Multispecific proteins and related methods

Abstract

Provided herein are, inter alia, multispecific proteins that are, e.g., capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) expressed on the surface of the same cell; nucleic acid molecules encoding the same; and cells expressing the same. The disclosure further relates to pharmaceutical composition comprising the same; and methods of utilizing the same, including, e.g., methods of treating cancer.

Description

MULTISPECIFIC PROTEINS AND RELATED METHODS1. FIELD

[0001] This disclosure is related to, inter alia, multispecific proteins that are, e.g., capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) expressed on the surface of the same cell; nucleic acid molecules encoding the same; and cells expressing the same. The disclosure further relates to, inter alia, pharmaceutical composition comprising the same; and methods of utilizing the same, including, e.g., methods of treating cancer.2. BACKGROUND

[0002] Cancer can generally be characterized as a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Cancers can be categorized in multiple ways, including as solid tumors (e.g., mass(es) of solid cancer cells) and liquid cancers (e.g., cancers present in body fluids (the blood and bone marrow)). Some of the more common cancers in the United States in recent years include, e.g., breast, prostate, lung, and colorectal cancers. Cancer continues to have a major impact on society in the United States and across the world.3. SUMMARY

[0003] Provided herein are, inter alia, multispecific proteins that are, e.g., capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) expressed on the surface of the same cell; nucleic acid molecules encoding the same; and cells expressing the same. The disclosure further relates to pharmaceutical composition comprising the same; and methods of utilizing the same, including, e.g., methods of treating cancer, methods of depleting or killing a population of cells (e.g., cells expressing CD163 and EpCAM on the surface) in a subject.

[0004] Accordingly, in one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., human EpCAM (hEpCAM))) comprising (i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 16, or comprising the amino acid sequence set forth in SEQ ID NO: 16 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequenceof the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 17, or comprising the amino acid sequence set forth in SEQ ID NO: 17 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18, or comprising the amino acid sequence set forth in SEQ ID NO: 18 and consisting of 1, 2, or 3 amino acid variations; and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 13, or comprising the amino acid sequence set forth in SEQ ID NO: 13 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14, or comprising the amino acid sequence set forth in SEQ ID NO: 14 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 15, or comprising the amino acid sequence set forth in SEQ ID NO: 15 and consisting of 1, 2, or 3 amino acid variations; and (b) a second antigen binding domain (e.g., that specifically binds cluster of differentiation 163 (CD163) (e.g., human CD163 (hCD163))) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR- H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

[0005] In one aspect provided herein are multispecific proteins comprising (a) a first antigenbinding domain e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 16; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 17; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 13; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 15; and (b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0006] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and (b) a second antigen binding domain (e.g., that specifically binds CD 163 (e.g., hCD163)) comprising (i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence setforth in SEQ ID NO: 27.

[0007] In some embodiments, (a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and (b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

[0008] In some embodiments, (a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 20; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 19; and (b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 27.

[0009] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 20; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 19; and (b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27.

[0010] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., human EpCAM (hEpCAM))) comprising (i) a variable light (VL) region comprising a CDR-L1, aCDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 8, or comprising the amino acid sequence set forth in SEQ ID NO: 8 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9, or comprising the amino acid sequence set forth in SEQ ID NO: 9 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10, or comprising the amino acid sequence set forth in SEQ ID NO: 10 and consisting of 1, 2, or 3 amino acid variations; and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 5, or comprising the amino acid sequence set forth in SEQ ID NO: 5 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6, or comprising the amino acid sequence set forth in SEQ ID NO: 6 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 7, or comprising the amino acid sequence set forth in SEQ ID NO: 7 and consisting of 1, 2, or 3 amino acid variations; and (b) a second antigen binding domain (e.g., that specifically binds cluster of differentiation 163 (CD163) (e.g., human CD163 (hCD163))) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising theamino acid sequence set forth in SEQ ID NO: 23 and consisting of 1 , , or 3 amino acid variations.

[0011] In one aspect provided herein arc multispccific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising a CDR-L1 , a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 8; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 5; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 7; and (b) a second antigen binding domain e.g., that specifically binds CD163 e.g., hCD163)) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0012] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and (b) a second antigen binding domain (e.g., that specifically binds CD 163 (e.g., hCD163)) comprising (i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and (ii) aVH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

[0013] In some embodiments, (a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and (b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

[0014] In some embodiments, (a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 12; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 11; and (b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 27.

[0015] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 12; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 11; and (b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27.

[0016] In one aspect provided herein are multispecific proteins comprising (a) a first antigenbinding domain (e.g., that specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., human EpCAM (hEpCAM))) comprising (i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32, or comprising the amino acid sequence set forth in SEQ ID NO: 32 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33, or comprising the amino acid sequence set forth in SEQ ID NO: 33 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34, or comprising the amino acid sequence set forth in SEQ ID NO: 34 and consisting of 1, 2, or 3 amino acid variations; and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 29, or comprising the amino acid sequence set forth in SEQ ID NO: 29 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30, or comprising the amino acid sequence set forth in SEQ ID NO: 30 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 31, or comprising the amino acid sequence set forth in SEQ ID NO: 31 and consisting of 1, 2, or 3 amino acid variations; and (b) a second antigen binding domain (e.g., that specifically binds cluster of differentiation 163 (CD163) (e.g., human CD163 (hCD163))) comprising (i) a VL region comprising a CDR-L1 , a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and (ii) a VH region comprising a CDR-H1, a CDR- H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acidsequence set forth in SEQ ID NO: 22 and consisting of 1 , 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

[0017] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 29; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 31; and (b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and (ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0018] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36; and (ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and (b) a second antigen binding domain (e.g.,that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 29.

[0019] In some embodiments, (a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and (b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

[0020] In some embodiments, (a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 36; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 35; and (b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 27.

[0021] In one aspect provided herein are multispecific proteins comprising (a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 36; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 35; and (b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising theamino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27.

[0022] The following embodiments are relevant to any of the foregoing aspects and should be treated as if explicitly recited with direct reference to each of the foregoing aspects.

[0023] In some embodiments, the first antigen binding domain specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., human EpCAM (hEpCAM)). In some embodiments, the second antigen binding domain specifically binds cluster of differentiation 163 (CD163) (e.g., human CD 163 (hCD163)). In some embodiments, the multispecific protein is capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163). In some embodiments, the multispecific protein is capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) expressed on the surface of the same cell, hi some embodiments, the cells expressing EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) on the surface are tumor macrophage hybrid cells (as defined herein). In some embodiments, the cells expressing EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) on the surface are circulating tumor macrophage hybrid cells (CHCs) (as defined herein) and / or cancer-associated macrophagelike cells (CAMLs) (as defined herein).

[0024] In some embodiments, the multispecific protein is not substantially capable of binding to a cell that expresses EpCAM on the surface but does not express CD163 (e.g., hCD163) on the surface. In some embodiments, the multispecific protein is not substantially capable of binding to a cell that expresses CD 163 on the surface but does not express EpCAM (e.g., hEpCAM) on the surface.

[0025] In some embodiments, the protein comprises a single an antigen binding domain that specifically binds EpCAM. In some embodiments, the protein comprises a single antigen binding domain that specifically binds CD 163. In some embodiments, the protein comprises a plurality of antigen binding domains that each specifically bind EpCAM. In some embodiments, the protein comprises a plurality of antigen binding domains that each specifically bind CD 163.

[0026] In some embodiments, the multispecific protein is bivalent. In some embodiments, the multispecific protein is trivalent. In some embodiments, the multispecific protein is tetravalent. In some embodiments, the multispecific protein is bispecific.

[0027] In some embodiments, the multispecific protein is bispecific and bivalent comprising one antigen binding domain that specifically binds EpCAM and one antigen binding domain thatspecifically binds CD163. Tn some embodiments, the multispecific protein is bispecific and trivalcnt comprising one antigen binding domain that specifically binds EpCAM and two antigen binding domains that each specifically bind CD 163. In some embodiments, the multispecific protein is bispecific and trivalent comprising one antigen binding domain that specifically binds CD 163 and two antigen binding domains that each specifically bind EpCAM.

[0028] In some embodiments, wherein the multispecific protein comprises a first human Ig (hlg) Fc region and a second hlg Fc region that associate via at least one covalent (e.g., disulfide) bond.

[0029] In some embodiments, the hlg is a hlgG. In some embodiments, the hlgG is hlgGl or hIgG4. In some embodiments, the hlgG is hlgGl.

[0030] In some embodiments, the antibody the amino acid sequence of the first Fc region and / or the amino acid sequence of the second Fc region comprise one or more amino acid substitution that promotes the association (e.g., heterodimerization) of the first and second Fc regions.

[0031] In some embodiments, the amino acid sequence of the first Fc region comprises an amino acid substitution at amino acid positions T366, E368, and Y407, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the first Fc comprises a serine at amino acid position T366, an alanine at amino acid position E368, and a valine at amino acid position Y407, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the first Fc region comprises an amino acid substitution at amino acid position Y349, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the first Fc region comprises a cysteine at amino acid position Y349, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the second Fc region comprises an amino acid substitution at amino acid position T366, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the second Fc region comprises a tryptophan at amino acid position T366, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the second Fc region of the antibody comprises an amino acid substitution at amino acid position S354, numbering according to the EU index of Kabat. In some embodiments, the amino acid sequence of the second Fc region of the antibody comprises a cysteine at amino acid position S354, numbering according to the EU index of Kabat.

[0032] In some embodiments, one of the first or second antigen binding domains comprises: (a) a light : heavy chain pair wherein the heavy chain comprises from N- to C-tcrminus the VL region, a CHI region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CL region; (b) a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VH region, a CL region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VL region and a CHI region; or (c) a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CL region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CHI region.

[0033] In some embodiments, one of the first antigen binding domain comprises a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CHI region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CL region.

[0034] In some embodiments, one of the second antigen binding domain comprises a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CHI region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C- terminus the VH region and a CL region.

[0035] In some embodiments, the multispecific protein is capable of inducing one or more of the following upon binding to cells expressing CD 163 and EpCAM on the surface: (a) antibodydependent cellular cytotoxicity (ADCC); (b) antibody-dependent cellular phagocytosis (ADCP); (c) complement-dependent cytotoxicity (CDC); and / or (d) binding to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))).

[0036] In some embodiments, the multispecific protein is substantially incapable of inducing one or more of the following upon binding to cells expressing CD 163 on the surface that do not express EpCAM on the surface: (a) ADCC; (b) ADCP; (c) CDC; and / or (d) binding to one or more human Fc receptor e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))). In some embodiments, the multispecific protein is substantially incapable of inducing one or more of the following upon binding to cells expressing EpCAM on the surface that do not express CD163 on the surface: (a) ADCC; (b) ADCP; (c) CDC; and / or (d) binding to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc,FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))).

[0037] In some embodiments, the multispccific protein has enhanced Ig effector function. In some embodiments, the multispecific protein has any one or more of the following: (a) enhanced ADCC; (b) enhanced ADCP; (c) enhanced CDC; and / or (d) enhanced binding affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))) relative to a reference protein.

[0038] In some embodiments, the multispecific protein comprises one or more amino acid variation (relative to a reference protein) that enhances one or more Ig effector function. In some embodiments, the multispecific protein comprises varied (e.g., reduced glycosylation (e.g., fucosylation)) (relative to a reference protein) that enhances one or more Ig effector function. In some embodiments, the multispecific protein comprises one or more variations set forth in Table 6.

[0039] In some embodiments, the multispecific protein comprises a linker. In some embodiments, the linker comprises a peptide about 2-50 amino acids in length (e.g., a glycine linker, a glycine / serine linker, etc.). In some embodiments, the linker comprises an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 65- 73.

[0040] In some embodiments, the multispecific protein further comprises one or more heterologous moiety. In some embodiments, the heterologous moiety comprises a small molecule, protein, peptide, nucleic acid molecule (e.g., DNA molecule, RNA molecule), carbohydrate, lipid, synthetic polymer, carrier, or vector. In some embodiments, the heterologous moiety is detectable (e.g., fluorescent agent, radiation agent, imaging agent, etc.). In some embodiments, the heterologous moiety comprises a cytotoxic agent. In some embodiments, the heterologous moiety comprises a radionuclide.

[0041] In some embodiments, the multispecific protein comprises four polypeptide chains comprising (i) a first polypeptide chain comprising N- to C-terminus the VL region of (a)(i) and a CL region; (ii) a second polypeptide chain comprising from N- to C-terminus the VH of (a)(ii) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a third polypeptide chain comprising from N- to C-terminus the VH region of (b)(i) region and a CL region; (iv) a fourth polypeptide chain comprising from N-to C-terminus the VL region of (b)(ii), a CHI region,a hinge region, a CH2 region, and a CH3 region; wherein the VL region first polypeptide and the VH region second polypeptide associate to form the first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), and wherein the VL region of the fourth polypeptide associates with the VH region of the third polypeptide to form the second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)).

[0042] In some embodiments, the multispecific protein comprises four polypeptide chains comprising (i) a first polypeptide chain comprising N- to C-terminus the VL region of (b)(i) and a CL region; (ii) a second polypeptide chain comprising from N- to C-terminus the VH of (b)(ii) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a third polypeptide chain comprising from N- to C-terminus the VH region of (a)(i) region and a CL region; (iv) a fourth polypeptide chain comprising from N-to C-terminus the VL region of (a)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region; wherein the VL region first polypeptide and the VH region second polypeptide associate to form the second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), and wherein the VL region of the fourth polypeptide associates with the VH region of the third polypeptide to form the first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)).

[0043] In some embodiments, the multispecific protein comprises a third antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., hEpCAM)) comprising (c) (i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR- H3.

[0044] In some embodiments, (i) the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 16, or comprising the amino acid sequence set forth in SEQ ID NO: 16 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 17, or comprising the amino acid sequence set forth in SEQ ID NO: 17 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18, or comprising the amino acid sequence set forth in SEQ ID NO: 18 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising theamino acid sequence set forth in SEQ ID NO: 13, or comprising the amino acid sequence set forth in SEQ ID NO: 13 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14, or comprising the amino acid sequence set forth in SEQ ID NO: 14 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 15, or comprising the amino acid sequence set forth in SEQ ID NO: 15 and consisting of 1, 2, or 3 amino acid variations.

[0045] In some embodiments, (i) the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 8, or comprising the amino acid sequence set forth in SEQ ID NO: 8 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9, or comprising the amino acid sequence set forth in SEQ ID NO: 9 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10, or comprising the amino acid sequence set forth in SEQ ID NO: 10 and consisting of1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 5, or comprising the amino acid sequence set forth in SEQ ID NO: 5 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6, or comprising the amino acid sequence set forth in SEQ ID NO: 6 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 7, or comprising the amino acid sequence set forth in SEQ ID NO: 7 and consisting of 1,2, or 3 amino acid variations.

[0046] In some embodiments, (i) the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32, or comprising the amino acid sequence set forth in SEQ ID NO: 32 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33, or comprising the amino acid sequence set forth in SEQ ID NO: 33 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34, or comprising the amino acid sequence set forth in SEQ ID NO: 34 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 29, or comprising the amino acid sequence set forthin SEQ ID NO: 29 and consisting of 1 , 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30, or comprising the amino acid sequence set forth in SEQ ID NO: 30 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 31, or comprising the amino acid sequence set forth in SEQ ID NO: 31 and consisting of 1, 2, or 3 amino acid variations.

[0047] In some embodiments, the multispecific protein comprises five polypeptide chains: (i) a first polypeptide chain comprising N- to C-terminus the VL region of (a)(i) and a CL region; (ii) a second polypeptide chain comprising from N- to C-terminus the VH region of (a)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a third polypeptide chain comprising from N- to C-terminus the VH of (b)(ii) region and a CL region; (iv) a fourth polypeptide chain comprising from N-to C-terminus the VH region of (c)(ii), a CHI region, a linker, the VL region of (b)(i) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; and (v) a fifth polypeptide chain comprising from N- to C-terminus the VL region of (c)(i) and a CL region; wherein the VL region of (a)(i) of first polypeptide and the VH region of (a)(ii) of second polypeptide associate to form an antigen binding domain (e.g., that specifically binds EpCAM); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), wherein the VH region of (c)(ii) of the fourth polypeptide and the VL region of (c)(i) of the fifth polypeptide associate to form an antigen binding domain (e.g., that specifically binds EpCAM); and wherein the VL region of (b)(ii) of the fourth polypeptide associates with the VH region of (b)(i) of the third polypeptide to form an antigen binding domain (e.g., that specifically binds CD 163).

[0048] In some embodiments, the multispecific protein comprises a third antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (CD163) (e.g., hCD163)) comprising (c) (i) a variable light (VL) region comprising a CDR-LI, a CDR-L2, a CDR-L3, and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR-H3.

[0049] In some embodiments, (c)(i) the amino acid sequence of the CDR-LI comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations;and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

[0050] In some embodiments, the multispecifrc protein comprises five polypeptide chains: (i) a first polypeptide chain comprising N- to C-terminus the VL region of (b)(i) and a CL region; (ii) a second polypeptide chain comprising from N- to C-terminus the VH region of (b)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a third polypeptide chain comprising from N- to C-terminus the VH of (a)(ii) region and a CL region; (iv) a fourth polypeptide chain comprising from N-to C-terminus the VH region of (c)(ii), a CHI region, a linker, the VL region of (a)(i) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; and (v) a fifth polypeptide chain comprising from N- to C-terminus the VL region of (c)(i) and a CL region; wherein the VL region of (b)(i) of first polypeptide and the VH region of (b)(ii) of second polypeptide associate to form an antigen binding domain (e.g., that specifically binds CD163); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent e.g., disulfide bond), wherein the VH region of (c)(ii) of the fourth polypeptide and the VL region of (c)(i) of the fifth polypeptide associate to form an antigen binding domain (e.g., that specifically binds CD163); and wherein the VL region of (a)(ii) of the fourth polypeptide associates with the VH region of (a)(i) of the third polypeptide to form an antigen binding domain (e.g., that specifically binds EpCAM).

[0051] In some embodiments, the multispecific protein comprises (i) a first polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 74; (ii) a second polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the aminoacid sequence set forth in SEQ ID NO: 75; (iii) a third polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 76; and (iv) a fourth polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 77.

[0052] In some embodiments, the multispecific protein comprises (i) a first polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 78; (ii) a second polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 79; (iii) a third polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 77; (iv) a fourth polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 76; and (iv) a fifth polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 76.

[0053] In some embodiments, the multispecific protein is a multispecific protein set forth in Table 10.

[0054] In one aspect, provided herein are conjugates comprising a multispecific protein described herein and a heterologous moiety. In some embodiments, the heterologous moiety comprises a small molecule, protein, peptide, nucleic acid molecule (e.g., DNA molecule, RNA molecule), carbohydrate, lipid, synthetic polymer, carrier, or vector. In some embodiments, the heterologous moiety is a cytotoxic agent. In some embodiments, the heterologous moiety is a radionuclide.

[0055] In one aspect, provided herein are fusion proteins comprising a multispecific protein described herein and a heterologous protein.

[0056] In one aspect, provided herein are one or more nucleic acid molecules encoding one or more polypeptide of a multispecific protein described herein. In some embodiments, the nucleicacid molecules are RNA or DNA.

[0057] In one aspect, provided herein arc vectors comprising one of more nucleic acid molecule described herein (e.g., encoding one or more polypeptide of a multispecific protein described herein). In some embodiments, the vector is a viral vector or a non-viral vector (e.g., a plasmid).

[0058] In one aspect, provided herein are carriers comprising a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, or a vector described herein. In some embodiments, the carrier is a lipid nanoparticle.

[0059] In one aspect, provided herein are carriers conjugated to a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, or a vector described herein. In some embodiments, the carrier is a lipid nanoparticle.

[0060] In one aspect, provided herein are cells comprising a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, or a carrier described herein.

[0061] In one aspect, provided herein are cells (e.g., a therapeutic cells) expressing a multispecific protein described herein, a conjugate described herein, a fusion protein described herein.

[0062] In one aspect, provided herein are cells (e.g., a therapeutic cells) genetically engineered to comprise within the cell’s genome the nucleic acid molecule described herein (e.g., wherein the nucleic acid molecule encodes a multispecific protein described herein, a conjugate described herein, or a fusion protein described herein).

[0063] In some embodiments, the cell is a therapeutic cell. In some embodiments, the cell expresses a protein comprising a multispecific protein described herein, a conjugate described herein, or a fusion protein described herein on the surface of the cell. In some embodiments, the cell expresses a chimeric antigen receptor on the surface of the cell, wherein the chimeric antigen receptor comprises a multispecific protein described herein. In some embodiments, the cell is an immune cell (e.g., a T cell (e.g., a CD8+ T cell or a CD4+ T cell), an NK cell).

[0064] In one aspect, provided herein are chimeric antigen receptor (CAR) cells (e.g., T cells (e.g., CD8+ T cells)) expressing a CAR comprising a multispecific protein described herein on thesurface of the cell.

[0065] In one aspect, provided herein arc pharmaceutical compositions comprising a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, or a cell described herein, and a pharmaceutically acceptable excipient.

[0066] In one aspect, provided herein are kits comprising a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, and optional instructions for use.

[0067] In one aspect, provided herein are methods of delivering a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, to thereby deliver the multispecific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition to a subject to the subject.

[0068] In one aspect, provided herein are methods of killing a population of cells in a subject in need thereof, the method comprising administering to the subject a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, to thereby kill the population of cancer cells in the subject.

[0069] In some embodiments, the population of cells express CD 163 and EpCAM on the surface. In some embodiments, the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs). In some embodiments, the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or (c) CDC. In some embodiments, the subject has cancer. In some embodiments, the subject has or had cancer that is in remission (e.g., partial or full remission).

[0070] In one aspect, provided herein are methods method of treating, ameliorating, or preventing a cancer in a subject in need thereof, the method comprising administering to the subject a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier describedherein, a cell described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the cancer in the subject.

[0071] In some embodiments, the cancer is in remission (e.g., partial or full remission). In some embodiments, the treatment, amelioration , or prevention of the cancer in the subject is mediated in part through the killing of a population of cells in the subject. In some embodiments, the population of cells express CD163 and EpCAM on the surface. In some embodiments, the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs). In some embodiments, the killing of the cells is mediated by one or more of (a) ADCC;(b) ADCP; and / or (c) CDC.

[0072] In one aspect, provided herein are methods of preventing recurrence of a cancer in a subject in need thereof, the method comprising administering to the subject a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, to thereby prevent recurrence of a cancer in the subject.

[0073] In some embodiments, the cancer is in remission (e.g., partial or full remission). In some embodiments, the prevention of the recurrence of the cancer in the subject is mediated in part through the killing of a population of cells in the subject. In some embodiments, the population of cells express CD 163 and EpCAM on the surface. In some embodiments, the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs). In some embodiments, the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or(c) CDC.

[0074] In one aspect, provided herein are methods of preventing progression and / or metastasis of a cancer in a subject in need thereof, the method comprising administering to the subject a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, to thereby prevent progression and / or metastasis of the cancer in the subject.

[0075] In some embodiments, the prevention of the progression and / or metastasis of the cancer in the subject is mediated in part through the killing of a population of cells in the subject. In some embodiments, the population of cells express CD163 and EpCAM on the surface. In someembodiments, the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs). In some embodiments, the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or (c) CDC.

[0076] In one aspect, provided herein are methods of predicting the likelihood of recurrence of a cancer in a subject, the method comprising (a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells; (b) determining (or having determined) if at least a portion of the cancer cells are tumor macrophage hybrid cells; and wherein the cancer is predicted to recur if at least a portion of the cells in the population are tumor macrophage hybrid cells.

[0077] In some embodiments, the at least a portion of the population of cells simultaneously express CD163 and EpCAM on the surface. In some embodiments, the method further comprises administering a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein to the subject if the cancer is predicted to recur.

[0078] In one aspect, provided herein are methods of selecting a subject having cancer for treatment with a multispecific protein that specifically binds EpCAM and CD 163, the method comprising (a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells; (b) determining (or having determined) if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells utilizing a multispecific protein described herein; and (c) selecting the subject for treatment with the multispecific protein that specifically binds EpCAM and CD 163 if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells. In some embodiments, the method further comprises administering to the treatment to the subject.

[0079] In one aspect, provided herein are methods of selecting a subject having cancer for treatment with a multispecific protein that specifically binds EpCAM and CD 163, the method comprising (a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells; (b) determining (or having determined) if at least a portion of the cancer cells are tumor macrophage hybrid cells; and (c) selecting the subject for treatment with a multispecific protein that specifically binds EpCAM and CD 163 if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells.

[0080] In some embodiments, the method further comprises administering a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein to the subject if the subject is selected.

[0081] In one aspect, provided herein are methods of predicting and / or evaluating the responsiveness of a subject having cancer to a treatment comprising a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein, the method comprising (a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells; (b) determining (or having determined) if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells; and wherein the subject is predicted or evaluated to be responsive to the treatment if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells.

[0082] In some embodiments, the cancer is a recurrence of a cancer.

[0083] In some embodiments, the method further comprises administering a multispecific protein described herein, a conjugate described herein, a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a carrier described herein, a cell described herein, or a pharmaceutical composition described herein to the subject predicted or evaluated to be responsive to the treatment.

[0084] The following embodiments are relevant to any of the foregoing methods and should be treated as if explicitly recited with direct reference to each of the foregoing method aspect.

[0085] In some embodiments, the multispecific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition is administered to the subject in combination with one or more anti-neoplastic agent (e.g., described herein). In some embodiments, the multispecific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition is administered to the subject as an adjuvant. In some embodiments, the cancer in the subject has been determined to be resistant to one or more anti-neoplastic agent (e.g., one or more standard of care regimen comprising one or more neoplastic agent).

[0086] In some embodiments, the subject is a human.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] FIG. 1 is a series of immunofluorescence images showing the co-expression of EpCAM and CD 163 in both CAMLs and CHCs. The arrows indicate CAMLs and arrowheads indicate CHCs expressing both CD163 and EpCAM. Field 1 scale bar 10 pm and Field 2 scale bar 20 pm.

[0088] FIG. 2 is a series of immunofluorescence images showing the co-localization of EpCAM and CD 163 expressed on the surface of HEK293 cells. Scale bar 60 pm.

[0089] FIG. 3 is a series of immunofluorescence images showing the co-localization of EpCAM and CD 163 expressed on the surface of CAMLs (top) and CHCs (bottom). Scale bar 60 pm.

[0090] FIG. 4A is a line graph showing the binding of each indicated agent to HEK293 cells expressing EpCAM. FIG. 4B is a line graph showing the binding of each indicated agent to HEK293 cells expressing CD 163. FIG. 4C is a line graph showing the binding of each indicated agent to HEK293 cells expressing EpCAM and CD 163.

[0091] FIG. 5 is a bar graph showing the ADCC mediated killing of the indicated cells (HEK293-WT, HEK293-EpCAM. HEK293-CD163, HEK293-EpCAM / CD163) by an antiCD 163 reference antibody or an anti-EpCAM reference antibody (as indicated).

[0092] FIG. 6A is a line graph showing the ADCC-mediated killing of HEK293 cells expressing EpCAM (but not CD163) by multispecific protein 1 (MP-1) and multispecific protein 2 (MP-2). FIG. 6B is a line graph showing the ADCC-mediated killing of HEK293 cells expressing CD163 (but not EpCAM) by multispecific protein 1 (MP-1) and multispecific protein 2 (MP-2). FIG. 6C is a line graph showing the ADCC-mediated killing of HEK293 cells coexpressing EpCAM and CD 163 by multispecific protein 1 (MP-1) and multispecific protein 2 (MP-2).

[0093] FIG. 7 is a graph showing the density of EpCAM and CD 163 expressed by each cell type (HEK293-WT, HEK293-EpCAM. HEK293-CD163, HEK293-EpCAM / CD163).

[0094] FIG. 8A is a bar graph showing the expression levels of EpCAM and CD 163 on hybrid cells, CD163+ monocytes, and EpCAM-i- CTCs on PBMCs from OHS 55. FIG. 8B is a bar graph showing the expression levels of EpCAM and CD163 on hybrid cells, CD163+ monocytes, and EpCAM-i- CTCs on PBMCs from OHS 56. FIG. 8C is a bar graph showing the expression levels of EpCAM and CD163 on hybrid cells, CD163+ monocytes, and EpCAM-i- CTCs on PBMCs fromOHS 57. FIG. 8D is a bar graph showing the expression levels of EpCAM and CD163 on hybrid cells, CD 163+ monocytes, and EpCAM+ CTCs on PBMCs from OHS 58. FIG. 8E is a bar graph showing the ADCC-mediating killing of EpCAM+ / CD163+ hybrid cells (but not CD 163+ monocytes) when hlgGl isotype, anti-EpCAM (Ref A), or MP-1 is added directly to patient PBMCs.

[0095] FIG. 9A is a bar graph showing the density of EpCAM and CD 163 expressed by in vitro generated MCF7 hybrid cells (healthy M2). FIG. 9B is a line graph showing the normalized live cell count of MCF7-M2 hybrid cells treated with MP-1, NK + Target cell only, or Target cell only.

[0096] FIG. 10A is a bar graph showing the density of EpCAM and CD 163 expressed by in vitro generated CTC colon hybrid cells (healthy M2 or Patient M2). FIG. 10B is a line graph showing the normalized live cell count of CTC colon hybrid cells treated with MP-1, NK + Target cell only, or Target cell only.

[0097] FIG. 11 is a line graph showing the tumor volume (mm3) in mice treated with MP-1 (3mg / kg or lOmg / kg) or control human IgGl antibody.5. DETAILED DESCRIPTIONTABLE OF CONTENTS5.1 Definitions5.2 Multispecific Proteins5.2.1 EpCAM Binding Domains5.2.2 Exemplary Combinations of CD163 and EpCAM Binding Domains5.2.3 Ig Constant Regions5.2.3.1 Ig Effector Function5.2.3.1(i) Enhanced Ig Effector Function5.2.3.1(H) Reduced Effector Function5.2.4 Promotion of Heavy Chain Heterodimerization5.2.5 Promotion of Heavy Chain and Light Chain Pairing5.2.6 Linkers5.2.7 Exemplary Formats5.2.7.1 1:1 Format (VH / VL-KiH)2:1 (EpCAM:CD163) (VH / VL-KiH 1:2 (EpCAM:CD163) (VH / VL-KiH) Exemplary Multispecific Proteins Exemplary Properties of Multispecific Proteins Fusion Proteins and Conjugates Radioisotopes Chimeric Antigen Receptors Methods of Making Proteins Nucleic Acid Molecules DNA Molecules RNA Molecules Vectors Non-Viral Vectors Viral Vectors Cells Carriers Carriers of Multispecific Proteins Carriers Conjugated to Multispecific Proteins Combination Regimens Combination Compositions Pharmaceutical Compositions Cancers Anti-Neoplastic Agents Subjects Methods of Use Methods of Delivery Methods of Depleting a Population of Cells (e.g., Tumor Macrophage Hybrid Cells) Methods of Killing a Population of Cells (e.g., Tumor Macrophage Hybrid Cells) Methods of Treating, Ameliorating, or Preventing a Cancer5.17.5 Methods of Preventing the Recurrence of a Cancer5.17.6 Methods of Preventing the Progression and / or Metastasis of a Cancer5.17.7 Diagnostic and Prognostic Methods5.18 Kits5.1 Definitions

[0098] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0099] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0100] In this disclosure, the use of the singular includes the plural unless specifically stated otherwise. For example, as used in the specification and the appended claims, the singular’ forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0101] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and “consisting essentially of’ are also provided herein.

[0102] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “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 aspects: 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).

[0103] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0104] The term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. When particular values or compositions are provided in the disclosure, unless otherwise stated, the meaning of “about” should be assumed to be within an acceptable error range for that particular value or composition.

[0105] Where proteins are described herein, it is understood that nucleic acid molecules (e.g., RNA (e.g., mRNA) or DNA nucleic acid molecules) encoding the protein are also provided herein.

[0106] Where proteins, nucleic acid molecules, vectors, carriers, etc. are described herein, it is understood that isolated forms of the proteins, nucleic acid molecules, vectors, carriers, etc. are also provided herein.

[0107] Where proteins, nucleic acid molecules, etc. are described herein, it is understood that recombinant forms of the proteins, nucleic acid molecules, etc. are also provided herein.

[0108] Where polypeptides or sets of polypeptides are described herein, it is understood that proteins comprising the polypeptides or sets of polypeptides folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein and vice versa.

[0109] Where proteins are described herein, it is understood that polypeptides comprising the same amino acid sequence either linear or folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein.

[0110] As used herein, the term “administering” refers to the physical introduction of an agent (e.g., a multispecific protein described herein), e.g., a therapeutic agent (or a precursor of an agent (e.g., a precursor of a therapeutic agent) that is metabolized or altered within the body of the subject to produce the agent (e.g., therapeutic agent) in vivo) to a subject, using any of the various methods and delivery systems known to those skilled in the ail. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0111] The terms “agent” and “moiety” are used interchangeably herein and are used generically to describe any macro or micro molecule (and any combination thereof). Exemplary agents include, but are not limited to proteins, peptides, nucleic acid molecules (e.g., DNA, RNA), small molecules, carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG), conjugates, and any combination of the foregoing. Agents may contain more than one individual agent (wherein the individual agents are the same or different).

[0112] As used herein, the term “affinity” refers to the strength of the binding of one protein (e.g., an Antibody) to another protein (e.g., an Antigen). The affinity of a protein is measured by the dissociation constant Kd, defined as [Antibody] x [Antigen] / [Antibody-Antigen] where [Antibody-Antigen] is the molar concentration of the Antibody- Antigen complex, [Antibody] is the molar concentration of the unbound Antibody and [Ligand] is the molar concentration of the unbound Antigen. The affinity constant Ka is defined by 1 / Kd. Standard methods of measuring affinity are known to the person of ordinary skill in the art. Exemplary methods of measuring affinity include, surface plasmon resonance (SPR) (e.g., BIAcore®-based assay), a common method known in the art (see, e.g., Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 55:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, the full contents of each of which are incorporated by reference herein for all purposes).

[0113] As used herein, the term “antibody” or “antibodies” is used in the broadest sense and encompasses various immunoglobulin (Ig) (e.g., human Ig (hlg), murine Ig (mlg)) structures, including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific (e.g., bispecific, trispecific) antibodies, and antibody fragments so long as they exhibit the desired antigen-binding activity (i.e., antigen binding fragments or variants). The term antibody thus includes, for example, full-length antibodies; antigen-binding fragments of full-length antibodies; molecules comprising antibody CDRs, VH regions, and / or VL regions; and antibody-like scaffolds (e.g., fibronectins). Examples of antibodies include, without limitation, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, camelized antibodies, intrabodies, a variable domain of a new antigen receptor beta-lactamase (VNAR fragments), affybodies, diabodies, tribodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (e.g.,VHH, (VHH)2), single chain antibodies, single-chain Fvs (scFv; (scFv) ), Fab fragments (e.g., Fab, single chain Fab (scFab), F(ab’)2 fragments, disulfide-linked Fvs (sdFv), Fc fusions (e.g., Fab-Fc, scFv- Fc, VHH-Fc, (SCFV) -FC, (VHH) -FC), and antigen-binding fragments of any of the above, and conjugates or fusion proteins comprising any of the above. Antibodies can be of Ig isotype (e.g., IgG, IgE, IgM, IgD, or IgA), any class (e.g., IgGi, IgG2, IgGa, IgGr, IgAi or IgA2), or any subclass (e.g., IgG2a or IgG b) of Ig). In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgGi or IgG4) or subclass thereof. In certain embodiments, antibodies described herein are mlgG antibodies, or a class (e.g., mlgGl or mIgG2a) or subclassthereof. In some embodiments, the antibody is a human, humanized, or chimeric IgGi or IgG4 monoclonal antibody. In some embodiments, the term antibodies refers to a monoclonal or polyclonal antibody population. Antibodies described herein can be produced by any standard methods known in the art, e.g., recombinant production in host cells, see, e.g., § 5.6; or synthetic production.

[0114] As used herein, the term “antibody dependent cell mediated cytotoxicity” or “ADCC” refers to an immune mechanism leading to the lysis of antibody (or an Fc region containing protein)-coated target cells by immune effector cells (e.g., NK cells). As used herein, the term “reduced ADCC” and the like refers to either a decrease in the number of target cells that are lysed in a given time, at a given concentration of antibody (or an Ig Fc region containing protein) in the medium surrounding the target cells, by the mechanism of ADCC defined above, and / or an increase in the concentration of antibody (or an Fc region containing protein) (e.g., an Fc containing fusion protein described herein) in the medium surrounding the target cells, required to achieve the lysis of a given number of target cells in a given time, by the mechanism of ADCC defined above. The reduction in ADCC is relative to the ADCC mediated by the same antibody (or an Fc region containing protein) produced by the same type of host cells, using the same standard production, purification, formulation and storage methods (which are known to those skilled in the art), but that has not been engineered (e.g., does not comprise one or more amino acid variation, e.g., amino acid substitution, that mediates a decrease in ADCC). For example the reduction in ADCC mediated by an antibody (or an Fc region containing protein) comprising in its Fc region an amino acid substitution that reduces ADCC, is relative to the ADCC mediated by the same antibody (or an Fc region containing protein) without said amino acid substitution in the Fc region. As used herein, the term “enhanced ADCC” and the like refers to either an increase in the number of target cells that are lysed in a given time, at a given concentration of antibody (or an Ig Fc region containing protein) in the medium surrounding the target cells, by the mechanism of ADCC defined above, and / or a decrease in the concentration of antibody (or an Fc region containing protein) (e.g., an Fc containing fusion protein described herein) in the medium surrounding the target cells, required to achieve the lysis of a given number of target cells in a given time, by the mechanism of ADCC defined above. The enhanced in ADCC is relative to the ADCC mediated by the same antibody (or an Fc region containing protein) produced by the same type of host cells, using the same standard production, purification, formulation and storagemethods (which are known to those skilled in the art), but that has not been engineered (e.g., does not comprise one or more amino acid variation, e.g., amino acid substitution, that mediates an increase in ADCC). For example the increase in ADCC mediated by an antibody (or an Fc region containing protein) comprising in its Fc region an amino acid substitution that increases ADCC, is relative to the ADCC mediated by the same antibody (or an Fc region containing protein) without said amino acid substitution in the Fc region.

[0115] As used herein, the terms “anti-neoplastic agent” or “anti-cancer agent” refers to any agent used for the treatment of cancer. Anti-neoplastic agents include for example, but are not limited to, chemotherapeutic agents (e.g., alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors corticosteroids, and enzymes), biologic anti-cancer agents, immune checkpoint modulators, etc.

[0116] The terms “cancer” and “tumor” are used interchangeably herein and refer to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that can invade neighboring tissues and may also metastasize to distant parts of the body through, e.g., the lymphatic system or bloodstream.

[0117] As used herein, the terms “cancer treatment regimen” or “anti-neoplastic regimen” refers to a clinically accepted dosing protocol for the treatment of cancer that includes administration of one or more anti-neoplastic agents to a subject in specific amounts on a specific schedule.

[0118] As used herein, the term “CDR” or “complementarity determining region” refers to the noncontiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), the entire contents of each of which is incorporated herein by reference for all purposes. Unless otherwise specified, the term “CDR” is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). A person of ordinary skill in the ail would be able to determine the CDRs as defined by another scheme, e.g., Chothia, IMGT, using ordinary methods known in the art.

[0119] The terms “CHI” and “CHI region” are used interchangeably herein and refer to the first constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplaryreference hlgGl CHI region is set forth in SEQ TD NO: 37.

[0120] The terms “CH2” and “CH2 region” arc used interchangeably herein and refer to the second constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CH2 region is set forth in SEQ ID NO: 39.

[0121] The terms “CH3” and “CH3 region” are used interchangeably herein and refer to the third constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CH3 region is set forth in SEQ ID NO: 40.

[0122] The terms “constant region” and “constant domain” are used interchangeably herein and refer to a carboxyl terminal portion of a light and / or heavy chain of a full-length antibody which is not directly involved in binding of an antibody to antigen, but which can exhibit various effector functions, such as interaction with an Ig Fc receptor (e.g., Fc gamma receptor). The constant region of an Ig molecule generally has a more conserved amino acid sequence relative to an Ig variable domain.

[0123] As used herein, the term “disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology. In some embodiments, the disease is cancer. In preferred embodiments, the disease is a solid tumor. The term disease includes infection (e.g., a viral, bacterial, fungal, protozoal infection).

[0124] The terms “DNA” and “polydeoxyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple deoxyribonucleotides that are polymerized via phosphodiester bonds. Deoxyribonucleotides are nucleotides in which the sugar is deoxyribose.

[0125] The term “effector function” when used in reference to an Ig Fc region or a protein comprising an Ig Fc region (e.g., a full-length antibody) refers to those biological activities attributable to the Ig Fc region of a typical full-length antibody, which therefore vary with the antibody isotype. Antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), Fc receptor binding (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla)), and Clq binding.

[0126] As used herein, the term “EU numbering system” refers to the EU numbering convention for the constant regions of an antibody, as described in Edelman, G.M. et al., Proc.Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al, Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991, the entire contents of each of which is incorporated herein by reference for all purposes.

[0127] As used herein, the term “Fab” includes antigen binding domains that comprise a Fab heavy chain that comprises from N- to C-terminus a VH region and a CHI region; and a light chain comprising from N- to C-terminus a VL region and a CL region; and wherein the Fab heavy chain and the light chain associate to form an antigen binding domain. The aforementioned structure of the structure of naturally occurring Fabs. In some embodiments, the structure of the Fab is altered in order to selectively pair two chains (e.g., to create an antigen binding domain) (see, e.g., § 5.2.6). For example, the VH and VL within a Fab may be swapped. In such embodiments, the Fab would comprise a Fab heavy chain that comprises from N- to C-terminus a VL region and a CHI region; and a light chain comprising from N- to C-terminus a VH region and a CL region; and wherein the Fab heavy chain and the light chain associate to form an antigen binding domain.

[0128] As used herein, the term “Fc region” refers to the C-terminal region of a Ig e.g., a human Ig) heavy chain that comprises from N- to C-terminus at least a CH2 region operably connected to a CH3 region. In some embodiments, the Fc region comprises an Ig hinge region or at least a portion of an Ig hinge region operably connected to the N-terminus of the CH2 region. In some embodiments, the Fc region is engineered relative to a reference Fc region (e.g., comprises one or more amino acid modification), see, e.g., §§ 5.2.4. l(i), 5.2.4. l(ii), 5.2.5. Additional examples of proteins with engineered Fc regions can be found in Saunders 2019 (K. O. Saunders, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” 2019, Frontiers in Immunology, V. 10, Art. 1296, pp. 1-20, the entire contents of which is incorporated herein by reference for all purposes).

[0129] As used herein, the terms “first” and “second” with respect to Fc regions etc., are used for convenience of distinguishing when there is more than one of each type of moiety. Use of these terms is not intended to confer a specific order or orientation in the protein unless explicitly so stated. For example, an antibody described herein (e.g., in the case of a full-length antibody) may contain two Fc regions that associate e.g., via one or more covalent (e.g., disulfide) bond.

[0130] As used herein, the term “framework region” or “FR region” refers to the amino acid residues that are part of the variable region of an antibody, but are not part of the CDRs (e.g., using the Kabat definition of CDRs).

[0131] As used herein, the term “full-length antibody” includes antibodies having a structure substantially similar to a native antibody structure (i) a first Ig light chain comprising from N- to C-terminus a light chain variable region (VL) region and a light chain constant region (CL) region; (ii) a first Ig heavy chain comprising from N- to C-terminus a heavy chain variable region (VH) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a second Ig heavy chain comprising from N- to C-terminus a VH region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iv) a second Ig light chain comprising from N- to C-terminus a VL region and a VH region; wherein said first light chain and said first heavy chain associate to form a first antigen binding domain; wherein said second light chain and said second heavy chain associate to form a second antigen binding domain; and wherein said first heavy chain and said second heavy chain associate to form a dimer. In some embodiments, the structure of the full-length antibody is modified (e.g., comprises a modified Fab (e.g., a modified Fab described herein)). For example, the VH and VL regions may be swapped in one of the antigen binding domains of the full-length antibody. In such embodiments, the full length antibody would comprise (i) a first Ig light chain comprising from N- to C-terminus a VH region and a CL region; (ii) a first Ig heavy chain comprising from N- to C-terminus a VL region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iii) a second Ig heavy chain comprising from N- to C-terminus a VH region, a CHI region, a hinge region, a CH2 region, and a CH3 region; (iv) a second Ig light chain comprising from N- to C-terminus a VL region and a VH region; wherein said first light chain and said first heavy chain associate to form a first antigen binding domain; wherein said second light chain and said second heavy chain associate to form a second antigen binding domain; and wherein said first heavy chain and said second heavy chain associate to form a dimer. Antibody chains can differ based on sequence and also differ due to e.g., post-translational modifications, such as C-terminal cleavage of lysine residues, alternative glycosylation patterns, etc.

[0132] The term “functional variant” as used herein in reference to a protein refers to a protein that comprises at least one but no more than 20%, not more than 15%, not more than 12%, no more than 10%, no more than 8% amino acid variation (e.g., substitution, deletion, addition) compared to the amino acid sequence of a reference protein, wherein the protein retains at least one particular function of the reference protein. Not all functions of the reference protein e.g., wild type) need be retained by the functional variant of the protein. In some instances, one or more functions are selectively reduced or eliminated. In some embodiments, the reference protein is a wild typeprotein.

[0133] The term “functional fragment” as used herein in reference to a protein refers to a fragment of a reference protein that retains at least one particular function. Not all functions of the reference polypeptide or protein need be retained by a functional fragment of the protein. In some instances, one or more functions are selectively reduced or eliminated. In some embodiments, the reference protein is a wild type protein.

[0134] As used herein, the term “fuse” and grammatical equivalents thereof refer to the operable connection of at least a first polypeptide to a second polypeptide. In some embodiments, the first and second polypeptides are different. The term fuse encompasses both a direct connection of the at least two polypeptides through a peptide bond, and the indirect connection through a linker (e.g., a peptide linker).

[0135] As used herein, the term “fusion protein” and grammatical equivalents thereof refers to a protein that comprises a first polypeptide fused to a second polypeptide, wherein the first and second polypeptides are not found operably connected in nature. In some embodiments, the first and second polypeptides are different. The at least two polypeptides of the fusion protein can be directly operably connected through a peptide bond; or can be indirectly operably connected through a linker (e.g., a peptide linker). Therefore, for example, the term fusion protein encompasses embodiments, wherein Polypeptide A is directly operably connected to Polypeptide B through a peptide bond (Polypeptide A - Polypeptide B), and embodiments, wherein Polypeptide A is operably connected to Polypeptide B through a peptide linker (Polypeptide A - peptide linker - Polypeptide B).

[0136] As used herein, the term “heterologous,” when used to describe a first element in reference to a second element means that the first element and second element do not exist in nature disposed as described. For example, a nucleic acid molecule comprising a “heterologous moiety” means a nucleic acid molecule that is joined to a moiety (e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that is not joined to the nucleic acid molecule in nature.

[0137] The terms “hinge” or “hinge region” are used interchangeably herein and refer to the hinge region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl hinge region is set forth in SEQ ID NO: 38.

[0138] As used herein, the term “isolated” with reference to an agent (e.g., a protein, nucleicacid molecule, etc.) refers to an agent (e.g., a protein, nucleic acid molecule, etc.) that is substantially free of other cellular components with which it is associated in the natural state.

[0139] As used herein, the term “modified nucleotide,” “nucleotide modification,” or use of the term “modification” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleotide comprising a chemical modification, e.g., a modified sugar moiety, a modified nucleobase, and / or a modified internucleoside linkage, or any combination thereof. Exemplary modifications are provided herein, see, e.g., § 5.7. In certain embodiments of the instant disclosure, inclusion of a deoxynucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within an RNA oligonucleotide is considered to constitute a modified nucleotide.

[0140] The terms “nucleic acid molecule,” “polynucleotide,” and “oligonucleotide” are used interchangeably herein and refer to a polymer of DNA or RNA. The nucleic acid molecule can be single- stranded or double-stranded; contain natural, non-natural, or altered nucleotides; and contain a natural, non-natural, or altered internucleoside linkage, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule. Nucleic acid molecules include, but are not limited to, all nucleic acid molecules which are obtained by any means available in the art, including, without limitation, recombinant means, e.g., the cloning of nucleic acid molecules from a recombinant library or a cell genome, using ordinary cloning technology and polymerase chain reaction, and the like, and by synthetic means. The skilled artisan will appreciate that, except where otherwise noted, nucleic acid sequences set forth in the instant application will recite thymidine (T) in a representative DNA sequence but where the sequence represents RNA (e.g., mRNA), the thymidines (Ts) would be substituted for uracils (Us). Thus, any of the RNA polynucleotides encoded by a DNA identified by a particular sequence identification number may also comprise the corresponding RNA (e.g., mRNA) sequence encoded by the DNA, where each thymidine (T) of the DNA sequence is substituted with uracil (U).

[0141] As used herein, the term “operably connected” refers to the linkage of two agents in a functional relationship. For example, a polypeptide is operably connected to another polypeptide when they are linked (either directly or indirectly via a peptide linker) in frame such that both polypeptides are functional (e.g., a fusion protein described herein). Or for example, a transcription regulatory polynucleotide e.g., a promoter, enhancer, or other expression control element isoperably linked to a polynucleotide that encodes a protein if it affects the transcription of the polynucleotide that encodes the protein. The term “operably connected” also refers for example to the conjugation of a first agent (e.g., a protein (e.g., an antibody)) to a second agent (e.g., an oligonucleotide) wherein the first and second agent are both capable of mediating their function.

[0142] The determination of “percent identity” between two sequences (e.g., protein (amino acid sequences) or oligonucleotide (nucleic acid sequences)) can be accomplished using a mathematical algorithm. Determinations of identity (as described herein) are independent of nucleotide chemical modifications (e.g., as described herein). For example, (mC) is identical to (C) for the purposes of determining identity. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, which is herein incorporated by reference in its entirety. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similarto those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches arc counted.

[0143] As used herein, the term “pharmaceutical composition” means a composition that is suitable for administration to an animal, e.g., a human subject, and comprises a therapeutic agent (e.g., a conjugate described herein) and a pharmaceutically acceptable carrier or diluent. A “pharmaceutically acceptable carrier or diluent” means a substance intended for use in contact with the tissues of human beings and / or non-human animals, and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable therapeutic benefit / risk ratio.

[0144] As used herein, the term “plurality” means 2 or more (e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 9 or more, or 10 or more).

[0145] As used herein, the terms “protein”, “polypeptide”, and peptide refers to a polymer of at least 2 (e.g., at least 5) amino acids linked by a peptide bond. The term “polypeptide” does not denote a specific length of the polymer chain of amino acids. It is common in the art to refer to shorter polymers of amino acids (e.g., approximately 2-50 amino acids) as peptides; and to refer to longer polymers of amino acids (e.g., approximately over 50 amino acids) as polypeptides. However, the terms “peptide” and “polypeptide” and “protein” are used interchangeably herein. In some embodiments, the protein is folded into its three-dimensional structure. Where polypeptides (e.g., in a linear (i.e., primary) structure are contemplated herein, it should be understood that proteins folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein and vice versa. Proteins include e.g., naturally occurring proteins, variant (e.g., functional valiants) of naturally occurring proteins, fragments (e.g., functional fragments) of naturally occurring proteins, and synthetic proteins (i.e., not naturally occurring proteins).

[0146] The terms “RNA” and “polyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple ribonucleotides that are polymerized via phosphodiester bonds. Ribonucleotides are nucleotides in which the sugar is ribose. RNA may contain modified nucleotides; and contain natural, non-natural, or altered intemucleoside linkages, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule.

[0147] As used herein, the term “specifically binds” refers to preferential interaction, i.e.,significantly higher binding affinity, between a first protein (e.g., an antibody) and a second protein (e.g., an antigen) relative to other amino acid sequences. Herein, when a first protein is said to “specifically bind” to a second protein, it is understood that the first protein specifically binds to an epitope of the second protein. The term “epitope” refers to the portion of the second protein that the first protein specifically recognizes. The term specifically binds includes molecules that are cross-reactive with the same epitope of a different species. For example, an antibody that specifically binds human CD163 may be cross reactive with CD163 of another species (e.g., cynomolgus, murine, etc.), and still be considered herein to specifically bind human CD163. A protein can specifically bind more than one different protein. Specific binding can be measured, e.g., through measuring binding affinity e.g., using standard methods known in the art and described herein (e.g., surface plasmon resonance (SPR) (e.g., BIAcore®-based assay), a common method known in the art (see, e.g., Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 55:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, the full contents of each of which are incorporated by reference herein for all purposes).

[0148] As used herein, the term “subject” includes any animal, such as a human or other animal. In some embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In some embodiments, the subject is a human. In some embodiments, the method subject is a non-human mammal. In some embodiments, the subject is a non-human mammal is such as a non-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse), or lagomorph (e.g., rabbit). In some embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus), Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots).

[0149] As used herein, the term “therapeutic agent” refers to an agent capable of achieving a desired therapeutic result in a subject or ex vivo (e.g., capable of treating a disease as defined herein) when administered at a therapeutically effective amount.

[0150] As used herein, the term “therapeutically effective amount” of a therapeutic agent refers to any amount of the therapeutic agent that, when used alone or in combination with another therapeutic agent, improves a disease condition, e.g., protects a subject against the onset of a disease (or infection); improves a symptom of disease or infection, e.g., decreases severity ofdisease or infection symptoms, decreases frequency or duration of disease or infection symptoms, increases disease or infection symptom- free periods; prevents or reduces impairment or disability due to the disease or infection; or promotes disease (or infection) regression. The ability of a therapeutic agent to improve a disease condition can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0151] As used herein, the term “translatable RNA” refers to any RNA that encodes at least one peptide or protein and can be translated to produce the encoded peptide or protein in vitro, in vitro, in situ or ex vivo. This includes, e.g., messenger RNA (mRNA).

[0152] As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disease and / or symptom(s) associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disease does not require that the disease, or symptom(s) associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of e.g., a conjugate described herein (or a carrier, pharmaceutical composition, etc. comprising the same).

[0153] As used herein, the term “tumor macrophage hybrid cell” or “TMHC” refers to a cell that simultaneously expresses at least one molecule (e.g., protein) predominantly expressed on the surface of epithelial cells i.e., an epithelial cell surface marker) and at least one molecule (e.g., protein) predominantly expressed on the surface of macrophages (i.e., a macrophage cell surface marker). In some preferred embodiments, the tumor macrophage hybrid cell expresses CD 163 (macrophage cell surface marker) and EpCAM (epithelial cell surface marker). Various subtypes of tumor macrophage hybrid cells exist. For example, “cancer-associated macrophage-like cells” or “CAMLs” are a subtype of TMHCs that are generally characterized as being e.g., multinucleated, relatively larger (e.g., a diameter of approximately > 25 pm), containing cytoplasmic structure, and expressing CD14. Another TMHC subtype is the “circulating hybrid cell” or “CHC”. CHCs are generally characterized as being, e.g., relatively smaller (e.g., a diameterof about 5-20 pm) round cells, with 1-2 nuclei. See, e.g., Sutton TL, Patel RK, Anderson AN, et al. Circulating Cells with Macrophagc-likc Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer. Cancers (Basel). 2022;14(16):3871. Published 2022 Aug 11. doi:10.3390 / cancersl4163871, the entire contents of which are incorporated herein by reference for all purposes. In some embodiments, the TMHC is a CHC. In some embodiments, the TMHC is a CHC that expresses CD163 and EpCAM. In some embodiments, the TMHC is a CAML. In some embodiments, the TMHC is a CAML that expresses CD 163 and EpCAM. In some embodiments, the TMHC is a CHC. In some embodiments, the TMHC is not characterized as a CHC or CAML. In some embodiments, the TMHC is not characterized as a CHC or CAML and expresses CD163 and EpCAM.

[0154] As used herein, the term “variation” or “variant” or use the like in reference to a nucleotide or nucleic acid sequence refers to a nucleic acid molecule that comprises at least one substitution, addition, or deletion of one or more nucleotide compared to a reference nucleic acid molecule. Likewise, as used herein, the term “variation” or “variant” or use the like with reference to a peptide or protein refers to a peptide or protein that comprises at least one substitution, addition, or deletion of an amino acid residue compared to a reference peptide or protein.

[0155] A “variation that promotes heterodimerization of a first Fc region and a second Fc region” (or similar phrasing) is a manipulation of the peptide backbone or the post-translational modifications of an Fc region that reduces or prevents the association of a polypeptide comprising the Fc region with an identical polypeptide to form a homodimer. A modification promoting association as used herein particularly includes separate modifications made to each of the two Fc regions desired to associate (i.e., a first Fc region and a second Fc region), wherein the modifications are complementary to each other so as to promote association of the two Fc regions. For example, a modification promoting association may alter the structure or charge of one or both of the Fc regions so as to make their association sterically or electrostatically favorable, respectively. Thus, heterodimerization occurs between a polypeptide comprising the first Fc region and a polypeptide comprising the second Fc region, which might be non-identical in the sense that further components fused to each of the Fc regions (e.g., antigen binding domains) are not the same. In some embodiments the modification promoting association comprises an amino acid mutation in the Fc region, specifically an amino acid substitution. In a particular embodiment, the modification promoting association comprises a separate amino acid mutation, specifically one ormore amino acid substitution, in each of the first Fc region and the second Fc region. See, e.g., § 5.2.5.

[0156] As used herein, the term “variable region” refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In particular embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0157] The terms “VL” and “VL region” are used interchangeably to refer to an immunoglobulin light chain variable region. A VL region can be incorporated into an antibody, e.g., a scFv, a Fab, a full-length antibody. For example, a scFv comprises a VL region operably connected via a peptide linker to a VH region. Throughout the instant disclosure the term “VL” followed by “-antigen” is used to indicate a VL that when paired with a corresponding VH binds the specific antigen. For example, the term “VL-EpCAM” indicates a VL region that when paired with a corresponding VH region forms an antigen binding domain that specifically binds EpCAM.

[0158] The terms “VH” and “VH region” are used interchangeably to refer to an immunoglobulin heavy chain variable region. A VH region can be incorporated into an antibody, e.g., a scFv, a Fab, a full-length antibody. For example, a scFv comprises a VH region operably connected via a peptide linker to a VL region. Throughout the instant disclosure the term “VH” followed by “-antigen” is used to indicate a VH that when paired with a corresponding VL binds the specific antigen. For example, the term “VH-EpCAM” indicates a VH region that when paired with a corresponding VL region forms an antigen binding domain that specifically binds EpCAM.5.2 Multispecific Proteins

[0159] Provided herein are, inter alia, multispecific proteins, useful in, inter alia, selectively targeting, depleting, killing, etc. cells that express both EpCAM and CD163 on the surface. In some embodiments, the multispecific proteins described herein comprise at least two antigen binding domains, one that mediates specific binding to EpCAM and one that mediates specific (e.g., and simultaneous) binding to CD 163.

[0160] In some embodiments, the multispecific protein comprises a single an antigen binding domain that specifically binds EpCAM. In some embodiments, the multispecific protein the protein comprises a plurality (i.e., 2 or more) antigen binding domains that specifically bind EpCAM. In some embodiments, the multispecific protein comprises at least 2 antigen binding domains that specifically binds EpCAM. In some embodiments, the multispecific protein comprises a single an antigen binding domain that specifically binds EpCAM; and at least 2 (e.g., 2) antigen binding domains that specifically bind CD 163.

[0161] In some embodiments, the multispecific protein comprises a single an antigen binding domain that specifically binds CD163. In some embodiments, the multispecific protein comprises a plurality of antigen binding domains that specifically bind CD 163. In some embodiments, the multispecific protein the protein comprises at least 2 antigen binding domains that specifically bind CD 163. In some embodiments, the multispecific protein comprises a single antigen binding domain that specifically binds CD163; and at least 2 (e.g., 2) antigen binding domains that specifically bind EpCAM.

[0162] In some embodiments, the multispecific protein comprises a single an antigen binding domain that specifically binds EpCAM and a single an antigen binding domain that specifically binds CD 163.

[0163] In some embodiments, the multispecific protein is bivalent. In some embodiments, the multispecific protein is trivalent. In some embodiments, the multispecific protein is tetravalent. In some preferred embodiments, the multispecific protein is bispecific. In some embodiments, the multispecific protein is trispecific. In some embodiments, the multispecific protein is tetraspecific. In some embodiments, the multispecific protein is bivalent and bispecific. In some embodiments, the multispecific protein is trivalent and bispecific.

[0164] In some embodiments, the multispecific protein is a bivalent bispecific protein that comprises a single an antigen binding domain that specifically binds EpCAM and a single an antigen binding domain that specifically binds CD 163.5.2.1 EpCAM Binding Domains

[0165] Epithelial cell adhesion molecule (EpCAM) is a cell surface type 1 transmembrane glycoprotein expressed by epithelial cells. EpCAM is known to function in, e.g., mediating Camindependent homotypic cell-cell adhesion in epithelia. EpCAM plays a role in, inter alia, cell signaling, migration, proliferation, and differentiation. The amino acid sequence of a reference mature human EpCAM (hEpCAM) protein is set forth in SEQ ID NO: 1. The amino acid sequence of a reference immature human hEpCAM protein is set forth in SEQ ID NO: 2. See Table 1, herein.Table 1. The Amino Acid Sequence of a Reference hEpCAM Protein.

[0166] The EpCAM binding domain can be any suitable format. For example, a Fab, Fab', F(ab')2, scFv, Fv, a single domain antibody (sdAb) (e.g., a VHH), or a (sdAb)2 (e.g., a (VHH ). In some embodiments, the EpCAM binding domain comprises a Fab. In some embodiments, the EpCAM binding domain comprises a F(ab')2. In some embodiments, the EpCAM binding domain comprises a scFv. In some embodiments, the EpCAM binding domain comprises a sdAb.

[0167] Exemplary antibody based binding domains that specifically bind hEpCAM include those described in, e.g., US7803618, US20050180979, and US8337843B2, the entire contents of each of which is incorporated herein by reference for all purposes.

[0168] The amino acid sequence of exemplary EpCAM binding domains that can be utilized in the multispecific proteins described herein is provided in Table 2. The CDRs set forth in Table 2, are denoted according to Kabat. A person of ordi nary skill in the art would be able to determine the CDRs as defined by another scheme, e.g., Chothia, IMGT, using ordinary methods known inthe art.Table 2. The Amino Acid Sequence of Exemplary EpCAM Binding Domains.

[0169] In some embodiments, the EpCAM binding domain comprises an EpCAM binding domain provided in Table 2.

[0170] In some embodiments, the EpCAM binding domain comprises a VH that comprises: CDR-H1, CDR-H2, and CDR-H3; and a VL that comprises: CDR-L1, CDR-L2, and CDR-L3.

[0171] In some embodiments, the CD 163 binding domain comprises a VH that comprises: a CDR-H1, a CDR-H2, and a CDR-H3 set forth in Table 2; and VL comprises CDR-L1, a CDR-L2, and a CDR-L3 set forth in Table 2.

[0172] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence of a CDR-H2 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H3 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0173] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence of a CDR-H1 set forth in Table 2, or the amino acid sequence of a CDR- H1 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence of a CDR-H2 set forth in Table 2, or the amino acid sequence of a CDR-H2 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g.,substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence of a CDR-H3 set forth in Table 2, or the amino acid sequence of a CDR-H3 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e. ., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence of a CDR-L1 set forth in Table 2, or the amino acid sequence CDR1 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence of a CDR-L2 set forth in Table 2, or the amino acid sequence of a CDR-L2 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence of a CDR-L3 set forth in Table 2, or the amino acid sequence of a CDR-L3 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0174] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 of a VH set forth in Table 2, or the amino acid sequence of a CDR- H2 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 of a VH set forth in Table 2, or the amino acid sequence of a CDR- H3 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g.,substitution, deletion, addition, etc.).

[0175] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 set forth in Table 2, or the amino acid sequence of a CDR-H1 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR- H2 set forth in Table 2, or the amino acid sequence of a CDR-H2 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 set forth in Table 2, or the amino acid sequence of a CDR-H3 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 set forth in Table 2, or the amino acid sequence CDR1 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 set forth in Table 2, or the amino acid sequence of a CDR-L2 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 set forth in Table 2, or the amino acid sequence of a CDR-L3 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0176] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR- H2 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H3 of a VH set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L2 of a VL set forth in Tabic 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0177] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 set forth in Table 2, or the amino acid sequence of a CDR-H1 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 set forth in Table 2, or the amino acid sequence of a CDR-H2 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 set forth in Table 2, or the amino acid sequence of a CDR-H3 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 set forth in Table 2, or the amino acid sequence CDR1 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 set forth in Table 2, or the amino acid sequence of a CDR-L2 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 set forth in Table 2, or the amino acid sequence of a CDR-L3 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0178] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 of a VH set forth in Table 2; the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 of a VH set forth in Table 2; the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 of a VH set forth in Table 2; the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 of a VL set forth in Table 2; the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 of a VL set forth in Table 2; and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 of a VL set forth in Table 2.

[0179] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 set forth in Tabic 2; the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 set forth in Table 2; the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 set forth in Table 2; the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 set forth in Table 2; the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 set forth in Table 2; and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 set forth in Table 2.

[0180] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 of a VH set forth in Table 2, or the amino acid sequence of a CDR- H2 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 2, or the amino acid sequence of a CDR- H3 of a VH set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0181] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 set forth in Table 2, or the amino acid sequence of a CDR-H1 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 set forth in Table 2, or the amino acid sequence of a CDR-H2 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 set forth in Table 2, or the amino acid sequence of a CDR-H3 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 set forth in Table 2, or the amino acid sequence CDR1 of a VL set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 set forth in Table 2, or the amino acid sequence of a CDR-L2 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 set forth in Table 2, or the amino acid sequence of a CDR-L3 set forth in Table 2 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0182] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR- H2 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 2, or the amino acid sequence of a CDR-H3 of a VH set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L2 consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 2, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations(e.g., substitution, deletion, addition, etc.).

[0183] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 set forth in Table 2, or the amino acid sequence of a CDR-H1 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 set forth in Table 2, or the amino acid sequence of a CDR-H2 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- H3 consists of the amino acid sequence of a CDR-H3 set forth in Table 2, or the amino acid sequence of a CDR-H3 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 set forth in Table 2, or the amino acid sequence CDR1 of a VL set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 set forth in Table 2, or the amino acid sequence of a CDR-L2 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 set forth in Table 2, or the amino acid sequence of a CDR-L3 set forth in Table 2 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0184] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 2; the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 of a VH set forth in Table 2; the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 2; the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 2; the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 2; and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 2.

[0185] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 set forth in Table 2; the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 set forth in Table 2; the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 set forth in Table 2; the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 set forth in Table 2; the amino acidsequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 set forth in Table 2; and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 set forth in Table 2.

[0186] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 2. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 2.

[0187] In some embodiments, the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%,89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 2.

[0188] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2.

[0189] In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 2.

[0190] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acidsequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 2. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 2; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 2.

[0191] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0192] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion,addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0193] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0194] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acidsequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0195] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 5; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 6; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 7; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 8; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 9; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10.

[0196] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1consists of the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0197] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0198] In some embodiments, the amino acid sequence of CDR-HI consists of the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence setforth in SEQ ID NO: 7 consisting of 1 , 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0199] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 5; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 6; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 7; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 8; the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 9; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10.

[0200] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11 . In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0201] In some embodiments, the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 12.

[0202] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In someembodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 12.

[0203] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion,addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0204] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L1 comprises the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0205] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 14,or the amino acid sequence set forth in SEQ ID NO: 14 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0206] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0207] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 13; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 14; the amino acid sequence of CDR-H3 comprises theamino acid sequence set forth in SEQ ID NO: 15; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 16; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 17; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0208] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 comprising or consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L1 consists of the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0209] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 comprising 1, 2, or 3amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0210] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0211] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 13; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 14; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 15; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 16; the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 17; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0212] In some embodiments, the amino acid sequence of the VH comprises or consists of anamino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19.

[0213] In some embodiments, the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20.In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 20.

[0214] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20. In someembodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 20.

[0215] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, or the amino acid sequence set forth in SEQ ID NO: 31 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 33, or the amino acid sequence set forth in SEQ ID NO: 33 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO: 34 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0216] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 31, or the amino acid sequence set forth in SEQ ID NO: 31 comprising or consisting of 1, 2, or 3 aminoacid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L1 comprises the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 33, or the amino acid sequence set forth in SEQ ID NO:33 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO: 34 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0217] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 31, or the amino acid sequence set forth in SEQ ID NO: 31 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 33, or the amino acid sequence set forth in SEQ ID NO: 33 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO:34 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0218] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3comprises the amino acid sequence set forth in SEQ TD NO: 31 , or the amino acid sequence set forth in SEQ ID NO: 31 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 33, or the amino acid sequence set forth in SEQ ID NO: 33 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO: 34 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.).

[0219] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 29; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 30; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 31; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 32; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 33; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 34.

[0220] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 31, or the amino acid sequence set forth in SEQ ID NO: 31 comprising or consisting of 1 , 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L1 consists of the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 33, or the amino acid sequence set forth in SEQ ID NO: 33 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion,addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO: 34 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0221] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 31, or the amino acid sequence set forth in SEQ ID NO: 31 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 33, or the amino acid sequence set forth in SEQ ID NO: 33 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO: 34 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0222] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 29, or the amino acid sequence set forth in SEQ ID NO: 29 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 30, or the amino acid sequence set forth in SEQ ID NO: 30 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 31, or the amino acid sequence set forth in SEQ ID NO: 31 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 32, or the amino acid sequence set forth in SEQ ID NO: 32 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 33, or the aminoacid sequence set forth in SEQ ID NO: 33 consisting of 1 , 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 34, or the amino acid sequence set forth in SEQ ID NO: 34 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0223] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 29; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 30; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 31; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 32; the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 33; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 34.

[0224] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 35.

[0225] In some embodiments, the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ TD NO: 36. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 36.

[0226] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acidsequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 36.5.2.2 CD163 Binding Domains

[0227] Scavenger receptor cysteine-rich type 1 protein M130 (referred to herein as CD163) is a cell surface glycoprotein expressed by cells of the monocyte / macrophage lineage. CD163 is a member of the scavenger receptor cysteine-rich (SRCR) superfamily class B. CD 163 is known to function as, e.g., the high affinity scavenger receptor for the hemoglobin-haptoglobin complex and in the absence of haptoglobin - with lower affinity - for hemoglobin alone. The amino acid sequence of a reference mature human CD163 (hCD163) protein is set forth in SEQ ID NO: 3. The amino acid sequence of a reference immature hCD163 protein is set forth in SEQ ID NO: 4. See Table 3, herein.Table 3. The Amino Acid Sequence of a Reference hCD163 Protein.

[0228] Exemplary antibody based binding domains that specifically bind hCD163 include those described in, e.g., US11827715B2, the entire contents of which are incorporated herein by reference for all purposes.

[0229] The amino acid sequence of exemplary CD163 binding domains that can be utilized in the multispccific proteins described herein is provided in Table 4. The CDRs set forth in Table 4, are denoted according to Kabat. A person of ordinary skill in the ait would be able to determine the CDRs as defined by another scheme, e.g., Chothia, IMGT, using ordinary methods known in the art.Table 4. The Amino Acid Sequence of Exemplary CD163 Binding Domains.

[0230] In some embodiments, the CD 163 binding domain comprises a CD 163 binding domain provided in Table 4.

[0231] In some embodiments, the CD 163 binding domain comprises a VH that comprises: a CDR-H1, a CDR-H2, and a CDR-H3; and VL comprises CDR-L1, a CDR-L2, and a CDR-L3.

[0232] In some embodiments, the CD 163 binding domain comprises a VH that comprises: a CDR-H1, a CDR-H2, and a CDR-H3 set forth in Table 4; and VL comprises CDR-L1, a CDR-L2, and a CDR-L3 set forth in Table 4.

[0233] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence of a CDR-H2 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 4, or theamino acid sequence of a CDR-H3 of a VH set forth in Table 4 comprising or consisting of 1 , 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0234] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists of the amino acid sequence of a CDR-H1 set forth in Table 4, or the amino acid sequence of a CDR- H1 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence of a CDR-H2 set forth in Table 4, or the amino acid sequence of a CDR-H2 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence of a CDR-H3 set forth in Table 4, or the amino acid sequence of a CDR-H3 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence of a CDR-L1 set forth in Table 4, or the amino acid sequence CDR1 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence of a CDR-L2 set forth in Table 4, or the amino acid sequence of a CDR-L2 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence of a CDR-L3 set forth in Table 4, or the amino acid sequence of a CDR-L3 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0235] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 of a VH set forth in Table 4, or the amino acid sequence of a CDR- H2 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 of a VH set forth in Table 4, or the amino acid sequence of a CDR- H3 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0236] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 set forth in Table 4, or the amino acid sequence of a CDR-H1 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR- H2 set forth in Table 4, or the amino acid sequence of a CDR-H2 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 set forth in Table 4, or the amino acid sequence of a CDR-H3 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 set forth in Table 4, or the amino acid sequence CDR1 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2comprises the amino acid sequence of a CDR-L2 set forth in Table 4, or the amino acid sequence of a CDR-L2 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 set forth in Table 4, or the amino acid sequence of a CDR-L3 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0237] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR- H2 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H3 of a VH set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L2 comprises the amino acid sequence of a CDR-L2 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0238] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 set forth in Table 4, or the amino acid sequence of a CDR-H1 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 set forth in Table 4, or the amino acid sequence of a CDR-H2 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 set forth in Table 4, or the amino acid sequenceof a CDR-H3 set forth in Table 4 consisting of 1 , 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 set forth in Table 4, or the amino acid sequence CDR1 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 set forth in Table 4, or the amino acid sequence of a CDR-L2 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 set forth in Table 4, or the amino acid sequence of a CDR-L3 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0239] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 of a VH set forth in Table 4; the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 of a VH set forth in Table 4; the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 of a VH set forth in Table 4; the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 of a VL set forth in Table 4; the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 of a VL set forth in Table 4; and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 of a VL set forth in Table 4.

[0240] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence of a CDR-H1 set forth in Table 4; the amino acid sequence of CDR-H2 comprises the amino acid sequence of a CDR-H2 set forth in Table 4; the amino acid sequence of CDR-H3 comprises the amino acid sequence of a CDR-H3 set forth in Table 4; the amino acid sequence of CDR-L1 comprises the amino acid sequence of a CDR-L1 set forth in Table 4; the amino acid sequence of CDR-L2 comprises the amino acid sequence of a CDR-L2 set forth in Table 4; and the amino acid sequence of CDR-L3 comprises the amino acid sequence of a CDR-L3 set forth in Table 4.

[0241] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 4 comprising or consisting of 1 , 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 4, or the amino acid sequence of a CDR- H3 of a VH set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0242] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 set forth in Table 4, or the amino acid sequence of a CDR-H1 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR- H2 set forth in Table 4, or the amino acid sequence of a CDR-H2 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 set forth in Table 4, or the amino acid sequence of a CDR-H3 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 set forth in Table 4, or the amino acid sequence CDR1 of a VL set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 set forth in Table 4, or the amino acid sequence of a CDR-L2 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 set forth in Table 4, or the amino acid sequence of a CDR-L3 set forth in Table 4 comprising or consisting of 1, 2, or 3 amino acid variations (e.g., substitution,deletion, addition, etc.).

[0243] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H1 of a VH set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR- H2 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H2 of a VH set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 4, or the amino acid sequence of a CDR-H3 of a VH set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L1 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L2 consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L2 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 4, or the amino acid sequence of a CDR-L3 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0244] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 set forth in Table 4, or the amino acid sequence of a CDR-H1 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 set forth in Table 4, or the amino acid sequence of a CDR-H2 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- H3 consists of the amino acid sequence of a CDR-H3 set forth in Table 4, or the amino acid sequence of a CDR-H3 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 set forth in Table 4, or the amino acid sequence CDR1 of a VL set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 setforth in Table 4, or the amino acid sequence of a CDR-L2 set forth in Table 4 consisting of 1 , 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 set forth in Table 4, or the amino acid sequence of a CDR-L3 set forth in Table 4 consisting of 1, 2, or 3 amino acid variations (e.g., substitution, deletion, addition, etc.).

[0245] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 of a VH set forth in Table 4; the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 of a VH set forth in Table 4; the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 of a VH set forth in Table 4; the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 of a VL set forth in Table 4; the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 of a VL set forth in Table 4; and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 of a VL set forth in Table 4.

[0246] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence of a CDR-H1 set forth in Table 4; the amino acid sequence of CDR-H2 consists of the amino acid sequence of a CDR-H2 set forth in Table 4; the amino acid sequence of CDR-H3 consists of the amino acid sequence of a CDR-H3 set forth in Table 4; the amino acid sequence of CDR-L1 consists of the amino acid sequence of a CDR-L1 set forth in Table 4; the amino acid sequence of CDR-L2 consists of the amino acid sequence of a CDR-L2 set forth in Table 4; and the amino acid sequence of CDR-L3 consists of the amino acid sequence of a CDR-L3 set forth in Table 4.

[0247] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 4. In someembodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 4.

[0248] In some embodiments, the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 4.

[0249] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4.

[0250] In some embodiments, the amino acid sequence of the VH comprises an amino acidsequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 4.

[0251] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a VL set forth in Table 4. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence of a VH set forth in Table 4; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence of a VL set forth in Table 4.

[0252] In some embodiments, the CD 163 binding domain comprises a VH that comprises: a CDR-H1, a CDR-H2, and a CDR-H3; and VL that comprises CDR-L1, a CDR-L2, and a CDR- L3.

[0253] In some embodiments, the amino acid sequence of CDR-H1 comprises or consists ofthe amino acid sequence set forth in SEQ ID NO: 21 , or the amino acid sequence set forth in SEQ ID NO: 21 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0254] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L1 comprises the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO:25 comprising or consisting of 1 , 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0255] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO:26 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0256] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acidsequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0257] In some embodiments, the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0258] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR- L1 consists of the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 comprising or consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0259] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21comprising 1 , 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 comprising 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0260] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0261] In some embodiments, the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0262] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

[0263] In some embodiments, the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0264] In some embodiments, the amino acid sequence of the VH comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identicalto the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.5.2.3 Exemplary Combinations of CD163 and EpCAM Binding Domains

[0265] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the aminoacid sequence set forth in SEQ TD NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and (ii) an antigen binding domain that specifically binds CD 163 that comprises VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (a CD 163 binding domain), wherein the amino acid sequence of CDR- H1 comprises the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0266] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 13; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 14; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 15; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 16; the amino acid sequence of CDR- L2 comprises the amino acid sequence set forth in SEQ ID NO: 17; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18; and (ii) an antigenbinding domain that specifically binds CD163 that comprises VH region that comprises a CDR- Hl, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (a CD163 binding domain), wherein the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23; the amino acid sequence of CDR- L1 comprises the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0267] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 13, or the amino acid sequence set forth in SEQ ID NO: 13 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 14, or the amino acid sequence set forth in SEQ ID NO: 14 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 15, or the amino acid sequence set forth in SEQ ID NO: 15 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 16, or the amino acid sequence set forth in SEQ ID NO: 16 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 17, or the amino acid sequence set forth in SEQ ID NO: 17 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 18, or the amino acid sequence set forth in SEQ ID NO: 18 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.) ; and (ii) an antigen binding domain that specifically binds CD163 that comprises VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR- Ll, a CDR-L2, and a CDR-L3 (a CD163 binding domain), wherein the amino acid sequence ofCDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0268] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 13; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 14; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 15; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 16; the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 17; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 18; and (ii) an antigen binding domain that specifically binds CD 163 that comprises VH region that comprises a CDR- Hl, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (a CD 163 binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22; the amino acid sequence of CDR-H3 consistsof the amino acid sequence set forth in SEQ ID NO: 23; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of CDR- L2 consists of the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0269] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0270] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0271] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0272] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0273] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequenceat least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0274] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0275] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and (ii) an antigen binding domain that specifically binds CD 163 that comprises VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, aCDR-L2, and a CDR-L3 (a CD 163 binding domain), wherein the amino acid sequence of CDR- H1 comprises the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO: 22 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0276] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 5; the amino acid sequence of CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 6; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 7; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 8; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 9; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10; and (ii) an antigen binding domain that specifically binds CD 163 that comprises VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (a CD 163 binding domain), wherein the amino acid sequence of CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of CDR-H2 comprises the amino acidsequence set forth in SEQ ID NO: 22; the amino acid sequence of CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 23; the amino acid sequence of CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0277] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 5, or the amino acid sequence set forth in SEQ ID NO: 5 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 6, or the amino acid sequence set forth in SEQ ID NO: 6 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 7, or the amino acid sequence set forth in SEQ ID NO: 7 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 8, or the amino acid sequence set forth in SEQ ID NO: 8 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 9, or the amino acid sequence set forth in SEQ ID NO: 9 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 10, or the amino acid sequence set forth in SEQ ID NO: 10 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.) ; and (ii) an antigen binding domain that specifically binds CD163 that comprises VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR- Ll, a CDR-L2, and a CDR-L3 (a CD 163 binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21, or the amino acid sequence set forth in SEQ ID NO: 21 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22, or the amino acid sequence set forth in SEQ ID NO:22 consisting of 1 , 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23, or the amino acid sequence set forth in SEQ ID NO: 23 consisting of 1, 2, or 3 amino acid modifications e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24, or the amino acid sequence set forth in SEQ ID NO: 24 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 25, or the amino acid sequence set forth in SEQ ID NO: 25 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.); and the amino acid sequence of CDR-L3 consists of the amino acid sequence set forth in SEQ ID NO: 26, or the amino acid sequence set forth in SEQ ID NO: 26 consisting of 1, 2, or 3 amino acid modifications (e.g., substitution, deletion, addition, etc.).

[0278] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region that comprises a CDR-H1, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (an EpCAM binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 5; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 6; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 7; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 8; the amino acid sequence of CDR-L2 consists of the amino acid sequence set forth in SEQ ID NO: 9; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 10; and (ii) an antigen binding domain that specifically binds CD 163 that comprises VH region that comprises a CDR- Hl, a CDR-H2, and a CDR-H3; and a VL region that comprises a CDR-L1, a CDR-L2, and a CDR-L3 (a CD 163 binding domain), wherein the amino acid sequence of CDR-H1 consists of the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of CDR-H2 consists of the amino acid sequence set forth in SEQ ID NO: 22; the amino acid sequence of CDR-H3 consists of the amino acid sequence set forth in SEQ ID NO: 23; the amino acid sequence of CDR-L1 consists of the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of CDR- L2 consists of the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 26.

[0279] In some embodiments, the multi specific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0280] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0281] In some embodiments, the multispecific protein comprises (i) an antigen binding domain that specifically binds EpCAM that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL comprises anamino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL comprises an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0282] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0283] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.

[0284] In some embodiments, the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and the aminoacid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and (ii) an antigen binding domain that specifically binds CD 163 that comprises a VH region and a VL region, wherein the amino acid sequence of the VH consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 27; and the amino acid sequence of the VL consists of an amino acid sequence 100% identical to the amino acid sequence set forth in SEQ ID NO: 28.5.2.4 Ig Constant Regions

[0285] In some embodiments, the multispecific protein comprises one or more Ig (e.g., hlgG (e.g., hlgGl, hIgG4)) constant region (e.g., one or more CHI region, hinge region, CH2 region, CH3 region, Fc region, CL region). In some embodiments, the multispecific protein comprises a full-length antibody (e.g., a full-length antibody comprising a CrossMab format (see, e.g., § 5.2.6); a full-length antibody comprising a swapped VH and VL in one of the antigen binding domains). In some embodiments, the multispccific protein comprises one or more Ig (e.g., hlgG (e.g., hlgGl, hIgG4)) CHI region, hinge region, CH2 region, and / or CH3 region. In some embodiments, the multispecific protein comprises one or more hlgG CHI region, hinge region, CH2 region, and / or CH3 region. In some embodiments, the multispecific protein comprises one or more hlgGl CHI region, hinge region, CH2 region, and / or CH3 region. In some embodiments, the multispecific protein comprises one or more hIgG4 CHI region, hinge region, CH2 region, and / or CH3 region. Exemplary full formats are provided herein, see, e.g., § 5.2.8.

[0286] In some embodiments, the multispecific protein comprises one or more Ig (e.g., hlg) light chain constant region (e.g., a hlg light chain kappa constant region (KCL) or a hlg light chain lambda constant region ( CL).

[0287] The amino acid sequence of exemplary reference hlgGl and hIgG4 heavy chain and light chain constant regions, which can be incorporated in one or more of the embodiments described herein (e.g., multispecific proteins described herein) (or varied or modified versions thereof), is provided in Table 5.Table 5. The Amino Acid Sequence of Exemplary hlg Heavy Chain and Light Chain Constant Regions and Components Thereof.

[0288] In some embodiments, the multispecific protein comprises one or more hlg constant region, wherein the amino acid sequence of the one or more hlg constant region comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a polypeptide set forth in Table 5. In some embodiments, the amino acid sequence of the one or more hlg constantregion comprises or consists of an amino acid sequence set forth in Table 5.

[0289] In some embodiments, the amino acid sequence of the one or more hlg constant region comprises or consists of an amino acid sequence set forth in Table 5, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%), amino acid variations (e.g., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the one or more hlg constant region comprises or consists of an amino acid sequence set forth in Table 5, comprising or consisting of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations (e.g., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the one or more hlg constant region comprises or consists of an amino acid sequence set forth in Table 5, comprising or consisting of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations (e.g., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of an amino acid sequence set forth in Table 5, comprising or consisting of about no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations (e.g., amino acid substitutions, deletions, or additions).

[0290] In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of an amino acid sequence set forth in Table 5, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%), amino acid substitutions. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of an amino acid sequence set forth in Table 5, comprising or consisting of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid substitutions. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of an amino acid sequence set forth in Table 5, comprising or consisting of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid substitutions. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of an amino acid sequence set forth in Table 5, comprising or consisting of about no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid substitutions.

[0291] In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 37-64. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ IDNOS: 37-64.

[0292] In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%), amino acid variations (e.g., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, comprising or consisting at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations e.g., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, comprising or consisting about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, comprising or consisting of no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., amino acid substitutions, deletions, or additions).

[0293] In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%), amino acid substitutions. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, comprising or consisting at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid substitutions. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, comprising or consisting about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the one or more hlg constant regions comprises or consists of the amino acid sequence of any one of SEQ ID NOS: 37-64, comprising or consisting of no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.5.2.4.1 Ig Effector Function

[0294] As described herein, in some embodiments, the multispecific protein comprises an Fc region (see, e.g., § 5.2.3). In some embodiments, the Fc region of an multispecific protein described herein exhibits one or more Fc effector. Exemplary Fc effector functions include, butare not limited to, antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), and binding affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and / or FcyRIIIb)).

[0295] Standard in vitro and / or in vivo assays known in the art can be conducted to evaluate Fc effector function, including, any one or more of ADCC, CDC, ADCP, Fc receptor (e.g., Fey receptor) binding affinity, and Clq binding affinity.

[0296] For example, ADCC activity can be assessed utilizing standard (radioactive and nonradioactive) methods known in the art (see, e.g., W02006 / 082515, W02012 / 130831), the entire contents of each of which is incorporated by reference herein for all purposes). For example, ADCC activity can be assessed using a chromium-5 (51Cr) assay. Briefly,51Cr is pre-loaded into target cells, NK cells are added to the culture, and radioactivity in the cell culture supernatant is assessed (indicative of lysis of the target cells by the NK cells). Similar non-radioactive assays can also be utilized that employ a similar method, but the target cells are pre-loaded with fluorescent dyes, such as calcein-AM, CFSE, BCECF, or lanthanide flurophore (Europium). See, e.g., Parekh, Bhavin S et al. “Development and validation of an antibody-dependent cell-mediated cytotoxicityreporter gene assay.” mAbs vol. 4,3 (2012): 310-8. Doi:10.4161 / mabs.19873, the entire contents of which is incorporated by reference herein for all purposes. Exemplary commercially available non-radioactive assays include, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (Cell Technology, Inc. Mountain View, Calif.; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wis.). Additional non-limiting examples of in vitro assays that can be used to assess ADCC activity of a fusion protein described herein include those described in US5500362; US5821337; Hellstrom, I., et al., Proc. Nat’l Acad. Sei. USA 83 (1986) 7059-7063; Hellstrom, I., et al., Proc. NatT Acad. Sei. USA 82 (1985) 1499-1502; and Bruggemann, M., et al., J. Exp. Med. 166 (1987) 1351-1361, the entire contents of each of which is incorporated by reference herein. Alternatively, or additionally, ADCC activity of a fusion protein described herein may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes, et al., Proc. NatT Acad. Sci. USA 95 (1998) 652-656, the entire contents of which is incorporated by reference herein for all purposes.

[0297] Clq binding assays can be utilized to assess the ability of a an multispecific protein described herein to bind Clq (or bind with less affinity than a reference fusion protein) and henceIlllack (or have decreased) CDC activity. The binding of an multispecific protein described herein to Clq can be determined by a variety of in vitro assays (e.g., biochemical or immunological based assays) known in the art for determining Fc-Clq interactions, including e.g., equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetic methods (e.g., surface plasmon resonance (SPR) analysis), and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis, and chromatography (e.g., gel filtration). These and other methods may utilize a label on one or more of the components being examined and / or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in e.g., Paul, W. E., ed., Fundamental Immunology, 4thEd., Lippincott-Raven, Philadelphia (1999), the entire contents of which is incorporated by reference herein. For example, see, e.g., Clq and C3c binding ELISAs described in W02006 / 029879 and W02005 / 100402, the entire contents of each of which is incorporated by reference herein for all purposes. Additional CDC activity assays include those described in e.g., Gazzano-Santoro, et al., J. Immunol. Methods 202 (1996) 163; Cragg, M. S., et al., Blood 101 (2003) 1045-1052; and Cragg, M. S., and Glennie, M. J., Blood 103 (2004) 2738- 2743), the entire contents of each of which is incorporated by reference herein for all purposes.

[0298] ADCP activity can be measured by in vitro or in vivo methods known in the art and also commercially available assays (see, e.g., van de Donk NW, Moreau P, Plesner T, et al. “Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma,” Blood, 127(6):681-695 (2016), the entire contents of each of which is incorporated by reference herein for all purposes). For example, a primary cell based ADCP assay can be used in which fresh human peripheral blood mononuclear cells (PBMCs) are isolated, monocytes isolated and differentiated in culture to macrophages using standard procedures. The macrophages are fluorescently labeled added to cultures containing fluorescently labeled target cells. Phagocytosis events can be analyzed using FACS screening and / or microscopy. A modified reporter version of the above described assay can also be used that employs an engineered cell line that stably expresses FcyRIIa (CD32a) as the effector cell line (e.g., an engineered T cell line, e.g., THP-1), removing the requirement for primary cells. Exemplary ADCP assays are described in e.g., Ackerman, M. E. et al. A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples. I. Immunol. Methods 366, 8-19 (2011); and Mcandrew, E. G. et al.Determining the phagocytic activity of clinical antibody samples. J. Vis. Exp. 3588 (201 1). Doi: 10.3791 / 3588; the entire contents of each of which is incorporated by reference herein.

[0299] Binding of an multispecific protein described herein to an Fc receptor can be determined by a variety of in vitro assays (e.g., biochemical or immunological based assays) known in the art for determining Fc-Fc receptor interactions, i.e., specific binding of an Fc region to an Fc receptor. Common assays include equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetic methods e.g., surface plasmon resonance (SPR) analysis), and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis, and chromatography (e.g., gel filtration). These and other methods may utilize a label on one or more of the components being examined and / or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in e.g., Paul, W. E., ed., Fundamental Immunology, 4” Ed., Lippincott-Raven, Philadelphia (1999), the entire contents of which is incorporated by reference herein for all purposes.(i) Enhanced Ig Effector Function

[0300] In some embodiments, the Ig Fc region exhibits an enhancement (e.g., an increase) in one or more Fc effector function relative to a reference (e.g., wild type) Ig Fc region. Exemplary Ig Fc effector functions include, but are not limited to, ADCC, ADCP, CDC, binding affinity to Clq, and binding affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., (e.g., FcyRI, FcyRIIa, FcyRIIIa, and / or FcyRIIIb). In some embodiments, the Fc region exhibits one or more enhanced Fc effector function, relative to a reference Ig (e.g., hlg).

[0301] In some embodiments, the hlg Fc region is modified (e.g., comprises one or more variation (e.g., one or more amino acid substitution, deletion, addition, etc.); altered glycosylation (e.g., afucosylation))) (referred to herein as a “modified hlg Fc”). In some embodiments, the modification (e.g., the variation (e.g., one or more amino acid substitution, deletion, addition, etc.); altered glycosylation (e.g., afucosylation))) enhances (e.g., increases) one or more Fc effector function, relative to a reference hlg Fc that does not comprise the modification (e.g., the one or more variation (e.g., the one or more amino acid substitution, deletion, addition, etc.; the altered glycosylation (e.g., afucosylation))).

[0302] In some embodiments, a multispecific protein (e.g., described herein) comprising themodified Ig (e.g., hlg, mlg) Fc exhibits enhanced ADCC compared to a reference multispecific protein that docs not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, a multispecific protein (e.g., described herein) the modified Ig (e.g., hlg) Fc exhibits enhanced CDC compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg,) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced ADCP compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0303] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits reduced binding affinity to one or more Fc receptor (e.g., human Fc receptor) (e.g., an Fey receptor (e.g., FcyRIIb)) compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to one or more Fc receptor (e.g., human Fc receptor) (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIIa and / or FcyRIIIb) compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0304] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits reduced binding affinity to FcyRIIb compared to a reference multispecific protein that does not comprise the hlg Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0305] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to FcyRI, FcyRIIa, FcyRIIIa, and / or FcyRIIIb compared to a reference multispecific protein that does not comprise the hlg Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0306] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to FcyRI compared to a referencemultispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0307] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to FcyRIIa compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0308] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to FcyRIIb compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0309] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to FcyRIIIa compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0310] In some embodiments, a multispecific protein (e.g., described herein) comprising the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to FcyRIIIb compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0311] In some embodiments, a multispecific protein (e.g., described herein) the modified Ig (e.g., hlg) Fc exhibits enhanced binding affinity to Clq compared to a reference multispecific protein that does not comprise the Ig (e.g., hlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0312] Amino acid substitutions and glycoengineering that enhance (e.g., increase) one or more hlg Fc effector function are known in the art. See for example, Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment. Antibodies (Basel). 2020;9(4):64. Published 2020 Nov 17. doi:10.3390 / antib9040064; van der Horst HJ, Nijhof IS, Mutis T, Chamuleau MED. Fc- Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies. Cancers (Basel). 2020;12(10):3041. Published 2020 Oct 19. Doi:10.3390 / cancersl2103041; and Saunders Kevin, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” Frontiers in Immunology, vlO (June 7,2019) DOI=10.3389 / fimmu.2019.01296, the full contents of each of which is incorporated by reference herein for all purposes.

[0313] Table 6 below, provides exemplary amino acid substitutions (and combinations thereof) and glycoengineering that can be utilized to increase one or more hlg Fc effector function. Amino acids in Table 6 are numbered according to the EU numbering scheme. The effects on effector function set forth in Table 6 are exemplary only and not intended to be limiting. The amino acid substitutions set forth in Table 6 are with reference to an IgGl Fc region (except where noted). However, a person of ordinary skill in the could identify the corresponding amino acid in a non- IgGl Fc region, for example in an IgG2 or IgG4 Fc region, should the base amino acid be different between the IgGl and non-IgGl Fc region.Table 6. Exemplary hlg Fc Variations and Glycoengineering to Increase Effector Function.

[0314] In some embodiments, the Ig Fc region is a hlg Fc region. In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises any one or more of the amino acid substitutions set forth in Table 6 (i.e., any one or more amino acid substitution set forth in any set of amino acid substitutions set forth in Table 6). In some embodiments, the hlg Fc (e.g., IgGl Fc) comprises any one or more of the sets of amino acid substitutions set forth in Table 6. In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises any one or more of the glycosylation changes set forth in Table 6.

[0315] In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises an amino acid substitution at any one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, o...

Claims

CLAIMSWhat is claimed is:

1. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., human EpCAM (hEpCAM))) comprising(i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 16, or comprising the amino acid sequence set forth in SEQ ID NO: 16 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 17, or comprising the amino acid sequence set forth in SEQ ID NO: 17 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18, or comprising the amino acid sequence set forth in SEQ ID NO: 18 and consisting of 1, 2, or 3 amino acid variations; and(ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR- H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 13, or comprising the amino acid sequence set forth in SEQ ID NO: 13 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14, or comprising the amino acid sequence set forth in SEQ ID NO: 14 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 15, or comprising the amino acid sequence set forth in SEQ ID NO: 15 and consisting of 1, 2, or 3 amino acid variations; and(b) a second antigen binding domain (e.g., that specifically binds cluster of differentiation 163 (CD163) (e.g., human CD163 (hCD 163))) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and theamino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

2. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 16; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 17; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 13; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 15; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forthin SEQ ID NO: 25; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

3. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and(ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and(ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

4. The multispecific protein of any one of claims 1-2, wherein(a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20; and(ii) the amino acid sequence of the VH region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQID NO: 19; and(b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and(ii) the amino acid sequence of the VH region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

5. The multispecific protein of any one of the preceding claims, wherein(a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 20; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 19; and(b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 27.

6. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 20; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 19; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27.

7. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth inSEQ ID NO: 8, or comprising the amino acid sequence set forth in SEQ ID NO: 8 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9, or comprising the amino acid sequence set forth in SEQ ID NO: 9 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10, or comprising the amino acid sequence set forth in SEQ ID NO: 10 and consisting of 1, 2, or 3 amino acid variations; and(ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR- H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 5, or comprising the amino acid sequence set forth in SEQ ID NO: 5 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR- H2 comprising the amino acid sequence set forth in SEQ ID NO: 6, or comprising the amino acid sequence set forth in SEQ ID NO: 6 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 7, or comprising the amino acid sequence set forth in SEQ ID NO: 7 and consisting of 1, 2, or 3 amino acid variations; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2comprising the amino acid sequence set forth in SEQ TD NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

8. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 8; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 5; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 7; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

9. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and(ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and(ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

10. The multispecific protein of any one of claims 7-8, wherein(a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12; and(ii) the amino acid sequence of the VH region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11; and(b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and(ii) the amino acid sequence of the VH region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQID NO: 27.

11. The multispecific protein of any one of claims 7-10, wherein(a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 12; and (ii) the amino acid sequence of the VH region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 11; and(b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 27.

12. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 12; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 11; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27.

13. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32, or comprising the amino acid sequence set forth in SEQ ID NO: 32 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33, or comprising the amino acid sequence set forth in SEQ ID NO: 33 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34, or comprising the amino acid sequence set forth in SEQ ID NO: 34 and consisting of 1, 2, or 3 amino acid variations; and(ii) a variable heavy (VH) region comprising a CDR-H1 , a CDR-H2, and a CDR- H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 29, or comprising the amino acid sequence set forth in SEQ ID NO: 29 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30, or comprising the amino acid sequence set forth in SEQ ID NO: 30 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 31, or comprising the amino acid sequence set forth in SEQ ID NO: 31 and consisting of 1, 2, or 3 amino acid variations; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

14. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDR-L3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 32; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 29; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 31; and(b) a second antigen binding domain (e.g., that specifically binds CD163 e.g., hCD163)) comprising(i) a VL region comprising a CDR-L1, a CDR-L2, a CDRL-3, the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and(ii) a VH region comprising a CDR-H1, a CDR-H2, and a CDR-H3, the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23.

15. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising(i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36; and(ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising(i) a VL region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and(ii) a VH region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 29.

16. The multispecific protein of any one of claims 13-14, wherein(a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 36; and(ii) the amino acid sequence of the VH region of the first antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 35; and(b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 28; and(ii) the amino acid sequence of the VH region of the second antigen binding domain comprises an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 27.

17. The multispecific protein of any one of claims 13-16, wherein(a) (i) the amino acid sequence of the VL region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 36; and (ii) the amino acid sequenceof the VH region of the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 35; and(b) (i) the amino acid sequence of the VL region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 28; and (ii) the amino acid sequence of the VH region of the second antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 27.

18. A multispecific protein comprising(a) a first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 36; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 35; and(b) a second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)) comprising (i) a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28; and (ii) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27.

19. The multispecific protein of any one of the preceding claims, wherein the first antigen binding domain specifically binds EpCAM (e.g., hEpCAM).

20. The multispecific protein of any one of the preceding claims, wherein the second antigen binding domain specifically binds CD163 (e.g., hCD163).

21. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163).

22. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is capable of simultaneously binding EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) expressed on the surface of the same cell.

23. The multispecific protein of any one of the preceding claims, wherein the cells expressing EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) on the surface are tumor macrophage hybrid cells (as defined herein).

24. The multispecific protein of any one of the preceding claims, wherein the cells expressing EpCAM (e.g., hEpCAM) and CD163 (e.g., hCD163) on the surface are circulating tumor macrophage hybrid cells (CHCs) (as defined herein) and / or cancer-associated macrophage-like cells (CAMLs) (as defined herein).

25. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is not substantially capable of binding to a cell that expresses EpCAM on the surface but does not express CD163 (e. ., hCD163) on the surface.

26. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is not substantially capable of binding to a cell that expresses CD163 on the surface but does not express EpCAM (e.g., hEpCAM) on the surface.

27. The multispecific protein of any one of the preceding claims, wherein the protein comprises a single an antigen binding domain that specifically binds EpCAM.

28. The multispecific protein of any one of the preceding claims, wherein the protein comprises a single antigen binding domain that specifically binds CD 163.

29. The multispecific protein of any one of the preceding claims, wherein the protein comprises a plurality of antigen binding domains that each specifically bind EpCAM.

30. The multispecific protein of any one of the preceding claims, wherein the protein comprises a plurality of antigen binding domains that each specifically bind CD 163.

31. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is bivalent.

32. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is bivalent.

33. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is tetravalent.

34. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is bispecific.

35. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is bispecific and bivalent comprising one antigen binding domain that specifically binds EpCAM and one antigen binding domain that specifically binds CD 163.

36. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is bispecific and trivalent comprising one antigen binding domain that specifically binds EpCAM and two antigen binding domains that each specifically bind CD163.

37. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is bispecific and trivalent comprising one antigen binding domain that specifically binds CD163 and two antigen binding domains that each specifically bind EpCAM.

38. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises a first human Ig (hlg) Fc region and a second hlg Fc region that associate via at least one covalent e.g., disulfide) bond.

39. The multispecific protein of claim 38, wherein the hlg is a hlgG.

40. The multispecific protein of claim 39, wherein the hlgG is hlgGl or h!gG4.

41. The multispecific protein of claim 40, wherein the hlgG is hlgGl.

42. The multispecific protein of any one of claims 38-41, wherein the antibody the amino acid sequence of the first Fc region and / or the amino acid sequence of the second Fc region comprise one or more amino acid substitution that promotes the association (e.g., heterodimerization) of the first and second Fc regions.

43. The multispecific protein of any one of claims 38-42, wherein the amino acid sequence of the first Fc region comprises an amino acid substitution at amino acid positions T366, L368, and Y407, numbering according to the EU index of Kabat.

44. The multispecific protein of any one of claims 38-43, wherein the amino acid sequence of the first Fc comprises a serine at amino acid position T366, an alanine at amino acid position L368, and a valine at amino acid position Y407, numbering according to the EU index of Kabat.

45. The multispecific protein of any one of claims 38-44, wherein the amino acid sequence of the first Fc region comprises an amino acid substitution at amino acid position Y349, numbering according to the EU index of Kabat.

46. The multispecific protein of any one of claims 38-45, wherein the amino acid sequence of the first Fc region comprises a cysteine at amino acid position Y349, numbering according to the EU index of Kabat.

47. The multispecific protein of any one of claims 38-46, wherein the amino acid sequence of the second Fc region comprises an amino acid substitution at amino acid position T366, numbering according to the EU index of Kabat.

48. The multispecific protein of any one of claims 38-47, wherein the amino acid sequence of the second Fc region comprises a tryptophan at amino acid position T366, numbering according to the EU index of Kabat.

49. The multispecific protein of any one of claims 38-48, wherein the amino acid sequence of the second Fc region of the antibody comprises an amino acid substitution at amino acid position S354, numbering according to the EU index of Kabat.

50. The multispecific protein of any one of claims 38-50, wherein the amino acid sequence of the second Fc region of the antibody comprises a cysteine at amino acid position S354, numbering according to the EU index of Kabat.

51. The multispecific protein of any one of the preceding claims, wherein one of the first or second antigen binding domains comprises:(a) a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CHI region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CL region;(b) a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VH region, a CL region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VL region and a CHI region; or(c) a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CL region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CHI region.

52. The multispecific protein of any one of the preceding claims, wherein one of the first antigen binding domain comprises a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CHI region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CL region.

53. The multispecific protein of any one of the preceding claims, wherein one of the second antigen binding domain comprises a light : heavy chain pair wherein the heavy chain comprises from N- to C-terminus the VL region, a CHI region, a hinge, a CH2 region, and a CH3 region; and the light chain comprises from N- to C-terminus the VH region and a CL region.

54. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is capable of inducing one or more of the following upon binding to cells expressing CD 163 and EpCAM on the surface: (a) antibody-dependent cellular cytotoxicity (ADCC); (b) antibody -dependent cellular phagocytosis (ADCP); (c) complement-dependent cytotoxicity (CDC); and / or (d) binding to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))).

55. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is substantially incapable of inducing one or more of the following upon binding to cells expressing CD163 on the surface that do not express EpCAM on the surface: (a) ADCC; (b)ADCP; (c) CDC; and / or (d) binding to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, Fey R Ila, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))).

56. The multispecific protein of any one of the preceding claims, wherein the multispecific protein is substantially incapable of inducing one or more of the following upon binding to cells expressing EpCAM on the surface that do not express CD163 on the surface: (a) ADCC; (b) ADCP; (c) CDC; and / or (d) binding to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))).

57. The multispecific protein of any one of the preceding claims, wherein the multispecific protein has enhanced Ig effector function.

58. The multispecific protein of any one of the preceding claims, wherein the multispecific protein has any one or more of the following: (a) enhanced ADCC; (b) enhanced ADCP; (c) enhanced CDC; and / or (d) enhanced binding affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRIIIa, FcyRIIIb))) relative to a reference protein.

59. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises one or more amino acid variation (relative to a reference protein) that enhances one or more Ig effector function.

60. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises varied (e.g., reduced glycosylation (e.g., fucosylation)) (relative to a reference protein) that enhances one or more Ig effector function.

61. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises one or more variations set forth in Table 6.

62. The multispecific protein of any one of the preceding claims, comprising a linker.

63. The multispecific protein of claim 62, wherein the linker comprises a peptide about 2-50 amino acids in length (e.g., a glycine linker, a glycine / serine linker, etc.).

64. The multispecific protein of any one of claims 62 or 63, wherein the linker comprises an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 65-73.

65. The multispecific protein of any one of the preceding claims, further comprising one or more heterologous moiety.

66. The multispecific protein of claim 65, wherein the heterologous moiety comprises a small molecule, protein, peptide, nucleic acid molecule (e.g., DNA molecule, RNA molecule), carbohydrate, lipid, synthetic polymer, carrier, or vector.

67. The multispecific protein of any one of claims 65-66, wherein the heterologous moiety is detectable (e.g., fluorescent agent, radiation agent, imaging agent, etc.).

68. The multispecific protein of any one of claims 65-67, wherein the heterologous moiety comprises a cytotoxic agent.

69. The multispecific protein of any one of claims 65-68, wherein the heterologous moiety comprises a radionuclide.

70. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises four polypeptide chains comprising(i) a first polypeptide chain comprising N- to C-terminus the VL region of (a)(i) and a CL region;(ii) a second polypeptide chain comprising from N- to C-terminus the VH of (a)(ii) region, a CHI region, a hinge region, a CH2 region, and a CH3 region;(iii) a third polypeptide chain comprising from N- to C-terminus the VH region of (b)(i) region and a CL region;(iv) a fourth polypeptide chain comprising from N-to C-terminus the VL region of (b)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region; wherein the VL region first polypeptide and the VH region second polypeptide associate to form the first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), and wherein the VL region of the fourth polypeptide associates with the VH region of the third polypeptide to form the second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)).

71. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises four polypeptide chains comprising(i) a first polypeptide chain comprising N- to C-terminus the VL region of (b)(i) and a CL region;(ii) a second polypeptide chain comprising from N- to C-terminus the VH of (h)(ii) region, a CHI region, a hinge region, a CH2 region, and a CH3 region;(iii) a third polypeptide chain comprising from N- to C-terminus the VH region of (a)(i) region and a CL region;(iv) a fourth polypeptide chain comprising from N-to C-terminus the VL region of (a)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region; wherein the VL region first polypeptide and the VH region second polypeptide associate to form the second antigen binding domain (e.g., that specifically binds CD163 (e.g., hCD163)); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), and wherein the VL region of the fourth polypeptide associates with the VH region of the third polypeptide to form the first antigen binding domain (e.g., that specifically binds EpCAM (e.g., hEpCAM)).

72. The multispecific protein of any one of the preceding claims, wherein the multispecific protein comprises a third antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (EpCAM) (e.g., hEpCAM)) comprising (c) (i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR-H3.

73. The multispecific molecule of claim 72, wherein (i) the amino acid sequence of the CDR- L1 comprising the amino acid sequence set forth in SEQ ID NO: 16, or comprising the amino acid sequence set forth in SEQ ID NO: 16 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 17, or comprising the amino acid sequence set forth in SEQ ID NO: 17 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 18, or comprising the amino acid sequence set forth in SEQ ID NO: 18 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 13, or comprising the amino acid sequence set forth in SEQ ID NO: 13 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14, or comprising the amino acid sequence set forth in SEQ ID NO: 14 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of theCDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 15, or comprising the amino acid sequence set forth in SEQ ID NO: 15 and consisting of 1, 2, or 3 amino acid variations.

74. The multispecific molecule of claim 72, wherein (i) the amino acid sequence of the CDR- L1 comprising the amino acid sequence set forth in SEQ ID NO: 8, or comprising the amino acid sequence set forth in SEQ ID NO: 8 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 9, or comprising the amino acid sequence set forth in SEQ ID NO: 9 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10, or comprising the amino acid sequence set forth in SEQ ID NO: 10 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR- H1 comprising the amino acid sequence set forth in SEQ ID NO: 5, or comprising the amino acid sequence set forth in SEQ ID NO: 5 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6, or comprising the amino acid sequence set forth in SEQ ID NO: 6 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 7, or comprising the amino acid sequence set forth in SEQ ID NO: 7 and consisting of 1, 2, or 3 amino acid variations.

75. The multispecific molecule of claim 72, wherein (i) the amino acid sequence of the CDR- L1 comprising the amino acid sequence set forth in SEQ ID NO: 32, or comprising the amino acid sequence set forth in SEQ ID NO: 32 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 33, or comprising the amino acid sequence set forth in SEQ ID NO: 33 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34, or comprising the amino acid sequence set forth in SEQ ID NO: 34 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 29, or comprising the amino acid sequence set forth in SEQ ID NO: 29 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30, or comprising the amino acid sequence set forth in SEQ ID NO: 30 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of theCDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 31 , or comprising the amino acid sequence set forth in SEQ ID NO: 31 and consisting of 1, 2, or 3 amino acid variations.

76. The multispecific protein of any one of claims 72-75, wherein the multispecific protein comprises five polypeptide chains:(i) a first polypeptide chain comprising N- to C-terminus the VL region of (a)(i) and a CL region;(ii) a second polypeptide chain comprising from N- to C-terminus the VH region of (a)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region;(iii) a third polypeptide chain comprising from N- to C-terminus the VH of (b)(ii) region and a CL region;(iv) a fourth polypeptide chain comprising from N-to C-terminus the VH region of (c)(ii), a CHI region, a linker, the VL region of (b)(i) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; and(v) a fifth polypeptide chain comprising from N- to C-terminus the VL region of (c)(i) and a CL region; wherein the VL region of (a)(i) of first polypeptide and the VH region of (a)(ii) of second polypeptide associate to form an antigen binding domain (e.g., that specifically binds EpCAM); wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), wherein the VH region of (c)(ii) of the fourth polypeptide and the VL region of (c)(i) of the fifth polypeptide associate to form an antigen binding domain (e.g., that specifically binds EpCAM); and wherein the VL region of (b)(ii) of the fourth polypeptide associates with the VH region of (b)(i) of the third polypeptide to form an antigen binding domain (e.g., that specifically binds CD163).

77. The multispecific protein of any one of claims 1-71, wherein the multispecific protein comprises a third antigen binding domain (e.g., that specifically binds epithelial cellular adhesion molecule (CD163) (e.g., hCD163)) comprising (c) (i) a variable light (VL) region comprising a CDR-L1, a CDR-L2, a CDR-L3, and (ii) a variable heavy (VH) region comprising a CDR-H1, a CDR-H2, and a CDR-H3.

78. The multispecific molecule of claim 77, wherein (c)(i) the amino acid sequence of the CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 24, or comprising the amino acid sequence set forth in SEQ ID NO: 24 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 25, or comprising the amino acid sequence set forth in SEQ ID NO: 25 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 26, or comprising the amino acid sequence set forth in SEQ ID NO: 26 and consisting of 1, 2, or 3 amino acid variations; and (ii) the amino acid sequence of the CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 21, or comprising the amino acid sequence set forth in SEQ ID NO: 21 and consisting of 1, 2, or 3 amino acid variations; the amino acid sequence of the CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, or comprising the amino acid sequence set forth in SEQ ID NO: 22 and consisting of 1, 2, or 3 amino acid variations; and the amino acid sequence of the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 23, or comprising the amino acid sequence set forth in SEQ ID NO: 23 and consisting of 1, 2, or 3 amino acid variations.

79. The multispecific protein of any one of claims 77-78, wherein the multispecific protein comprises five polypeptide chains:(i) a first polypeptide chain comprising N- to C-terminus the VL region of (b)(i) and a CL region;(ii) a second polypeptide chain comprising from N- to C-terminus the VH region of (b)(ii), a CHI region, a hinge region, a CH2 region, and a CH3 region;(iii) a third polypeptide chain comprising from N- to C-terminus the VH of (a)(ii) region and a CL region;(iv) a fourth polypeptide chain comprising from N-to C-terminus the VH region of (c)(ii), a CHI region, a linker, the VL region of (a)(i) region, a CHI region, a hinge region, a CH2 region, and a CH3 region; and(v) a fifth polypeptide chain comprising from N- to C-terminus the VL region of (c)(i) and a CL region; wherein the VL region of (b)(i) of first polypeptide and the VH region of (b)(ii) of second polypeptide associate to form an antigen binding domain (e.g., that specifically binds CD163);wherein the second polypeptide and the fourth polypeptide associate via at least one covalent (e.g., disulfide bond), wherein the VH region of (c)(ii) of the fourth polypeptide and the VL region of (c)(i) of the fifth polypeptide associate to form an antigen binding domain e.g., that specifically binds CD 163); and wherein the VL region of (a)(ii) of the fourth polypeptide associates with the VH region of (a)(i) of the third polypeptide to form an antigen binding domain e.g., that specifically binds EpCAM).

80. The multispecific protein of any one of the preceding claims, comprising(i) a first polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 74;(ii) a second polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 75;(iii) a third polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 76; and(iv) a fourth polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 77.

81. The multispecific protein of any one of the preceding claims, comprising(i) a first polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 78;(ii) a second polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 79;(iii) a third polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 77;(iv) a fourth polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 76; and(iv) a fifth polypeptide that an amino acid sequence at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 76.

82. The multispecific protein of any one of the preceding claims, wherein the multispecific83. A conjugate comprising the multispecific protein of any one of claims 1-82 and a heterologous moiety.

84. The conjugate of claim 83, wherein the heterologous moiety comprises a small molecule, protein, peptide, nucleic acid molecule (e.g., DNA molecule, RNA molecule), carbohydrate, lipid, synthetic polymer, carrier, or vector.

85. The conjugate of any one of claims 83-84, wherein the heterologous moiety is a cytotoxic agent.

86. The conjugate of any one of claims 83-85, wherein the heterologous moiety is a radionuclide.

87. A fusion protein comprising the multispecific protein of any one of claims 1-82 and a heterologous protein.

88. One or more nucleic acid molecules encoding one or more polypeptide of a multispecific protein of any one of claims 1-82.

89. The nucleic acid molecule of claim 88, wherein the nucleic acid molecules are RNA or DNA.

90. A vector comprising one of more nucleic acid molecule of claim 88-89.9E The vector of claim 90, wherein the vector is a viral vector or a non- viral vector (e.g., a plasmid).

92. A carrier comprising the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, or the vector of any one of claims 90-91.

93. A carrier conjugated to the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, or the vector of any one of claims 90-91.

94. The carrier of any one of claims 92-95, wherein the carrier is a lipid nanoparticle.

95. A cell comprising the multispccific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, or the carrier of any one of claims 92-94.

96. A cell (e.g., a therapeutic cell) expressing the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, or the fusion protein of claim 87.

97. A cell (e.g., a therapeutic cell) genetically engineered to comprise within the cell’s genome the nucleic acid molecule of any one of claims 88-89 (e.g., wherein the nucleic acid molecule encodes the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, or the fusion protein of claim 87).

98. The cell of any one of claims 95-97, wherein the cell is a therapeutic cell.

99. The cell of any one of claims 95-98, wherein the cell expresses a protein comprising the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, or the fusion protein of claim 87 on the surface of the cell.

100. The cell of any one of claims 95-99, wherein the cell expresses a chimeric antigen receptor on the surface of the cell, wherein the chimeric antigen receptor comprises the multispecific protein of any one of claims 1-82.

101. The cell of any one of claims 95-100, wherein the cell is an immune cell (e.g., a T cell (e.g., a CD8+ T cell or a CD4+ T cell), an NK cell).

102. A chimeric antigen receptor (CAR) cell (e.g., T cell (e.g., CD8+ T cell)) expressing a CAR comprising the multispecific protein of any one of claims 1-82 on the surface of the cell.

103. A pharmaceutical composition comprising the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, or the cell of any one of claims 95-102, and a pharmaceutically acceptable excipient.

104. A kit the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88- 89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103, and optional instructions for use.

105. A method of delivering a multi specific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition to a subject, the method comprising administering to the subject the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88- 89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103, to thereby deliver the multispecific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition to a subject to the subject.

106. A method of killing a population of cells in a subject in need thereof, the method comprising administering to the subject the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103 to thereby kill the population of cancer cells in the subject.

107. The method of claim 106, wherein the population of cells express CD163 and EpCAM on the surface.

108. The method of claim 106 or 107, wherein the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs).

109. The method of any one of claims 106-108, wherein the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or (c) CDC.

110. The method of any one of claims 106-109, wherein the subject has cancer.

111. The methos of any one of claims 106- 110, wherein the subject has or had cancer that is in remission (e.g., partial or full remission).

112. A method of treating, ameliorating, or preventing a cancer in a subject in need thereof, the method comprising administering to the subject the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103, to thereby treat, ameliorate, or prevent the cancer in the subject.

113. The method of claim 112, wherein the cancer is in remission e.g., partial or full remission).

114. The method of any one of claims 1 12- 113, wherein the treatment, amelioration , or prevention of the cancer in the subject is mediated in part through the killing of a population of cells in the subject.

115. The method of any one of claims 112-114, wherein the population of cells express CD 163 and EpCAM on the surface.

116. The method of any one of claims 112-115, wherein the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs).

117. The method of any one of claims 112- 116, wherein the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or (c) CDC.

118. A method of preventing recurrence of a cancer in a subject in need thereof, the method comprising administering to the subject the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103, to thereby prevent recurrence of a cancer in the subject.

119. The method of claim 118, wherein the cancer is in remission e.g., partial or full remission).

120. The method of any one of claims 118-119, wherein the prevention of the recurrence of the cancer in the subject is mediated in part through the killing of a population of cells in the subject.

121. The method of any one of claims 118-120, wherein the population of cells express CD 163 and EpCAM on the surface.

122. The method of any one of claims 118-121, wherein the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs).

123. The method of any one of claims 118-122, wherein the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or (c) CDC.

124. A method of preventing progression and / or metastasis of a cancer in a subject in need thereof, the method comprising administering to the subject the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceuticalcomposition of claim 103, to thereby prevent progression and / or metastasis of the cancer in the subject.

125. The method of claim 124, wherein the prevention of the progression and / or metastasis of the cancer in the subject is mediated in part through the killing of a population of cells in the subject.

126. The method of any one of claims 124-125, wherein the population of cells express CD 163 and EpCAM on the surface.

127. The method of any one of claims 124-126, wherein the population of cells comprises tumor macrophage hybrid cells (defined herein) (e.g., CAMLs and / or CHCs).

128. The method of any one of claims 124-127, wherein the killing of the cells is mediated by one or more of (a) ADCC; (b) ADCP; and / or (c) CDC.

129. A method of predicting the likelihood of recurrence of a cancer in a subject, the method comprising(a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells;(b) determining (or having determined) if at least a portion of the cancer cells are tumor macrophage hybrid cells; and wherein the cancer is predicted to recur if at least a portion of the cells in the population are tumor macrophage hybrid cells.

130. The method of claim 129, wherein the at least a portion of the population of cells simultaneously express CD 163 and EpCAM on the surface.

131. The method of claim 129 or 130, further comprising administering the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103 to the subject if the cancer is predicted to recur.

132. A method of selecting a subject having cancer for treatment with a multispecific protein that specifically binds EpCAM and CD 163, the method comprising(a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells;(b) determining (or having determined) if at least a portion of the cancer cells in the population arc tumor macrophage hybrid cells utilizing the multispccific protein of any one of claims 1-82; and(c) selecting the subject for treatment with the multispecific protein that specifically binds EpCAM and CD 163 if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells.

133. The method of claim 132, further comprising administering to the treatment to the subject.

134. A method of selecting a subject having cancer for treatment with a multispecific protein that specifically binds EpCAM and CD 163, the method comprising(a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells;(b) determining (or having determined) if at least a portion of the cancer cells are tumor macrophage hybrid cells; and(c) selecting the subject for treatment with the multispecific protein that specifically binds EpCAM and CD 163 if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells.

135. The method of claim 134, further comprising administering the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103 to the subject if the subject is selected.

136. A method of predicting and / or evaluating the responsiveness of a subject having cancer to a treatment comprising the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103, the method comprising(a) obtaining (or having obtained) a sample from the subject comprising a population of cancer cells;(b) determining (or having determined) if at least a portion of the cancer cells in the population arc tumor macrophage hybrid cells; and wherein the subject is predicted or evaluated to be responsive to the treatment if at least a portion of the cancer cells in the population are tumor macrophage hybrid cells.

137. The method of claim 136, wherein the cancer is a recurrence of a cancer.

138. The method of claim 136 or 137, further comprising administering the multispecific protein of any one of claims 1-82, the conjugate of any one of claims 83-86, the fusion protein of claim 87, the nucleic acid molecule of any one of claims 88-89, the vector of any one of claims 90-91, the carrier of any one of claims 92-94, the cell of any one of claims 95-102, or the pharmaceutical composition of claim 103 to the subject predicted or evaluated to be responsive to the treatment.

139. The method of any one of claims 105-138, wherein the multispecific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition is administered to the subject in combination with one or more anti-neoplastic agent (e.g., described herein).

140. The method of any one of claims 105-139, wherein the multispecific protein, conjugate, nucleic acid molecule, vector, cell, carrier, or pharmaceutical composition is administered to the subject as an adjuvant.

141. The method of any one of claims 105-140, wherein the cancer in the subject has been determined to be resistant to one or more anti-neoplastic agent (e.g., one or more standard of care regimen comprising one or more neoplastic agent).

142. The method of any one of claims 105-141, wherein the subject is a human.

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