAFD PQVGVTAFDI CDR3 (SEQ ID NOTO) (SEQ ID NOTO) (SEQ ID NO: 11) (SEQ ID NOTO) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 28A2 heavy chain variable region (VH) (SEQ ID NO: 1) EVQLVESGGGVVQPGRSLRLSCAASGLTFSYYGMHWVRQAPGKGLEWVAIISYDGSIKKYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAPQVGVTAFDIWGQGTMVTVSSClone 28A2 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKTable 2: CEACAM5 Antibod y Clone 28A5AbM Chothia Contact Kabat VH- GFTFEDYGMS GFTFEDY EDYGMS DYGMS CDR1 (SEQ ID NO: 13) (SEQ ID NO: 14) (SEQ ID NO: 15) (SEQ ID NO: 16)VISYDGSYTFYA VH- VISYDGSYTF SYDGSY WVTVISYDGSYTFDSVKG CDR2 (SEQ ID NO: 17) (SEQ ID NO: 18) (SEQ ID NO: 19)(SEQ ID NOTO) VH- EGMTGTPGLEY EGMTGTPGLEY AKEGMTGTPGLE EGMTGTPGLEY CDR3 (SEQ ID NO:21) (SEQ ID NO:21) (SEQ ID NO:22) (SEQ ID NO:21) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 28A5 heavy chain variable region (VH) (SEQ ID NO: 12) QVQLVESGGGLVKPGGSLRLSCSASGFTFEDYGMSWVRQPPGKGLEWVTVISYDGSYTFYA DSVKGRFTISRDNSKNTVYLQMNSLKTEDTAVYYCAKEGMTGTPGLEYWGQGTLVTVSSClone 28A5 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKNAI-5011482438vl 89Table 3: CEACAM5 Antibody Clone 28B10AbM Chothia Contact Kabat RSGMH VH- GFTFSRSGMH GFTFSRS SRSGMH(SEQ ID NO:27) CDR1 (SEQ ID NO: 24) (SEQ ID NO:25) (SEQ ID NO:26)AISYDGTNKYYADS VH- AISYDGTNKY SYDGTN WVTAISYDGTNKYAKG CDR2 (SEQ ID NO:28) (SEQ ID NO:29) (SEQ ID NO:30)(SEQ ID NO:31) VH- DSSVLAPYHFDN DSSVLAPYHFDN AKDSSVLAPYHFD DSSVLAPYHFDN CDR3 (SEQ ID NO:32) (SEQ ID NO:32) (SEQ ID NO:33) (SEQ ID NO:32) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 28B10 heavy chain variable region (VH) (SEQ I DNO:23) EVQLVESGGGVVKPGGSLRLSCAASGFTFSRSGMH' WRQAPGKGLEWVTAISYDGTNKYYADS AI<GRFSVSRDNSI<NTLYLQMNSLRAEDTAVYYCAI< CD S S VLAPYHFDNWGRGTLVTVS S Clone 28B10 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKTable 4: CEACAM5 Antibod y Clone 28C2AbM Chothia Contact Kabat VH- GFTFSSYGMH GFTFSSY SSYGMH SYGMH CDR1 (SEQ ID NO:35) (SEQ ID NO:36) (SEQ ID NO: 37) (SEQ ID NO:38)VISYDGSYEKYADS VH- VISYDGSYEK SYDGSY WMA VISYDGSYEKVKG CDR2 (SEQ ID NO:39) (SEQ ID NO: 18) (SEQ ID NO:40)(SEQ ID NO:41) VH- GMTGTGAFDI GMTGTGAFDI ATGMTGTGAFD GMTGTGAFDI CDR3 (SEQ ID NO: 42) (SEQ ID NO:42) (SEQ ID NO:43) (SEQ ID NO:42) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 28C2 heavy chain variable region (VH) (SEQ ID NO:34) QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWMAVISYDGSYEKYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATGMTGTGAFDIWGQGTLVTVSSClone 28C2 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKNAI-5011482438vl 90Table 5: CEACAM5 Antibod y Clone 28C6AbM Chothia Contact Kabat VH- GFTFSIYGMN GFTFSIY SIYGMN IYGMN CDR1 (SEQ ID NO:45) (SEQ ID NO:46) (SEQ ID NO:47) (SEQ ID NO:48)VISYDGSYKFYADSV VH- VISYDGSYKF SYDGSY WVTVISYDGSYKFKG CDR2 (SEQ ID NO:49) (SEQ ID NO: 18) (SEQ ID NO:50)(SEQ ID NO:51) VH- TTTGTPGFDY TTTGTPGFDY ATTTTGTPGFD TTTGTPGFDY CDR3 (SEQ ID NO:52) (SEQ ID NO:52) (SEQ ID NO:53) (SEQ ID NO:52) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 28C6 heavy chain variable region (VH) (SEQ ID NO:44) EVQLVESGGGVVQPGRSLRLSCAASGFTFSIYGMNWVRQAPGKGLEWVTVISYDGSYKFYADSV KGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCATTTTGTPGFDYWGRGTLVTVSSClone 28C6 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKTable 6: CEACAM5 Antibod y Clone 30A1AbM Chothia Contact Kabat VH- GYTFTGYYIH GYTFTGY TGYYIH GYYIH CDR1 (SEQ ID NO:55) (SEQ ID NO:56) (SEQ ID NO:57) (SEQ ID NO:58)MINPSGGITSYAQKF VH- MINPSGGITS NPSGGI WMGMINPSGGITSQG CDR2 (SEQ ID NO: 59) (SEQ ID NO:60) (SEQ ID NO:61)(SEQ ID NO:62) VH- GDVQIVSGWYFDL GDVQIVSGWYFDL ARGDVQIVSGWYFD GDVQIVSGWYFDL CDR3 (SEQ ID NO:63) (SEQ ID NO:63) (SEQ ID NO: 64) (SEQ ID NO:63) VL RASQSISSYLN RASQSISSYLN SSYLNWY RASQSISSYLN CDR1 (SEQ ID NO: 127) (SEQ ID NO: 127) (SEQ ID NO: 128) (SEQ ID NO: 127) VL AASSLQS AASSLQS LLIYAASSLQ AASSLQS CDR2 (SEQ ID NO: 129) (SEQ ID NO: 129) (SEQ ID NO: 130) (SEQ ID NO: 129) VL QQSYSTPLT QQSYSTPLT QQSYSTPL QQSYSTPLT CDR3 (SEQ ID NO: 131) (SEQ ID NO: 131) (SEQ ID NO: 132) (SEQ ID NO: 131) Clone 30A1 heavy chain variable region (VH) (SEQ ID NO:54) QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYIHWVRQAPGQGLEWMGMINPSGGITSYAQK FQGRVTMTRDTSTRTVYMELSSLRSEDTAVYYCARGDVQIVSGWYFDLWGRGTLVTVSSClone 30Al / Vkl-39 light chain variable region (VL) (SEQ ID NO: 126)DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIKNAI-5011482438vl 91Table 7: CEACAM5 Antibody Clone 30A10AbM Chothia Contact Kabat VH- GFTFSDSGMH GFTFSDS SDSGMH DSGMH CDR1 (SEQ ID NO:66) (SEQ ID NO:67) (SEQ ID NO:68) (SEQ ID NO:69)VIWYDGSNKYYADS VH- VIWYDGSNKY WYDGSN WVSVIWYDGSNKYVKG CDR2 (SEQ ID NO: 70) (SEQ ID NO:71) (SEQ ID NO:72)(SEQ ID NO:73) DQAARPGISATGND ARDQAARPGISATG DQAARPGISATGND VH- DQAARPGISATGNDYY ND Y CDR3 (SEQ ID NO: 74)(SEQ ID NO:74) (SEQ ID NO:75) (SEQ ID NO: 74) VL RASQSISSYLN RASQSISSYLN SSYLNWY RASQSISSYLN CDR1 (SEQ ID NO: 127) (SEQ ID NO: 127) (SEQ ID NO: 128) (SEQ ID NO: 127) VL AASSLQS AASSLQS LLIYAASSLQ AASSLQS CDR2 (SEQ ID NO: 129) (SEQ ID NO: 129) (SEQ ID NO: 130) (SEQ ID NO: 129) VL QQSYSTPLT QQSYSTPLT QQSYSTPL QQSYSTPLT CDR3 (SEQ ID NO: 131) (SEQ ID NO: 131) (SEQ ID NO: 132) (SEQ ID NO: 131) Clone 30A10 heavy chain variable region (VH) (SEQ I DNO:65) EVQLVESGGGVVQPGRSLRLSCEASGFTFSDSGMHX WRQAPGKGLEWVSVIWYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCARI DQAARPGISATGND YWGQGTLVTVSSClone 30A10 / Vkl-39 light chain variable region (VL) (SEQ ID NO: 126)DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGQGTKVEIKTable 8: CEACAM5 Antibody Clone 7AbM Chothia Contact Kabat VH- GGSIISSNWWT GGSIISSN ISSNWWT SSNWWT CDR1 (SEQ ID NO:77) (SEQ ID NO:78) (SEQ ID NO:79) (SEQ ID NO: 80) VH- EIFYIGNTN FYIGN WIGEIFYIGNTN EIFYIGNTNYSPSLKS CDR2 (SEQ ID NO: 81) (SEQ ID NO: 82) (SEQ ID NO:83) (SEQ ID NO: 84)GTTGTTRYYYYMD ARGTTGTTRYYYY GTTGTTRYYYYMD VH- GTTGTTRYYYYMDVV MD V CDR3 (SEQ ID NO: 85)(SEQ ID NO:85) (SEQ ID NO: 86) (SEQ ID NO: 85) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 7 heavy chain variable region (VH) (SEQ ID NO:76) QVQLQESGPGLVKPSGTLSLTCAVSGGSIISSNWWTWVRQPPGKGLEWIGEIFYIGNTNYSPSLKS RVTISVDKSKSQFSLNLSSVTAADTAVYYCARGTTGTTRYYYYMDVWGKGTTVTVSSClone 7 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKNAI-5011482438vl 92Table 9: CEACAM5 Antibody Clone 104AbM Chothia Contact Kabat VH- GFTFSRSGMH GFTFSRS SRSGMH RSGMH CDR1 (SEQ ID NO: 24) (SEQ ID NO:25) (SEQ ID NO:26) (SEQ ID NO:27)AISYDGTNKYYADS VH- AISYDGTNKY SYDGTN WVTAISYDGTNKYAKG CDR2 (SEQ ID NO:28) (SEQ ID NO:29) (SEQ ID NO:30)(SEQ ID NO:31) VH- DSSVLAPYHFDN DSSVLAPYHFDN AKDSSVLAPYHFD DSSVLAPYHFDN CDR3 (SEQ ID NO:32) (SEQ ID NO:32) (SEQ ID NO:33) (SEQ ID NO:32) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 104 heavy chain variable region (VH) (SEQ ID NO: 87) QVQLVQSGGGLGQPGGSLRLSCAASGFTFSRSGMHWVRQAPGKGLEWVTAISYDGTNKYYADS AKGRFTVSRDNSKNTLYLQMNSLRAEDTAVYYCAKDSSVLAPYHFDNWGQGTLVTVSSClone 104 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKTable 1 0: CEACAM5 Antibody Clone 146AbM Chothia Contact Kabat VH- GFTFSYSGMH GFTFSYS SYSGMH YSGMH CDR1 (SEQ ID NO: 89) (SEQ ID NO:90) (SEQ ID NO:91) (SEQ ID NO: 92)VISYDGSNKYYADS VH- VISYDGSNKY SYDGSN WVAVISYDGSNKYVKG CDR2 (SEQ ID NO: 93) (SEQ ID NO:94) (SEQ ID NO:95)(SEQ ID NO:96) VH- DSSVIAPYYFAY DSSVIAPYYFAY AKDSSVIAPYYFA DSSVIAPYYFAY CDR3 (SEQ ID NO:97) (SEQ ID NO:97) (SEQ ID NO:98) (SEQ ID NO:97) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 146 heavy chain variable region (VH) (SEQ ID NO: 88) QVQLVESGGGVVQPGRSLRLSCAASGFTFSYSGMHWVRQAPGKGLEWVAVISYDGSNKYYADS VKGRFTVSRDNSKNTLYLQMNSLRPEDTAVYYCAKDSSVIAPYYFAYWGRGTLVTVSSClone 146 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKNAI-5011482438vl 93Table 11: CEACAM5 Antibody Clone 150AbM Chothia Contact Kabat VH- GGSIISSNWWS GGSIISSN ISSNWWS SSNWWS CDR1 (SEQ ID NO: 100) (SEQ ID NO:78) (SEQ ID NO: 101) (SEQ ID NO: 102)EIFYLGTTNYNPSLQ VH- EIFYLGTTN FYLGT WIGEIFYLGTTNS CDR2 (SEQ ID NO: 103) (SEQ ID NO: 104) (SEQ ID NO: 105)(SEQ ID NO: 106) ARGITGTTRYYYYM VH- GITGTTRYYYYMDV GITGTTRYYYYMDV GITGTTRYYYYMDV D CDR3 (SEQ ID NO: 107) (SEQ ID NO: 107) (SEQ ID NO: 107)(SEQ ID NO: 108)VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 150 heavy chain variable region (VH) (SEQ ID NO:99) QVQLQESGPGLVKPSGTLSLTCAVSGGSIISSNWWSWVRQSPGRGLEWIGEIFYLGTTNYNPSLQS RVTMSVDKSKNQFSLKLSSVTAADTAVYYCARGITGTTRYYYYMDVWGKGTTVTVSSClone 150 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKTable 12: CEACAM5 Antibod y Clone 13A01AbM Chothia Contact Kabat VH- GFTFSFYGLY GFTFSFY SFYGLY FYGLY CDR1 (SEQ ID NO: 110) (SEQ ID NO: 111) (SEQ ID NO: 112) (SEQ ID NO: 113)VISYDGSYTYYADS VH- VISYDGSYTY SYDGSY WVA VISYDGSYTYVKG CDR2 (SEQ ID NO: 114) (SEQ ID NO: 18) (SEQ ID NO: 115)(SEQ ID NO: 116) VH- AVMTGTPTFDY AVMTGTPTFDY ASAVMTGTPTFD AVMTGTPTFDY CDR3 (SEQ ID NO: 117) (SEQ ID NO: 117) (SEQ ID NO: 118) (SEQ ID NO: 117) VL RASQSVSSNLA RASQSVSSNLA SSNLAWY RASQSVSSNLA CDR1 (SEQ ID NO: 120) (SEQ ID NO: 120) (SEQ ID NO: 121) (SEQ ID NO: 120) VL GASTRAT GASTRAT LLIYGASTRA GASTRAT CDR2 (SEQ ID NO: 122) (SEQ ID NO: 122) (SEQ ID NO: 123) (SEQ ID NO: 122) VL QQYNNWPPWT QQYNNWPPWT QQYNNWPPW QQYNNWPPWT CDR3 (SEQ ID NO: 124) (SEQ ID NO: 124) (SEQ ID NO: 125) (SEQ ID NO: 124) Clone 13A01 heavy chain variable region (VH) (SEQ I D NO: 109) QVQLVESGGGVVQPGKSLRLSCAASGFTFSFYGLYV WRQAPGRGLEWVAVISYDGSYTYYADSV KGRFTISRDNSKNTLSLQMNSLRAEDTAVYYCASAA / MTGTPTF D Y WGQGTLVTVS SClone 13A01 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKNAI-5011482438vl 94Table 13: CEACAM5 Antibody Clone 150v8AbM Chothia Contact Kabat VH- GGSIISSNWWI (SEQ ID GGSIISSN (SEQ ID ISSNWWI (SEQ ID SSNWWI (SEQ ID CDR1 NO: 220) NO:78) NO: 221) NO: 222) VH- EIFYLGTTN (SEQ ID FYLGT (SEQ ID WIGEIFYLGTTN EIFYLGTTNYNPSLQ CDR2 NO: 103) NO: 104) (SEQ ID NO: 105) S (SEQ ID NO: 106) VH- GITGTVRYYYYMDV GITGTVRYYYYMDV ARGITGTVRYYYYM GITGTVRYYYYMDV CDR3 (SEQ ID NO: 223) (SEQ ID NO: 223) D (SEQ ID NO: 224) (SEQ ID NO: 223) VL RASQSVSSNLA (SEQ RASQSVSSNLA (SEQ SSNLAWY (SEQ ID RASQSVSSNLA (SEQ CDR1 ID NO: 120) ID NO: 120) NO:121) ID NO: 120) VL GASTRAT (SEQ ID GASTRAT (SEQ ID LLIYGASTRA (SEQ GASTRAT (SEQ ID CDR2 NO: 122) NO: 122) ID NO: 123) NO: 122) VL QQYNNWPPWT (SEQ QQYNNWPPWT (SEQ QQYNNWPPW (SEQ QQYNNWPPWT (SEQ CDR3 ID NO: 124) ID NO: 124) ID NO: 125) ID NO: 124) Clone 150v8 heavy chain variab e region (VH) (SEQ ID NO: 200) QVQLQESGPGLVKPSGTLSLT CAVSGGSIISSNWWIWVRQSPGRDLEWIGEIFYLGTTNYNPSLQS RVTMSVDKSKNQFSLKLSSVI AADTAVYYCARGITGTVRYYYYMDVWGKGTTVTVSSClone 150v8 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKTable 14: CEACAM5 Antibody Clone 150v9AbM Chothia Contact Kabat VH- GGSIISSNWWI (SEQ ID GGSIISSN (SEQ ID ISSNWWI (SEQ ID SSNWWI (SEQ ID CDR1 NO: 220) NO:78) NO: 221) NO: 222) VH- EIFYLGTTN (SEQ ID FYLGT (SEQ ID WIGEIFYLGTTN EIFYLGTTNYNPSLQ CDR2 NO: 103) NO: 104) (SEQ ID NO: 105) S (SEQ ID NO: 106) VH- GITGTVRYYYYMDV GITGTVRYYYYMDV ARGITGTVRYYYYM GITGTVRYYYYMDV CDR3 (SEQ ID NO: 223) (SEQ ID NO: 223) D (SEQ ID NO: 224) (SEQ ID NO: 223) VL RASQSVSSNLA (SEQ RASQSVSSNLA (SEQ SSNLAWY (SEQ ID RASQSVSSNLA (SEQ CDR1 ID NO: 120) ID NO: 120) NO:121) ID NO: 120) VL GASTRAT (SEQ ID GASTRAT (SEQ ID LLIYGASTRA (SEQ GASTRAT (SEQ ID CDR2 NO: 122) NO: 122) ID NO: 123) NO: 122) VL QQYNNWPPWT (SEQ QQYNNWPPWT (SEQ QQYNNWPPW (SEQ QQYNNWPPWT (SEQ CDR3 ID NO: 124) ID NO: 124) ID NO: 125) ID NO: 124) Clone 150v9 heavy chain variab e region (VH) (SEQ ID NO: 201) QVQLQESGPGLVKPSGTLSLT CAVSGGSIISSNWWIWVRQSPGRGLEWIGEIFYLGTTNYNPSLQS RVTMSVDKSKNQFSLKLSSVI AADTAVYYCARGITGTVRYYYYMDVWGKGTTVTVSSClone 150v9 / Vk3-15 light chain variable region (VL) (SEQ ID NO: 119)EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIKNAI-5011482438vl 95

[0189] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and / or (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from an antibody described herein (e.g., an antibody disclosed in Tables 1-14). In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises: (a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from an antibody described herein (e.g., an antibody disclosed in Tables 1-14).

[0190] In certain embodiments, the CEACAM5 -binding agent or CEACAM5 -binding domain is a variant of the CE AC AM5 -binding agent or CEACAM5 -binding domain described herein. In certain embodiments, the CEACAM5 -binding agent or CE AC AM5 -binding domain variant comprises amino acid substitutions in the VH and / or the VL as compared to theCE AC AM5 -binding agent or CEACAM5-binding domain described herein. In certain embodiments, the CEACAM5 -binding agent or CE AC AM5 -binding domain variant comprises amino acid substitutions in the VH-CDR1, VH-CDR2, and / or VH-CDR3 and / or the VL-CDR1, VL-CDR2, and / or VL-CDR3 as compared to the CE AC AM5 -binding agent (e.g., an antibody disclosed in Tables 1-14) or CE AC AM5 -binding domain described herein. In certain embodiments, the CEACAM5 -binding agent or CE AC AM5 -binding domain variant comprises one or more (e.g., 1, 2, 3, 4, etc.) amino acid substitutions in a CDR of the CEACAM5 -binding agent (e.g., an antibody disclosed in Tables 1-14) or CEACAM5 -binding domain described herein. In certain embodiments, the amino acid substitutions are conservative substitutions. In certain embodiments, a CDR comprises one amino acid substitution. In certain embodiments, a CDR comprises two amino acid substitutions. In certain embodiments, a CDR comprises three amino acid substitutions. In certain embodiments, a CDR comprises four amino acid substitutions. In certain embodiments, the CDR is a VH-CDR1. In certain embodiments, the CDR is a VH-CDR2. In certain embodiment, the CDR is a VH-CDR3. In certain embodiments, the CDR is a VL-CDR1. In certain embodiments, the CDR is a VL-CDR2. In certain embodiments, the CDR is a VL-CDR3. In certain embodiments, the substitutions are made as part of a humanization process. In certain embodiments, the substitutions are made as part of a germline humanization process. In certain embodiments, the substitutions are made as part of an affinity maturation process. In certain embodiments, the substitutions are made as part of an optimization process.

[0191] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises one or more VH-CDRs or VL-CDRs that have been modified to reduce deamidation within the CDR sequence.NAI-5011482438vl 96Deamidation is a chemical reaction in which an amide functional group in the side chain of the amino acids asparagine (Asn or N) or glutamine (Gin or Q) is removed or converted to another functional group. Generally, asparagine is converted to aspartic acid or isoaspartic acid and glutamine is converted to glutamic acid or polyglutamic acid. In some situations, deamidation may change the structure, function, and / or stability of a polypeptide, potentially resulting in decreased biological activity. In certain embodiments, the VH-CDR1, VH-CDR2, and / or VH-CDR3 of an antibody described herein is modified to reduce deamidation. In certain embodiments, the VL-CDR1, VL-CDR2, and / or VL-CDR3 of an antibody described herein is modified to reduce deamidation.

[0192] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises one or more VH-CDRs or VL-CDRs that have been modified to reduce isomerization. Isomerization is a chemical process by which a compound is transformed into any of its isomeric forms, i.e., forms with the same chemical composition but with different structure or configuration and, potentially with different physical and chemical properties. Studies have shown that aspartate (Asp or D) isomerization within a CDR can impact antibody binding and / or stability. In certain embodiments, the VH-CDR1, VH-CDR2, and / or VH-CDR3 of an antibody described herein is modified to reduce isomerization. In certain embodiments, the VL-CDR1, VL-CDR2, and / or VL-CDR3 is modified to reduce isomerization.

[0193] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises one or more VH-CDRs or VL-CDRs that have been modified to reduce oxidation. Oxidation is a chemical process by which an oxygen is added to an atom, for example, methionine is converted to methionine sulfoxide by addition of an oxygen to the sulfur atom. Oxidation of one or more amino acids can potentially affect the physical and chemical properties of a protein. Studies have shown that oxidation of methionine (Met or M) within a CDR has the potential to impact antibody binding and / or stability. In certain embodiments, the VH-CDR1, VH-CDR2, and / or VH-CDR3 of an antibody described herein is modified to reduce oxidation. In certain embodiments, the VL-CDR1, VL-CDR2, and / or VL-CDR3 of an antibody described herein is modified to reduce oxidation.

[0194] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH and / or a VL that comprises a modification within the amino acid sequence wherein the modification eliminates a glycosylation site. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises one or more VH-CDRs orNAI-5011482438vl 97VL-CDRs that have been modified to eliminate a glycosylation site. The consensus glycosylation site for N-linked glycans is N-X-S / T, wherein X can be any amino acid except proline. Generally, a glycosylation site within a variable region and / or within a CDR will impact antibody structure, binding, and / or stability.

[0195] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and / or a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from an antibody of Table 1 (designated as “28A2” herein), a humanized version thereof, or variants thereof. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 from antibody 28 A2 (Table 1). In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDRS from antibody 28A2 (Table 1). In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises: (a) a VH comprising a VH-CDR1, a VH-CDR2, a VH-CDR3; and (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody 28A2 (Table 1).

[0196] In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and / or a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1; and / or a VL comprising a VL-CDR1, a VL-CDR2, and / or a VL-CDRS as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119. In certain embodiments, the CEACAM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:1; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119.

[0197] In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:2, 3, 4, and 5; a VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:6, 7, 8, and 9; and a VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 and 11; and (b) a VL region comprising a VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; a VL-CDR2 comprising an amino acid sequence selected from the groupNAI-5011482438vl 98consisting of SEQ ID NOs:122 and 123; and a VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0198] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:5, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises: (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:5, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0199] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:7, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:7, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0200] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:8, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence ofNAI-5011482438vl 99SEQ ID NO: 121, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:8, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125.

[0201] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:2, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:6, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:2, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:6, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0202] In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 1; and / or a VL comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 119. In certain embodiments, the binding of the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain thereof to CEACAM5 (e.g, human CEACAM5) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the CE AC AM5 -bindingNAI-5011482438vl 100agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and / or a VL comprising the amino acid sequence of SEQ ID NO: 119. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 119.

[0203] In certain embodiments, the CEACAM5 -binding agent is antibody 28A2 (Table 1). In certain embodiments, the CE AC AM5 -binding agent is a humanized version of antibody 28A2 (Table 1). In certain embodiments, the CEACAM5 -binding agent is a variant of antibody 28A2 (Table 1) or a variant of a humanized version of antibody 28A2 (Table 1).

[0204] In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and / or a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from an antibody of Table 2 (designated as “28A5” herein), a humanized version thereof, or variants thereof. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 from antibody 28 A5 (Table 2). In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody 28A5 (Table 2). In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises: (a) a VH comprising a VH-CDR1, a VH-CDR2, a VH-CDR3; and (b) a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 from antibody 28A5 (Table 2).

[0205] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and / or a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 12; and / or a VL comprising a VL-CDR1, a VL-CDR2, and / or a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119. In certain embodiments, the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 12; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119.

[0206] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-NAI-5011482438vl 101CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:13, 14, 15, and 16; a VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:17, 18, 19, and 20; and a VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 22; and / or (b) a VL region comprising a VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; a VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and a VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

[0207] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21; and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises: (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21; and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0208] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21; and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21; and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising theNAI-5011482438vl 102amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0209] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:22; and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125. In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:22, and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125.

[0210] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, and / or (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124. In certain embodiments, the CE AC AM5 -binding agent e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises (a) a VH comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21; and (b) a VL comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

[0211] In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain comprises a VH comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12; and / or a VL comprisingNAI-5011482438vl 103an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 119. In certain embodiments, the binding of the CEACAM5 -binding agent (e.g., antibody or multispecific antibody) or CE AC AM5 -binding domain thereof to CEACAM5 (e.g., human CEACAM5) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). In certain embodiments, the CE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 12 and / or a VL comprising the amino acid sequence of SEQ ID NO: 119. In certain embodiments, theCE AC AM5 -binding agent (e.g., antibody or multispecific antibody) or CEACAM5 -binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 119.

[0212] In certain embodiments, the CEACAM5 -binding agent is antibody 28A5 (Table 2). In certain embodiments, the CE AC AM5 -binding agent is a humanized version of antibody 28A5 (Table 2). In certain embodiments, the CEACAM5 -binding agent is a variant of antibody 28A5 (Table 2) or a variant of a humanized version of antibody 28A5 (T...

Claims

WHAT IS CLAIMED IS:

1. A carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-binding agent comprising:(a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:201 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 200 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119;(c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:87; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:88; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:99; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 12; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:23; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ IDNAI-5011482438vl 322NO: 119; or(i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:34; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(k) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:54; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(l) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(m) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:76; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(n) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 109; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119.

2. The CEACAM5 -binding agent of claim 1, wherein the CEACAM5-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 220, 78, 221, and 222; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 104, 105, and 106; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 223 and 224; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the groupNAI-5011482438vl 323consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

3. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

4. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, 26, and 27; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 29, 30, and 31; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the groupNAI-5011482438vl 324consisting of SEQ ID NOs: 32 and 33; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

5. The CEACAM5 -binding agent of claim 4, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

6. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 89, 90, 91, and 92; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the groupNAI-5011482438vl 325consisting of SEQ ID NOs: 93, 94, 95, and 96; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 97 and 98; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

7. The CEACAM5 -binding agent of claim 6, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

8. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consistingNAI-5011482438vl 326of SEQ IDNOs: 100, 78, 101, and 102; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 104, 105, and 106; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 107 and 108; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

9. The CEACAM5 -binding agent of claim 8, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.NAI-5011482438vl 32710. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 3, 4, and 5; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 7, 8, and 9; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 and 11; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

11. The CEACAM5 -binding agent of claim 10, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:2, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:6, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:7, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:4, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:8, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:5, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 328NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

12. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 13, 14, 15, and 16; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, and 20; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 22; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

13. The CEACAM5 -binding agent of claim 12, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:22, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, the VH-NAI-5011482438vl 329CDR2 comprising the amino acid sequence of SEQ ID NO:20, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

14. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, 26, and 27; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 29, 30, and 31; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 and 33; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

15. The CEACAM5 -binding agent of claim 14, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, andNAI-5011482438vl 330the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

16. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 36, 37, and 38; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 18, 40, and 41; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 42 and 43; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

17. The CEACAM5 -binding agent of claim 16, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:35, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:39, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:36, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:37, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:40, the VH-CDR3 comprising theNAI-5011482438vl 331amino acid sequence of SEQ ID NO:43, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:38, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:41, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

18. The CEACAM5 -binding agent of claim 1, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 47, and 48; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, 18, 50, 51; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

19. The CEACAM5 -binding agent of claim 18, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:49, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:46, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; orNAI-5011482438vl 332(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:47, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:48, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:51, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

20. The CEACAM5 -binding agent of claim 1, wherein the CEACAM5-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 55, 56, 57, and 58; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 59, 60, 61, and 62; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 63 and 64; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 and 128; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.

21. The CEACAM5 -binding agent of claim 20, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:55, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:59, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:56, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:60, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence ofNAI-5011482438vl 333SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:57, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:61, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:64, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:58, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:62, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

22. The CEACAM5 -binding agent of claim 1, wherein the CEACAM5-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 68, and 69; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 71, 72, and 73; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 75; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 and 128; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.

23. The CEACAM5 -binding agent of claim 22, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:66, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:70, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:67, the VH-NAI-5011482438vl 334CDR2 comprising the amino acid sequence of SEQ ID NO:71, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:68, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:72, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:75, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:69, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:73, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

24. The CEACAM5 -binding agent of claim 1, wherein the CEACAM5-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 77, 78, 79, and 80; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 81, 82, 83, and 84; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 and 86; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

25. The CEACAM5 -binding agent of claim 24, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:77, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:81, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-NAI-5011482438vl 335CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:82, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:79, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:83, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:86, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:80, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:84, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

26. The CEACAM5 -binding agent of claim 1, wherein the CEACAM5-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 110, 111, 112, and 113; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 114, 18, 115, and 116; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 117 and 118; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.

27. The CEACAM5 -binding agent of claim 26, wherein the CE AC AM5 -binding agent comprises:(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, the VH-CDR3 comprising theNAI-5011482438vl 336amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 112, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 115, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

28. The CEACAM5 -binding agent of any one of claims 1-27, wherein the CEACAM5-binding agent comprises:(a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 99; and the VL comprising an amino acid sequenceNAI-5011482438vl 337having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 12; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:23; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:34; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:44; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (k) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (l) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 65; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (m) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:76; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (n) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 109; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

29. The CEACAM5 -binding agent of any one of claims 1-28, wherein the CEACAM5-binding agent comprises:(a) the VH comprising the amino acid sequence of SEQ ID NO:201; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(b) the VH comprising the amino acid sequence of SEQ ID NO:200; and the VL comprising the amino acid sequence of SEQ ID NO: 119; orNAI-5011482438vl 338(c) the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(e) the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(f) the VH comprising the amino acid sequence of SEQ ID NO: 1; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) the VH comprising the amino acid sequence of SEQ ID NO: 12; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) the VH comprising the amino acid sequence of SEQ ID NO:23; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) the VH comprising the amino acid sequence of SEQ ID NO:34; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) the VH comprising the amino acid sequence of SEQ ID NO:44; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(k) the VH comprising the amino acid sequence of SEQ ID NO:54; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(l) the VH comprising the amino acid sequence of SEQ ID NO:65; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(m) the VH comprising the amino acid sequence of SEQ ID NO:76; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(n) the VH comprising the amino acid sequence of SEQ ID NO: 109; and the VL comprising the amino acid sequence of SEQ ID NO: 119.

30. The CEACAM5 -binding agent of any one of claims 1-29, wherein the CEACAM5-binding agent is(a) an antibody;(b) a monoclonal antibody;(c) an antibody fragment comprising at least one antigen-binding site;(d) a chimeric antibody;(e) a humanized antibody; or(f) a multispecific antibody.NAI-5011482438vl 33931. The CEACAM5 -binding agent of claim 30, wherein the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody.

32. A polynucleotide or polynucleotides encoding the CE AC AM5 -binding agent or a portion thereof of any one of claims 1-31.

33. A vector or vectors comprising the polynucleotide or polynucleotides of claim 32 or a complementary polynucleotide or polynucleotides thereto.

34. A cell comprising the CEACAM5 -binding agent of any one of claims 1-31, the polynucleotide or polynucleotides of claim 32, or the vector or vectors of claim 33.

35. A pharmaceutical composition comprising the CE AC AM5 -binding agent of any one of claims 1-31 and a pharmaceutically acceptable excipient.

36. An amyloid precursor-like protein 2 (APLP2)-binding agent comprising:(a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:203; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 149; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 138; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 156; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 167; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; orNAI-5011482438vl 340(f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:205; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:207; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:119.

37. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 139, 140, 141, and 142; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34138. The APLP2-binding agent of claim 37, wherein the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

39. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 139, 140, 141, and 142; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34240. The APLP2-binding agent of claim 39, wherein the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

41. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 226, 227, and 142; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34342. The APLP2-binding agent of claim 41, wherein the APLP2-binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

43. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 228, 229, 230, and 231; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34444. The APLP2 -binding agent of claim 43, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

45. The APLP2-binding agent of claim 36, wherein the APLP2-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 225, 226, 227, and 142; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34546. The APLP2 -binding agent of claim 45, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

47. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 228, 229, 230, and 231; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34648. The APLP2 -binding agent of claim 47, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

49. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 139, 140, 141, and 142; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 151, 152, and 153; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 154 and 155; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34750. The APLP2 -binding agent of claim 49, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

51. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 139, 140, 141, and 142; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 143, 144, 145, and 146; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 147 and 148; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 and 121; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 122 and 123; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124 and 125.NAI-5011482438vl 34852. The APLP2 -binding agent of claim 51, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

53. The APLP2 -binding agent of claim 36, wherein the APLP2 -binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 157, 158, 159, and 160; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161, 162, 163, and 164; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 165 and 166; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 and 128; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.NAI-5011482438vl 34954. The APLP2 -binding agent of claim 53, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 157, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 161, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 158, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 159, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 163, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 164, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

55. The APLP2-binding agent of claim 36, wherein the APLP2-binding agent comprises:(i) the VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 168, 169, 170, and 171; and(ii) the VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 172, 173, 174, and 175; and(iii) the VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 176 and 177; and(iv) the VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127 and 128; and(v) the VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129 and 130; and(vi) the VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131 and 132.NAI-5011482438vl 35056. The APLP2 -binding agent of claim 55, wherein the APLP2 -binding agent comprises: (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 168, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 169, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 173, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 170, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 174, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 177, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131.

57. The APLP2-binding agent of any one of claims 36-56, wherein the APLP2-binding agent comprises:(a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 156; and the VL comprising an amino acid sequenceNAI-5011482438vl 351having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 167; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:205; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:206; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:207; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

58. The APLP2-binding agent of any one of claims 36-57, wherein the APLP2-binding agent comprises:(a) the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119(b) the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(c) the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) the VH comprising the amino acid sequence of SEQ ID NO: 156; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(e) the VH comprising the amino acid sequence of SEQ ID NO: 167; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(f) the VH comprising the amino acid sequence of SEQ ID NO:202; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) the VH comprising the amino acid sequence of SEQ ID NO:204; and the VLNAI-5011482438vl 352comprising the amino acid sequence of SEQ ID NO: 119; or(h) the VH comprising the amino acid sequence of SEQ ID NO:205; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) the VH comprising the amino acid sequence of SEQ ID NO:206; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) the VH comprising the amino acid sequence of SEQ ID NO:207; and the VL comprising the amino acid sequence of SEQ ID NO: 119.

59. The APLP2-binding agent of any one of claims 36-58, wherein the APLP2-binding agent is(a) an antibody;(b) a monoclonal antibody;(c) an antibody fragment comprising at least one antigen-binding site;(d) a chimeric antibody;(e) a humanized antibody; or(f) a multispecific antibody.

60. The APLP2-binding agent of claim 59, wherein the antibody fragment is a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a (scFv)2, a single chain antibody, a dual variable region antibody, a diabody, or a nanobody.

61. A polynucleotide or polynucleotides encoding the APLP2 -binding agent or a portion thereof of any one of claims 36-60.

62. A vector or vectors comprising the polynucleotide or polynucleotides of claim 61 or a complementary polynucleotide or polynucleotides thereto.

63. A cell comprising the APLP2 -binding agent of any one of claims 36-60, the polynucleotide or polynucleotides of claim 61, or the vector or vectors of claim 62.

64. A pharmaceutical composition comprising APLP2-binding agent of any one of claims 36-60 and a pharmaceutically acceptable excipient.

65. A multispecific binding agent comprising:(A) a carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-binding domain, wherein the CE AC AM5 -binding domain comprises:(a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:201 and a VL comprising a VL-CDR1,NAI-5011482438vl 353a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 200 and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119;(c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:87; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:88; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:99; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 12; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:23; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:34; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in aNAI-5011482438vl 354VH comprising the amino acid sequence of SEQ ID NO:44; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(k) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:54; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(l) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:65; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(m) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:76; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(n) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 109; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; and(B) an amyloid precursor-like protein 2 (APLP2)-binding domain, wherein the APLP2-binding domain comprises:(a) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:203; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(b) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 149; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(c) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 138; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 156; and a VL comprising a VL-CDR1,NAI-5011482438vl 355a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(e) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 167; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 126; or(f) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:205; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) a VH comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:207; and a VL comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 119.

66. The multispecific binding agent of claim 65, wherein(i) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:201 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:203 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VLNAI-5011482438vl 356comprising the amino acid sequence of SEQ ID NO: 119; or(ii) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:200 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:203 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119(iii) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:87 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or(iv) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:88 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or(v) (a) the CEACAM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:99 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or(vi) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence ofNAI-5011482438vl 357SEQ ID NO:87 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO:119; or(vii) (a) the CEACAM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:88 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119; or(viii) (a) the CE AC AM5 -binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and (b) the APLP2-binding domain comprising the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119.

67. The multispecific binding agent of claim 65 or 66, wherein(A) the CEACAM5 -binding domain comprises:(a) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:201 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 358NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (b) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 200 and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3NAI-5011482438vl 359comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (c) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (d) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQNAI-5011482438vl 360ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (e) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; orNAI-5011482438vl 361(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (f) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 1; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:2, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:6, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:3, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:7, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:4, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:8, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or(iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:5, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:9, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(g) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 12; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, the VH-CDR3NAI-5011482438vl 362comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:22, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:20, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:21, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (h) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:23; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the aminoNAI-5011482438vl 363acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(i) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:34; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:35, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:39, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:36, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:37, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:40, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:38, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:41, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:42, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (j) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:44; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the aminoNAI-5011482438vl 364acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:49, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:46, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:47, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:48, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:51, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:52, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(k) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:54; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:55, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:59, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:56, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:60, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQNAI-5011482438vl 365ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:57, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:61, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:64, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:58, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:62, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:63, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or(1) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:65; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:66, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:70, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:67, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:71, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:68, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:72, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:75, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:69, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:73, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:74, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQNAI-5011482438vl 366ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (m) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:76; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:77, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:81, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:82, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:79, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:83, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:86, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:80, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:84, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:85, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (n) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 109; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ IDNAI-5011482438vl 367NO:111, the VH-CDR2 comprising the amino acid sequence of SEQ IDN0:18, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:112, the VH-CDR2 comprising the amino acid sequence of SEQ IDNO:115, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (B) the APLP2-binding domain comprises:(a) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:NAI-5011482438vl 368142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124 ; or (b) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (c) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the aminoNAI-5011482438vl 369acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (d) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 156; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:158, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:162, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:159, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:163, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQNAI-5011482438vl 370ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 164, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 165, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (e) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO: 167; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 126, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 168, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 169, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 173, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 131; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 170, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 174, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 177, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 132; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 175, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 176, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 127, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO:129, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:131; or (f) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:202; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:NAI-5011482438vl 371139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (g) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:204; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3NAI-5011482438vl 372comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (h) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:205; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (i) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:206; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the aminoNAI-5011482438vl 373acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 225, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 226, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 227, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (j) the VH comprising the VH-CDR1, the VH-CDR2, and the VH-CDR3 as set forth in the VH comprising the amino acid sequence of SEQ ID NO:207; and the VL comprising the VL-CDR1, the VL-CDR2, and the VL-CDR3 as set forth in the VL comprising the amino acid sequence of SEQ ID NO: 119, and(i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 228, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 229, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; orNAI-5011482438vl 374(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 230, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 231, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

68. The multispecific binding agent of claim 67, wherein(1) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:220, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:221, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:224, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:222, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:223, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124, and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQNAI-5011482438vl 375ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or(2) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2NAI-5011482438vl 376comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (3) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-NAI-5011482438vl 377CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (4) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; orNAI-5011482438vl 378(iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 144, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 145, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (5) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:24, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:28, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQNAI-5011482438vl 379ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:29, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:26, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:30, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:33, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:27, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:32, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (6) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:89, the VH-CDR2 comprising the amino acid sequence ofNAI-5011482438vl 380SEQ ID NO:93, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:90, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:94, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:91, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:95, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:98, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:96, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:97, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the aminoNAI-5011482438vl 381acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (7) (a) the CEACAM5 -binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 103, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:78, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 106, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 107, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 143, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and (b) the APLP2-binding domain comprises (i) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 139, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 150, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (ii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 151, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQNAI-5011482438vl 382ID NO: 120, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; or (iii) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 155, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 125; or (iv) the VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 142, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, the VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, the VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 120, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 124.

69. The multispecific binding agent of any one of claims 65-68, wherein(A) the CEACAM5 -binding domain comprises:(a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 12; and the VL comprising an amino acid sequenceNAI-5011482438vl 383having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:23; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:34; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:44; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (k) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 54; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (l) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 65; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (m) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:76; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (n) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 109; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (B) the APLP2-binding domain comprises:(a) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (b) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (c) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (d) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 156; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; orNAI-5011482438vl 384(e) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 167; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (f) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (g) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (h) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:205; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (i) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:206; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or (j) the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:207; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

70. The multispecific binding agent of claim 69, wherein(1) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(2) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(3) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acidNAI-5011482438vl 385sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(4) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(5) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 138; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(6) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 87; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(7) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:88; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; or(8) (a) the CEACAM5 -binding domain comprises the VH comprising an amino acidNAI-5011482438vl 386sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 99; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 149; and the VL comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 119.

71. The multispecific binding agent of any one of claims 65-70, wherein(A) the CEACAM5 -binding domain comprises:(a) the VH comprising the amino acid sequence of SEQ ID NO:201; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(b) the VH comprising the amino acid sequence of SEQ ID NO:200; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(c) the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(e) the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(f) the VH comprising the amino acid sequence of SEQ ID NO: 1; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) the VH comprising the amino acid sequence of SEQ ID NO: 12; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) the VH comprising the amino acid sequence of SEQ ID NO:23; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) the VH comprising the amino acid sequence of SEQ ID NO:34; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) the VH comprising the amino acid sequence of SEQ ID NO:44; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(k) the VH comprising the amino acid sequence of SEQ ID NO:54; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(l) the VH comprising the amino acid sequence of SEQ ID NO:65; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(m) the VH comprising the amino acid sequence of SEQ ID NO:76; and the VL comprising the amino acid sequence of SEQ ID NO: 119; orNAI-5011482438vl 387(n) the VH comprising the amino acid sequence of SEQ ID NO: 109; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and(B) the APLP2-binding domain comprises:(a) the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119(b) the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(c) the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(d) the VH comprising the amino acid sequence of SEQ ID NO: 156; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(e) the VH comprising the amino acid sequence of SEQ ID NO: 167; and the VL comprising the amino acid sequence of SEQ ID NO: 126; or(f) the VH comprising the amino acid sequence of SEQ ID NO:202; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(g) the VH comprising the amino acid sequence of SEQ ID NO:204; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(h) the VH comprising the amino acid sequence of SEQ ID NO:205; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(i) the VH comprising the amino acid sequence of SEQ ID NO:206; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(j) the VH comprising the amino acid sequence of SEQ ID NO:207; and the VL comprising the amino acid sequence of SEQ ID NO: 119.

72. The multispecific binding agent of claim 71, wherein(1) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:201; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(2) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:200; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:203; and the VL comprising the amino acid sequence of SEQ ID NO: 119; orNAI-5011482438vl 388(3) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(4) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(5) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 138; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(6) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:87; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(7) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:88; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO: 119; or(8) (a) the CEACAM5 -binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO:99; and the VL comprising the amino acid sequence of SEQ ID NO: 119; and (b) the APLP2-binding domain comprises the VH comprising the amino acid sequence of SEQ ID NO: 149; and the VL comprising the amino acid sequence of SEQ ID NO:119.

73. The multispecific binding agent of any one of claims 65-72, comprising:(i) a first polypeptide comprising from N-terminus to C-terminus: a first VL and a first CL; (ii) a second polypeptide comprising from N-terminus to C-terminus: a first VH, a first CHI, a first CH2, and a first CH3;NAI-5011482438vl 389(iii) a third polypeptide comprising from N-terminus to C-terminus: a second VH, a second CHI, a second CH2, and a second CH3; and(iv) a fourth polypeptide comprising from N-terminus to C-terminus: a second VL and a second CL,wherein the first polypeptide and the second polypeptide form the first CEACAM5-binding domain, and the third polypeptide and the fourth polypeptide form the APLP2-binding domain.

74. The multispecific binding agent of claim 73, wherein the second polypeptide further comprises a first hinge domain between the first CHI and first CH2, and the third polypeptide further comprises a second hinge domain between the second CHI and second CH2; optionally wherein the first hinge domain and / or the second hinge domain comprises amino acid mutations that reduce Fc-mediated effector functions; further optionally wherein the first hinge domain and / or the second hinge domain comprises amino acid substitutions of L234A and L235A, numbering according to EU numbering by Kabat.

75. The multispecific binding agent of any one of claims 73 or 74, wherein (i) the first CH3 comprises amino acid substitutions of T366W and E356K, and the second CH3 comprises amino acid substitution of T366S, L368A, Y407V, and K439E; (ii) the first CH3 comprises amino acid substitutions of T366S, L368A, Y407V, and K439E, and the second CH3 comprises amino acid substitution of T366W and E356K, (iii) the first CH3 comprises amino acid substitutions of T366S, L368A and Y407V, and the second CH3 comprises amino acid substitution of T366W; (iv) the first CH3 comprises amino acid substitution of T366W, and the second CH3 comprises amino acid substitution of T366S, L368A and Y407V; (v) the first CH3 comprises amino acid substitutions of T366W, E356K, and D399K, and the second CH3 comprises amino acid substitution of T366S, L368A, Y407V, K392D, and K409D; or (vi) the first CH3 comprises amino acid substitutions of T366S, L368A, Y407V, K392D, and K409D, and the second CH3 comprises amino acid substitution of T366W, E356K, and D399K, numbering according to EU numbering by Kabat.

76. The multispecific binding agent of any one of claims 73-75, wherein the first polypeptide, and / or the fourth polypeptide comprises the amino acid sequence of SEQ ID NO:137.

77. The multispecific binding agent of any one of claims 73-76, wherein the second polypeptide and / or third polypeptide comprises the amino acid sequence of SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 179, SEQ ID NO: 180, SEQ NAI-5011482438vl 390ID NO: 196, SEQ IDNO:197, SEQ ID NO:198, SEQ IDNO:199, SEQ IDNO:216, SEQ ID NO:217, SEQ ID NO:218, or SEQ ID NO:219.

78. The multispecific binding agent of any one of claims 73-77, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 192, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 193, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181;(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 187, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 188, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181;(iii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 189, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 188, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181;(iv) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 190, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 191, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; or(v) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 182, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 185, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181;(vi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 183, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 185, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181;(vii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 184, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 185, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181;(viii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 182, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 186, and the fourth polypeptideNAI-5011482438vl 391comprises the amino acid sequence of SEQ ID NO: 181;(ix) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 183, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 186, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181; or(x) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 184, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 186, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 181.

79. A polynucleotide or polynucleotides encoding the multispecific binding agent or a portion thereof of any one of claims 65-78.

80. A vector or vectors comprising the polynucleotide or polynucleotides of claim 79 or a complementary polynucleotide or polynucleotides thereto.

81. A cell comprising the multispecific binding agent of any one of claims 65-78, the polynucleotide or polynucleotides of claim 79, or the vector or vectors of claim 80.

82. A pharmaceutical composition comprising the multispecific binding agent of any one of claims 65-78 and a pharmaceutically acceptable excipient.

83. A binding agent-drug conjugate has the structure of Formula (I),A-(L-D)y(i);wherein, A is the multispecific binding agent of any one of claims 65-78;L is a linker;D is a therapeutic agent;y represents the number of (L-D) moi eties linked to A, which is an integer from 1-10.

84. The binding agent-drug conjugate of claim 83, wherein the therapeutic agent is a cytotoxic agent.

85. The binding agent-drug conjugate of claim 84, wherein the cytotoxic agent is selected from the group consisting of the cytotoxic agents listed in Table 25.

86. The binding agent-drug conjugate of any one of claims 83-85, wherein the linker is selected from the group consisting of the cytotoxic agents listed in Table 26.NAI-5011482438vl 39287. The binding agent-drug conjugate of any one of claims 83-86, wherein y is two, four, six, eight, or ten.

88. The binding agent-drug conjugate of any one of claims 83-87, wherein the multispecific binding agent is a multispecific antibody.

89. A pharmaceutical composition comprising the binding agent-drug conjugate of any one of claims 83-88 and a pharmaceutically acceptable excipient.

90. A pharmaceutical composition comprising:(i) a first means for binding to CEACAM5 expressed on a cell;(ii) a second means for binding to APLP2 expressed on the cell,(iii) a therapeutic agent, wherein the first means and second means act together to deliver and retain the therapeutic agent in the cell to exert its therapeutic effects; and(iv) a pharmaceutically acceptable carrier.

91. A method for treating a cancer or a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the binding agent-drug conjugate of any one of claims 83-88, or the pharmaceutical composition of claim 89 or 90.

92. A method for alleviating one or more symptoms associated with a cancer or a tumor in a subject in need thereof, decreasing tumor size in a subject in need thereof comprising administering to the subject, or for enhancing tumor cell removal in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the binding agentdrug conjugate of any one of claims 83-88, or the pharmaceutical composition of claim 89 or 90.

93. The method of claim 91 or 92, wherein the cancer or tumor is selected from the group consisting of biliary tract cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, stomach cancer, liver cancer, melanoma, and pancreatic cancer.

94. Use of a therapeutically effective amount of the binding agent-drug conjugate of any one of claims 83-88, or the pharmaceutical composition of claim 89 or 90 for treating a cancer or a tumor in a subject in need thereof.

95. Use of a therapeutically effective amount of the binding agent-drug conjugate of any one of claims 83-88, or the pharmaceutical composition of claim 89 or 90 for alleviating one or more symptoms associated with a cancer or a tumor in a subject in need thereof, decreasing tumor sizeNAI-5011482438vl 393in a subject in need thereof comprising administering to the subject, or for enhancing tumor cell removal in a subject in need thereof.

96. The use of claim 94 or 95, wherein the cancer or tumor is selected from the group consisting of biliary tract cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, stomach cancer, liver cancer, melanoma, liver cancer, melanoma, and pancreatic cancer.

97. A binding agent-drug conjugate of any one of claims 83-88, or the pharmaceutical composition of claim 89 or 90 for use in the manufacture of a medicament for the treatment of a cancer or a tumor in a subject in need thereof.

98. A binding agent-drug conjugate of any one of claims 83-88, or the pharmaceutical composition of claim 89 or 90 for use in the manufacture of a medicament for alleviating one or more symptoms associated with a cancer or a tumor in a subject in need thereof, decreasing tumor size in a subject in need thereof comprising administering to the subject, or for enhancing tumor cell removal in a subject in need thereof.

99. The binding agent for use of claim 97 or 98, wherein the cancer or tumor is selected from the group consisting of biliary tract cancer, breast cancer, colorectal cancer, gastroesophageal cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, stomach cancer, liver cancer, melanoma, and pancreatic cancer.NAI-5011482438vl 394

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