Compositions and methods for selective modulation of vascular permeability

Abstract

Anti-syndecan-2 antibodies or antigen-binding fragments thereof, as well as compositions comprising the antibodies or antigen-binding fragments thereof, and methods useful for treating diseases associated with syndecan-2-mediated vascular permeability, are provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Serial No. 63 / 338,359, filed May 4, 2022, U.S. Serial No. 63 / 444,520, filed February 9, 2023, U.S. Serial No. 63 / 444,521, filed February 9, 2023, U.S. Serial No. 63 / 495,763, filed April 12, 2023, and U.S. Serial No. 63 / 495,765, filed April 12, 2023, each of which is incorporated herein by reference in its entirety. 1. Sequence Listing This application contains a computer readable sequence listing that has been submitted herewith in XML file format, which is incorporated herein by reference in its entirety. The Sequence Listing XML file submitted herewith, entitled "14765-010-228_SEQLISTING.xml," was created on May 3, 2023, and is 463,326 bytes in size.

[0002] 2. Field In certain aspects, provided herein are antibodies that bind to Sdc2, nucleic acids encoding the antibodies, vectors containing the nucleic acids, and recombinant cells containing the vectors, and compositions comprising the antibodies. Methods of making and using the antibodies are also provided. [Background technology]

[0003] 3. Background Vascular leakage associated with inflammation and tissue injury is an important factor in a wide variety of pathologies. Syndecan-2 (also known as Sdc2, SDC2, Sdc-2, and CD362) is a plasma membrane proteoglycan expressed by endothelial cells and neurons and contains a protein tyrosine phosphatase (DEP1) binding site on its extracellular domain. Sdc2 plays an important role in regulating vascular permeability. Previous studies have demonstrated that Sdc2 knockout mice exhibit reduced vascular leakage after stimulation with vascular endothelial growth factor (VEGF) signaling and polyclonal antibody directed against mouse Sdc2, similarly reducing vascular leakage in vivo. There is a need in the art for methods and compositions that inhibit Sdc2 signaling and thereby treat vascular leakage, including acute respiratory distress syndrome (ARDS), stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., age-related macular degeneration (AMD)), cardiovascular disorders (e.g., acute myocardial infarction (AMI)), and other disorders. The present disclosure addresses this need. Summary of the Invention

[0004] 4. Overview In certain aspects, provided herein are antibodies that bind to Sdc2, and methods of use thereof.

[0005] In some embodiments, the antibody that binds to Sdc2 is antibody clone 20-H19-AB. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 61, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 62. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 31, 32, and 33, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 34, 35, and 36, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 37, 38, and 39, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 40, 41, and 42, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 43, 44, and 45, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 46, 47, and 48, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 49, 50, and 51, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 52, 53, and 54, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 55, 56, and 57, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 58, 59, and 60, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 61. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 62. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 61, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 62. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 61. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 62. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 61, and (ii) a VL having the amino acid sequence of SEQ ID NO: 62. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 63. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 64. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 63, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 64. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence SEQ ID NO: 63. In another embodiment, the antibody comprises a light chain having the amino acid sequence SEQ ID NO: 64. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 63, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 64.

[0006] In some embodiments, the antibody that binds to Sdc2 is antibody clone TP-43327F. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 95, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 65, 66, and 67, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 68, 89, and 70, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 71, 72, and 73, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 74, 75, and 76, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 95. In one embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 96. In another embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 95, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 96. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 95. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 96. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 95, and (ii) a VL having the amino acid sequence of SEQ ID NO: 96. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 97. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 98. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 97, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 98. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence SEQ ID NO: 97. In another embodiment, the antibody comprises a light chain having the amino acid sequence SEQ ID NO: 98. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 97, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 98.

[0007] In some embodiments, the antibody that binds to Sdc2 is antibody clone TP-43329F. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 129, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 99, 100, and 101, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 102, 103, and 104, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 105, 106, and 107, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 108, 109, and 110, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 111, 112, and 113, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 114, 115, and 116, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 117, 118, and 119, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 120, 121, and 122, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 123, 124, and 125, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 126, 127, and 128, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 129. In one embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 130. In another embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 129, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 130. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 129. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 130. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 129, and (ii) a VL having the amino acid sequence of SEQ ID NO: 130. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 131. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 132. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 131, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 132. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 131. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 132. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 131, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 132.

[0008] In some embodiments, the antibody that binds to Sdc2 is antibody clone 8-G17A. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 163, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 164. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 133, 134, and 135, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 139, 140, and 141, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 142, 143, and 144, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 145, 146, and 147, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 148, 149, and 150, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 151, 152, and 153, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 154, 155, and 156, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 157, 158, and 159, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 160, 161, and 162, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 163. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 164. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 163, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 164. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 163. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 164. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 163, and (ii) a VL having the amino acid sequence of SEQ ID NO: 164. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 165. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 166. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 165, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 166. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 165. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 166. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 165, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 166.

[0009] In some embodiments, the antibody that binds to Sdc2 is antibody clone 6-N03-A. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 197, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 198. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 167, 168, and 169, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 170, 171, and 172, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 197. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 198. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 197, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 198. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 197. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 198. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 197, and (ii) a VL having the amino acid sequence of SEQ ID NO: 198. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 199. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 200. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 199, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 200. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 199. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 200. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 199, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 200.

[0010] In some embodiments, the antibody that binds to Sdc2 is antibody clone R3-P3-C11. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 231, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 232. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 201, 202, and 203, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 204, 205, and 206, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 207, 208, and 209, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 210, 211, and 212, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 213, 214, and 215, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 216, 217, and 218, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 219, 220, and 221, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 222, 223, and 224, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 225, 226, and 227, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 228, 229, and 230, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 231. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 232. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 231, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 232. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 231. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 232. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 231, and (ii) a VL having the amino acid sequence of SEQ ID NO: 232. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 233. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 234. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 233, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 234. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 233. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 234. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 233, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 234.

[0011] In some embodiments, the antibody that binds to Sdc2 is antibody clone R4M-P3-E06. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 265, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 266. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 235, 236, and 237, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 238, 239, and 240, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 241, 242, and 243, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 244, 245, and 246, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 247, 248, and 249, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 250, 251, and 252, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 253, 254, and 255, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 256, 257, and 258, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 259, 260, and 261, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 262, 263, and 264, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 265. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 266. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 265, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 266. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 265. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 266. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 265, and (ii) a VL having the amino acid sequence of SEQ ID NO: 266. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 267. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 268. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 267, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 268. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 267. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 268. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 267, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 268.

[0012] In some embodiments, the antibody that binds to Sdc2 is antibody clone R3-P3-E09. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 299, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 300. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 290, 292, and 292, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 293, 294, and 295, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 299. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 300. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 299, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 300. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 299. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 300. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 299, and (ii) a VL having the amino acid sequence of SEQ ID NO: 300. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 301. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 302. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 301, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 302. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 301. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 302. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 301, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 302.

[0013] In some embodiments, the antibody that binds to Sdc2 is antibody clone R3-P1-C02. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 333, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 334. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 303, 304, and 305, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 306, 307, and 308, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 309, 310, and 311, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 312, 313, and 314, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 315, 316, and 317, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 318, 319, and 320, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 321, 322, and 323, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 324, 325, and 326, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 327, 328, and 329, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 330, 331, and 332, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 333. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 334. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 333, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 334. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 333. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 334. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 333, and (ii) a VL having the amino acid sequence of SEQ ID NO: 334. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 335. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 336. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 335, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 336. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 335. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 336. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 335, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 336.

[0014] In some embodiments, the antibody that binds to Sdc2 is antibody clone R3-P3-A12. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 367, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 368. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 337, 338, and 339, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 340, 341, and 342, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 343, 344, and 345, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 346, 347, and 348, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 349, 350, and 351, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 352, 353, and 354, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 355, 356, and 357, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 358, 359, and 360, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 361, 362, and 363, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 364, 365, and 366, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 367. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 368. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 367, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 368. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 367. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 368. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 367, and (ii) a VL having the amino acid sequence of SEQ ID NO: 368. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 369. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 370. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 369, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 370. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 369. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 370. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 369, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 370.

[0015] In some embodiments, the antibody that binds to Sdc2 is antibody clone R4M-P3-A12. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 401, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 402. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 389, 390, and 391, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 395, 396, and 397, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 398, 399, and 400, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 401. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 402. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 401, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 402. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 401. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 402. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 401, and (ii) a VL having the amino acid sequence of SEQ ID NO: 402. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 403. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 404. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 403, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 404. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 403. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 404. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 403, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 404.

[0016] In some embodiments, the antibody that binds to Sdc2 is antibody clone R4M-P1-A10. In certain embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 435, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 436. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 405, 406, and 407, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 408, 409, and 410, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 411, 412, and 413, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 414, 415, and 416, respectively. In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 417, 418, and 419, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 420, 421, and 422, respectively. In other embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 423, 424, and 425, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 426, 427, and 428, respectively.In some embodiments, the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 429, 430, and 431, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 432, 433, and 434, respectively. In one embodiment, the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 435. In another embodiment, the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 436. In one embodiment, the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 435, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 436. In one embodiment, the antibody comprises a VH having the amino acid sequence SEQ ID NO: 435. In another embodiment, the antibody comprises a VL having the amino acid sequence SEQ ID NO: 436. In one embodiment, the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 435, and (ii) a VL having the amino acid sequence of SEQ ID NO: 436. In one embodiment, the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 437. In another embodiment, the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 438. In one embodiment, the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 437, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 438. In one embodiment, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 437. In another embodiment, the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 438. In one embodiment, the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 437, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 438.

[0017] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 amino acid sequences are according to the Kabat numbering system. In other embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 amino acid sequences are according to the Chothia numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 amino acid sequences are according to the AbM numbering system, and in other embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 amino acid sequences are according to the Contact numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 amino acid sequences are according to the IMGT numbering system.

[0018] In one embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is a fully human antibody. In one embodiment, the antibody is an IgG antibody. In one embodiment, the IgG antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In one embodiment, the antibody comprises a kappa light chain. In one embodiment, the antibody comprises a lambda light chain. In one embodiment, the antibody is a monoclonal antibody. In one embodiment, the antibody is multivalent. In one embodiment, the antibody is a multispecific antibody.

[0019] In one embodiment, the antibody specifically binds to Sdc2. In one embodiment, Sdc2 is present on the surface of endothelial cells. In one embodiment, Sdc2 is present on the surface of neuronal cells.

[0020] In one aspect, a nucleic acid encoding an Sdc2 antibody provided herein is provided. In another aspect, a vector comprising a nucleic acid encoding an Sdc2 antibody provided herein is provided. In one aspect, a host cell comprising a vector comprising a nucleic acid encoding an Sdc2 antibody provided herein is provided. In another aspect, a kit comprising a vector comprising a nucleic acid encoding an Sdc2 antibody provided herein is provided. In yet another aspect, a kit comprising an antibody provided herein is provided. In certain embodiments, the kit further comprises a container. In certain embodiments, the kit further comprises packaging. In certain embodiments, the kit further comprises instructions for use.

[0021] In another aspect, a pharmaceutical composition is provided comprising an Sdc2 antibody provided herein and a pharmaceutically acceptable carrier. In one aspect, a method of producing a pharmaceutical composition is provided, comprising combining an Sdc2 antibody with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition.

[0022] In one aspect, provided is a method of reducing vascular cell permeability (also referred to herein as vascular permeability), comprising contacting a vascular cell with an Sdc2 antibody provided herein. In one aspect, provided is a method of reducing endothelial cell permeability (also referred to herein as endothelial permeability), comprising contacting an endothelial cell with an Sdc2 antibody provided herein.

[0023] In one aspect, a method for reducing VEGFA-induced endothelial cell permeability is provided, comprising contacting endothelial cells with an Sdc2 antibody provided herein either before, during, or after contacting the endothelial cells with VEGFA. In one embodiment, the endothelial cells are contacted with the Sdc2 antibody before contacting with VEGFA. In one embodiment, the endothelial cells are contacted with the Sdc2 antibody while contacting with VEGFA. In one embodiment, the endothelial cells are contacted with the Sdc2 antibody after contacting with VEGFA.

[0024] In one aspect, a method is provided for reducing vascular permeability in a subject, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In one aspect, a method is provided for reducing vascular leakage in a subject, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In one aspect, a method is provided for reducing endothelial permeability in a subject, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In certain embodiments of the methods provided herein, the subject has a disease caused in whole or in part by cells expressing Sdc2.

[0025] In certain embodiments, the subject is a human. In certain embodiments, the subject is a subject in need thereof. In certain embodiments, the subject has or is at risk of having an Sdc2-mediated disease or disorder. In certain embodiments, the subject has or is at risk of having a disease or disorder associated with vascular permeability. In certain embodiments, the subject has or is at risk of having a disease or disorder associated with vascular leakage. In certain embodiments, the subject has or is at risk of having a disease or disorder associated with endothelial permeability. Exemplary diseases and disorders are provided elsewhere herein and are contemplated in the provided methods.

[0026] In another aspect, provided herein are methods for preventing, treating, or modulating a disease caused in whole or in part by cells that express Sdc2, comprising administering to a subject an effective amount of an Sdc2 antibody provided herein. In some embodiments, the cells are endothelial cells. In some embodiments, the cells are neuronal cells.

[0027] In certain embodiments of the various methods provided herein, the disease is associated with vascular permeability or vascular leakage. In one embodiment, the disease is associated with vascular permeability. In one embodiment, the disease is associated with vascular permeability. In one embodiment, the disease is acute respiratory distress syndrome (ARDS). In one embodiment, the disease is COVID-19 induced ARDS. In one embodiment, the disease is hemorrhagic stroke. In one embodiment, the disease is ischemic stroke. In one embodiment, the disease is a neurological disease in which the BBB is altered or disrupted. In one embodiment, the disease is Parkinson's disease. In one embodiment, the disease is Alzheimer's disease. In one embodiment, the disease is Huntington's disease. In one embodiment, the disease is peripheral neuropathy. In one embodiment, the disease is traumatic brain injury. In one embodiment, the disease is epilepsy. In one embodiment, the disease is multiple sclerosis. In one embodiment, the disease is a neovascular ocular disease. In one embodiment, the disease is a cardiovascular disease. In one embodiment, the disease is myocardial infarction (also referred to herein as acute myocardial infarction (AMI)). In one embodiment, the disease is congestive heart failure. In one embodiment, the disease is blunt trauma injury. In one embodiment, the disease is peripheral vascular disease. In one embodiment, the disease is lymphedema. In one embodiment, the disease is POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Plasma Cell Disorder, Skin Changes) syndrome. In one embodiment, the disease is Pediatric Capillary Leak Syndrome. In one embodiment, the disease is Adult Capillary Leak Syndrome. In one embodiment, the disease is hydrocephalus. In one embodiment, the disease is lymphedema. In one embodiment, the disease is inflammation-associated edema. In one embodiment, the disease is an inflammatory disease. In one embodiment, the disease is systemic lupus erythematosus. In one embodiment, the disease is rheumatoid arthritis cardiovascular disease. In one embodiment, the disease is neovascular ocular disease. In one embodiment, the disease is AMD. In one embodiment, the disease is diabetic retinopathy. In one embodiment, the disease is stroke. In one embodiment, the disease is ischemic stroke. In one embodiment, the disease is hemorrhagic stroke. In one embodiment, the disease is cancer.

[0028] In another aspect, a method of treating stroke in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In another aspect, a method of treating ischemic stroke in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In some embodiments, the subject is treated with an ischemic stroke-associated brain lesion region. In one embodiment, administration of the antibody results in a reduction in endothelial cell permeability in or around the brain lesion region. In one embodiment, the endothelial cell permeability is VEGFA-induced endothelial cell permeability. In one embodiment, administration of the antibody results in a reduction in vascular permeability in or around the brain lesion region. In one embodiment, administration of the antibody results in a reduction in the size of the penumbra in the brain lesion region. In one embodiment, administration of the antibody results in a reduction in the size of edema in the brain lesion region. In one embodiment, administration of the antibody results in a reduction in the size of infarct in the brain lesion region. In one embodiment, the reduction in size is detected by MRI and / or measured in area or volume. In another aspect, provided is a method of treating hemorrhagic stroke in a subject, the method comprising administering to the subject an effective amount of an Sdc2 antibody provided herein.

[0029] In another aspect, a method of reducing ocular inflammation in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In some embodiments, administration of the antibody results in a reduction of one or more inflammatory markers in the choroid of the subject's eye. In one embodiment, the inflammatory marker is CD31 or F4 / 80. In one embodiment, administration of the antibody results in substantially the same expression of one or more endothelial markers in the choroid of the subject's eye. In one embodiment, the endothelial marker is ERG. In another aspect, a method of treating a neovascular ocular disease in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In another aspect, a method of treating diabetic retinopathy in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In another aspect, a method of treating AMD in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In one embodiment, administration of the antibody results in a reduction of central retinal thickness in the subject's eye. In one embodiment, the reduction in central retinal thickness is measured by optical coherence tomography (OCT). In one embodiment, administration of the antibody results in a reduction in endothelial permeability in the subject's fundus tissue. In one embodiment, the endothelial permeability is VEGFA-induced endothelial cell permeability. In one embodiment, the endothelial permeability is measured by fundus fluorescence angiography (FFA). In one embodiment, administration of the antibody results in a reduction in vascular permeability in the subject's fundus tissue. In one embodiment, the vascular permeability is measured by FFA. In one embodiment, administration of the antibody results in upregulation of Dep-1 surface expression on cells in the subject's fundus tissue. In one embodiment, administration of the antibody results in enhanced dephosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) protein at residue Y951 in cells in the subject's fundus tissue. In one embodiment, administration of the antibody results in a reduction in inflammation in the subject's fundus tissue. In one embodiment, administration of the antibody results in a reduction in the expression of one or more inflammatory markers in the subject's fundus tissue. In one embodiment, the inflammatory marker is selected from a pro-inflammatory cytokine and an immune cell surface protein.In one embodiment, the inflammatory marker is F4 / 80. In one embodiment, administration of the antibody does not result in a change in angiogenesis in the subject's fundus tissue. In one embodiment, the angiogenesis is choroidal neovascularization (CNV). In one embodiment, administration of the antibody does not result in a substantial change in the expression of one or more endothelial markers in the subject's fundus tissue. In one embodiment, the endothelial marker is ERG. In one embodiment, the endothelial marker is CD31. In one embodiment, the fundus tissue is the retina of the eye. In one embodiment, the fundus tissue is the macula of the eye. In one embodiment, the fundus tissue is the choroid of the eye. In one embodiment, administration of the antibody improves the subject's visual acuity. In one embodiment, the subject is a human suffering from or at risk of developing AMD.

[0030] In another aspect, a method of treating cardiovascular disease in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In another aspect, a method of treating congestive heart failure in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In another aspect, a method of treating myocardial infarction in a subject is provided, comprising administering to the subject an effective amount of an Sdc2 antibody provided herein. In one embodiment, administration of the antibody results in reduced endothelial permeability in cardiac tissue of the subject. In one embodiment, the endothelial permeability is VEGFA-induced endothelial cell permeability. In one embodiment, the endothelial permeability is measured by Evans Blue assay or dextran perfusion assay. In one embodiment, administration of the antibody results in reduced vascular permeability in cardiac tissue of the subject. In one embodiment, the vascular permeability is measured by Evans Blue assay or dextran perfusion assay. In one embodiment, administration of the antibody results in upregulation of Dep-1 surface expression on cells in cardiac tissue of the subject. In one embodiment, administration of the antibody results in enhanced dephosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) protein at residue Y951 in cells in cardiac tissue of the subject. In one embodiment, administration of the antibody results in reduced inflammation in cardiac tissue of the subject. In one embodiment, administration of the antibody results in reduced expression of one or more inflammatory markers in cardiac tissue of the subject. In one embodiment, the inflammatory marker is selected from a pro-inflammatory cytokine and an immune cell surface protein. In one embodiment, the inflammatory marker is CD11b, GM-CSF, MIG, CCL11, IL-3, IL-6, or TNF-α. In one embodiment, the reduced expression of one or more inflammatory markers occurs within about 24 hours, about 36 hours, or about 72 hours after administration of the antibody. In one embodiment, administration of the antibody results in an increased left ventricular (LV) ejection fraction (LVEF) of the subject's heart. In one embodiment, administration of the antibody results in an increased cardiac output of the subject's heart. In one embodiment, administration of the antibody results in a reduced LV end-diastolic dimension (LVEDD) of the subject's heart. In one embodiment, administration of the antibody results in a reduction in the LV end-systolic dimension (LVESD) of the subject's heart.In one embodiment, administration of the antibody results in a reduction in LV end-diastolic volume of the subject's heart. In one embodiment, administration of the antibody results in a reduction in LV end-systolic volume of the subject's heart. In one embodiment, administration of the antibody results in a reduction in LV mass of the subject's heart. In one embodiment, administration of the antibody results in an enhancement of fractional shortening of the subject's heart. In one embodiment, administration of the antibody results in an enhancement of the subject's ejection fraction. In one embodiment, administration of the antibody results in a reduction in the risk or duration of post-infarction ventricular tachycardia (VT) in the subject. In one embodiment, post-infarction VT in the subject is measured by electrocardiography with programmed stimulation of the subject's heart. In one embodiment, an increase in the number of stimuli to induce VT indicates a reduced risk of post-infarction VT in the subject. In one embodiment, a reduction in the duration of induced VT under low potassium conditions indicates a reduced risk of post-infarction VT in the subject, and optionally, a longer cycle length of induced VT indicates a reduced risk of post-infarction VT in the subject. In one embodiment, administration of the antibody results in a reduction in the risk of the subject having heart failure. In one embodiment, the risk is having heart failure within 1 to 3 months after a myocardial infarction. In one embodiment, the subject is a human who has suffered from or is at risk of developing an AMI.

[0031] In some embodiments of the methods provided herein, the subject is a human. In certain embodiments of the methods provided herein, the subject is a human subject in need thereof.

[0032] 5. Brief description of the drawings The following detailed description of preferred embodiments of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments that are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentation of the embodiments shown in the drawings. [Brief explanation of the drawings]

[0033] [Figure 1]1 is a table illustrating a list of mAbs of the present invention with a summary of their affinity for human Sdc2 (Kd) and functional activity as inhibition of VEGFA-induced vascular permeability in vitro.

[0034] [Figure 2A-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts the number of red blood cell populations. [Figure 2A-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts the number of leukocyte populations. [Figure 2B-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts platelet counts. [Figure 2B-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts hemoglobin counts.

[0035] [Figure 3A-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts glucose levels. [Figure 3A-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts total triglyceride levels. [Figure 3B-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts levels of total cholesterol. [Figure 3B-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts levels of total CO.

[0036] [Figure 4-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts fibrinogen levels. [Figure 4-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts levels of C-reactive protein (CRP). [Figure 4-3] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts amylase levels.

[0037] [Figure 5-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts levels of markers of liver function, including ALT. [Figure 5-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts levels of markers of liver function, including AST. [Figure 5-3] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts levels of markers of liver function, including bilirubin.

[0038] [Figure 6-1] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts markers of renal function, including creatinine (CRE). [Figure 6-2] 1 illustrates clinical chemistry results from a toxicology study of clone 20-H19-AB in non-human primates. The graph depicts markers of renal function, including blood urea nitrogen (BUN).

[0039] [Figure 7] Illustrates clinical chemistry results of a Miles toxicity assay in non-human primates using clone 20-H19-AB 24 hours after mAb injection.

[0040] [Figure 8] Illustrates functional assays of the 8-G17 antibody clone.

[0041] [Figure 9] 1 illustrates an assay to determine the binding affinity of the 8-G17 antibody clone.

[0042] [Figure 10] Illustrates functional assays of the 20-H19-AB antibody clone.

[0043] [Figure 11] 1 illustrates an assay to determine the binding affinity of the 20-H19-AB antibody clone.

[0044] [Figure 12] 1 illustrates a functional assay of the 20-H19-AB antibody clone using non-human primate cells.

[0045] [Figure 13] Illustrates the functional assay of the R3-P3-C11 antibody clone.

[0046] [Figure 14] 1 illustrates an assay for determining the binding affinity of the R3-P3-C11 antibody clone.

[0047] [Figure 15] Illustrates functional assays of the R4M-P3-E06 antibody clone.

[0048] [Figure 16] 1 illustrates an assay for determining the binding affinity of the R4M-P3-E06 antibody clone.

[0049] [Figure 17] Illustrates the functional assay of the R3-P3-E09 antibody clone.

[0050] [Figure 18] 1 illustrates an assay for determining the binding affinity of the R3-P3-E09 antibody clone.

[0051] [Figure 19] Illustrates the functional assay of the R3-P1-C02 antibody clone.

[0052] [Figure 20] 1 illustrates an assay for determining the binding affinity of the R3-P1-C02 antibody clone.

[0053] [Figure 21] Illustrates the functional assay of the R3-P3-A12 antibody clone.

[0054] [Figure 22] 1 illustrates an assay for determining the binding affinity of the R3-P3-A12 antibody clone.

[0055] [Figure 23] Illustrates functional assays of the R4M-P3-A12 antibody clone.

[0056] [Figure 24] 1 shows an assay to determine the binding affinity of the R4M-P3-A12 antibody clone.

[0057] [Figure 25] Illustrates functional assays of the R4M-P1-A10 antibody clone.

[0058] [Figure 26] 1 shows an assay to determine the binding affinity of the R4M-P1-A10 antibody clone.

[0059] [Figure 27] 1 illustrates a table listing antibody clones used in epitope binning studies.

[0060] [Figure 28] Illustrates raw sensorgrams of epitope binning studies. Saturating antibodies were 19838-10-I12-A 1983-20-H19-A.

[0061] [Figure 29-1] Figure 1 illustrates a matrix of raw blocking data from an epitope binning study. Clones that showed no binding to antigen in the saturation step are highlighted in gray (19838-20H19-AA, 19844-R3-P1-E07, 19844-R4M-P1-B01). These clones did not significantly bind to antigen in this assay, so they were removed in both directions. Clones with very fast off-rates (19844-R3-P1-C02, 19844-R4M-P1-A10, 19844-R4M-P3-A12) are highlighted in darker gray. Because saturation was not possible with these clones, they were removed as ligand but retained in the analyte direction in the analysis. [Figure 29-2] Figure 1 illustrates a matrix of raw blocking data from an epitope binning study. Clones that showed no binding to antigen in the saturation step are highlighted in gray (19838-20H19-AA, 19844-R3-P1-E07, 19844-R4M-P1-B01). These clones did not significantly bind to antigen in this assay, so they were removed in both directions. Clones with very fast off-rates (19844-R3-P1-C02, 19844-R4M-P1-A10, 19844-R4M-P3-A12) are highlighted in darker gray. Because saturation was not possible with these clones, they were removed as ligand but retained in the analyte direction in the analysis.

[0062] [Figure 30] Illustrates epitope binning of 18 antibodies against huSdc2.

[0063] [Figure 31-1] Illustrates an epitope binning clustergram. Antibody clusters share similar, but not necessarily identical, competition profiles. [Figure 31-2]Illustrates an epitope binning clustergram. Antibody clusters share similar, but not necessarily identical, competition profiles.

[0064] [Figure 32] The target region of Sdc2 is illustrated. Figure 32A is a diagram of the human Sdc2 protein, highlighting the region of the extracellular domain that represents the DEP1-binding region. Below is the amino acid sequence of a portion of the Sdc2 protein, highlighting the "AG3 peptide" that corresponds to the DEP1-binding region. Figure 32B is an alignment of the AG3 peptide region from human (top), mouse (middle), and pig (bottom).

[0065] [Figure 33] VE-cadherin staining patterns in cell cultures treated with VEGFA in the absence (left panel) or presence (right panel) of anti-Sdc2 antibody are shown.

[0066] [Figure 34] FIG. 1 is a schematic diagram of the pathomechanisms of vascular leakage and edema.

[0067] [Figure 35] 1 shows the MCA obscuration procedure used to establish the disease model in non-human primates.

[0068] [Figure 36] Quantification of infarct size using 2D FLAIR sequences in each plane by AMIRA software is shown.

[0069] [Figure 37] Quantification of the change in cardiac output relative to sham in mm 3 is shown 1 and 3 days after treatment.

[0070] [Figure 38] 1 shows exemplary MRI image buildups of test subjects receiving vehicle and anti-Sdc2 antibody.

[0071] [Figure 39A] This figure illustrates that intravitreal or systemic injection of polyclonal rabbit anti-mouse Sdc2 antibody (Ab3) was effective in reducing vascular leakage and lesion volume in a mouse model of AMD. Fundus fluorescence angiography (FFA) images obtained on day 7 after laser photocoagulation are shown from mice that received intravitreal or systemic injection of Ab3, anti-VEGF antibody, or vehicle control on days 3 and 6 after photocoagulation. [Figure 39B] 1 illustrates that intravitreal or systemic injection of polyclonal rabbit anti-mouse Sdc2 antibody (Ab3) was effective in reducing vascular leakage and lesion volume in an AMD mouse model. Quantification of vascular leakage at the lesion site on day 7 (end of experiment) is shown. [Figure 39C] This figure illustrates that intravitreal or systemic injection of a polyclonal rabbit anti-mouse Sdc2 antibody (Ab3) was effective in reducing vascular leakage and lesion volume in a mouse model of AMD. Optical coherence tomography (OCT) images obtained 7 days after laser photocoagulation are shown from mice that received intravitreal or systemic injections of anti-Sdc2 antibody, anti-VEGF antibody, or vehicle control on days 3 and 6 after photocoagulation. [Figure 39D] 1 illustrates that intravitreal or systemic injection of polyclonal rabbit anti-mouse Sdc2 antibody (Ab3) was effective in reducing vascular leakage and lesion volume in an AMD mouse model. Quantification of lesion volume at day 7 (end of experiment) is shown.

[0072] [Figure 40-1] Electroretinography (ERG) results from mice receiving intravitreal or systemic injection of anti-Sdc2 antibody Ab3, anti-VEGF antibody, or vehicle control on days 3 and 6 after photocoagulation are shown. As shown, the A- and B-wave amplitudes of control mice and mice injected with anti-Sdc2 antibody at different light intensities were not significantly different, indicating that injection of anti-Sdc2 antibody did not result in retinal dysfunction. [Figure 40-2]Electroretinography (ERG) results from mice receiving intravitreal or systemic injection of anti-Sdc2 antibody Ab3, anti-VEGF antibody, or vehicle control on days 3 and 6 after photocoagulation are shown. As shown, the A- and B-wave amplitudes of control mice and mice injected with anti-Sdc2 antibody at different light intensities were not significantly different, indicating that injection of anti-Sdc2 antibody did not result in retinal dysfunction.

[0073] [Figure 41A] Figure 1 illustrates that both intravitreal and systemic injection of anti-Sdc2 antibody Ab3 inhibited inflammatory infiltrates. Immunofluorescence microscopy images of dissected flat mounts of mouse choroid / retinal pigment epithelium (RPE) stained to visualize CD31, ERG, and F4 / 80 expression in mice receiving intravitreal or systemic injection of anti-Sdc2 or anti-VEGF antibodies are shown. [Figure 41B] 1 shows and illustrates that both intravitreal and systemic injection of anti-Sdc2 antibody Ab3 inhibited inflammatory infiltrates. Quantification of CD31, ERG, and F4 / 80 positive areas, respectively, is shown. [Figure 41C] 1 shows and illustrates that both intravitreal and systemic injection of anti-Sdc2 antibody Ab3 inhibited inflammatory infiltrates. Quantification of CD31, ERG, and F4 / 80 positive areas, respectively, is shown. [Figure 41D] 1 shows and illustrates that both intravitreal and systemic injection of anti-Sdc2 antibody Ab3 inhibited inflammatory infiltrates. Quantification of CD31, ERG, and F4 / 80 positive areas, respectively, is shown.

[0074] [Figure 42] Figure 1 illustrates that anti-Sdc2 antibody inhibited VEGFA-induced permeability in endothelial cells (EC). The Y-axis indicates the strength of cell adhesion, expressed as delta cell index (a unitless measurement). The X-axis indicates the time (in hours) after adding VEGFA or anti-Sdc2 antibody (Ab3) to endothelial cell cultures.

[0075] [Figure 43A]This study demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1 binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. Post-infarction left ventricular (LV) function (LVEF) (%) was measured. The dotted line represents the value of normal mice before surgery (from the literature). [Figure 43B] This demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1-binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. Cardiac output (ml / min) was measured. The dotted line represents the value for normal mice before surgery (from reference). [Figure 43C]This study demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1 binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. End-diastolic LV internal diameter (LVIDd) (mm) was measured. The dotted line represents the value of normal mice before surgery (from the literature). [Figure 43D] This study demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1 binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. End-systolic LV internal diameter (LVID) (mm) was measured. The dotted line represents the value of normal mice before surgery (from the literature). [Figure 43E]This demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1-binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function of these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. Ejection fraction (%) was measured. The dotted line represents the value for normal mice before surgery (from reference). [Figure 43F] This demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1-binding region of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function of these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. Fractional shortening (%) was measured. The dotted line represents the value for normal mice before surgery (from reference). [Figure 43G]This demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1-binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. LV mass (mg). The dotted line represents the value for normal mice before surgery (from reference). [Figure 43H] This study demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1 binding region of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. Cardiac output (μL) was measured. The dotted line represents the value of normal mice before surgery (from the literature). [Figure 43I]This study demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1 binding region of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. LV end-diastolic volume (μL) was measured. The dotted line represents the value of normal mice before surgery (from the literature). [Figure 43J] This study demonstrates that treatment with a polyclonal anti-Sdc2 antibody (Ab3) that binds to the Dep-1 binding domain of Sdc2 prevented the progression of post-myocardial infarction heart failure in a mouse myocardial infarction (MI) model. The MI model was created by surgically occluding the left anterior descending coronary artery (LAD) with a suture for 1 hour to induce ischemia, followed by removal of the suture to restore blood flow and tissue reperfusion. This procedure is sometimes referred to as ischemia-reperfusion (IR) surgery. MI model mice were treated with a single 4 mg / kg body weight dose of anti-Sdc2 antibody Ab3 administered intravenously via the tail vein immediately after reperfusion. A control group of mice received an equivalent amount of IgG instead of the anti-Sdc2 antibody. Cardiac function in these treated mice was measured using echocardiography (cardiac ultrasound) at 1, 7, 14 days, and 1 month after IR surgery. LV end-systolic volume (μL) was measured. The dotted line represents the value of normal mice before surgery (from the literature).

[0076] [Figure 44A]This figure illustrates that treatment with polyclonal anti-Sdc2 antibody (Ab3) reduced infarct size and infection in the hearts of MI model mice. Figure 44A shows Masson's trichrome staining images of the hearts of MI model mice treated with Ab3 or an IgG control. These images were taken one month after IR surgery. Each row represents a series of cross-sectional images of the mouse hearts at different cross-sectional depths. As shown, cardiac infarct size was visibly smaller in the Ab3-treated group compared with the IgG control group. Figure 44B shows immunohistochemical staining visualizing CD11b, a macrophage marker, in the cardiac tissue of MI mice treated with Ab3 or IgG. These images were taken one month after IR surgery. As shown, macrophage infiltration in cardiac tissue was reduced in the Ab3-treated group compared with the IgG control group, indicating that the level of tissue damage and inflammation in cardiac tissue was reduced after anti-Sdc2 treatment. Figure 44C shows 2,3,5-triphenyltetrazolium chloride (TTC) staining images of the hearts of MI model mice treated with Ab3 or IgG control. These images were taken 24 hours after IR surgery, and Figure 44D shows quantification of infarct size from this study. As shown, cardiac infarct size was significantly smaller in the group receiving Ab3 treatment compared to the group receiving the IgG control. [Figure 44B]This figure illustrates that treatment with polyclonal anti-Sdc2 antibody (Ab3) reduced infarct size and infection in the hearts of MI model mice. Figure 44A shows Masson's trichrome staining images of the hearts of MI model mice treated with Ab3 or an IgG control. These images were taken one month after IR surgery. Each row represents a series of cross-sectional images of the mouse hearts at different cross-sectional depths. As shown, cardiac infarct size was visibly smaller in the Ab3-treated group compared with the IgG control group. Figure 44B shows immunohistochemical staining visualizing CD11b, a macrophage marker, in the cardiac tissue of MI mice treated with Ab3 or IgG. These images were taken one month after IR surgery. As shown, macrophage infiltration in cardiac tissue was reduced in the Ab3-treated group compared with the IgG control group, indicating that the level of tissue damage and inflammation in cardiac tissue was reduced after anti-Sdc2 treatment. Figure 44C shows 2,3,5-triphenyltetrazolium chloride (TTC) staining images of the hearts of MI model mice treated with Ab3 or IgG control. These images were taken 24 hours after IR surgery, and Figure 44D shows quantification of infarct size from this study. As shown, cardiac infarct size was significantly smaller in the group receiving Ab3 treatment compared to the group receiving the IgG control. [Figure 44C]This figure illustrates that treatment with polyclonal anti-Sdc2 antibody (Ab3) reduced infarct size and infection in the hearts of MI model mice. Figure 44A shows Masson's trichrome staining images of the hearts of MI model mice treated with Ab3 or an IgG control. These images were taken one month after IR surgery. Each row represents a series of cross-sectional images of the mouse hearts at different cross-sectional depths. As shown, cardiac infarct size was visibly smaller in the Ab3-treated group compared with the IgG control group. Figure 44B shows immunohistochemical staining visualizing CD11b, a macrophage marker, in the cardiac tissue of MI mice treated with Ab3 or IgG. These images were taken one month after IR surgery. As shown, macrophage infiltration in cardiac tissue was reduced in the Ab3-treated group compared with the IgG control group, indicating that the level of tissue damage and inflammation in cardiac tissue was reduced after anti-Sdc2 treatment. Figure 44C shows 2,3,5-triphenyltetrazolium chloride (TTC) staining images of the hearts of MI model mice treated with Ab3 or IgG control. These images were taken 24 hours after IR surgery, and Figure 44D shows quantification of infarct size from this study. As shown, cardiac infarct size was significantly smaller in the group receiving Ab3 treatment compared to the group receiving the IgG control. [Figure 44D]This figure illustrates that treatment with polyclonal anti-Sdc2 antibody (Ab3) reduced infarct size and infection in the hearts of MI model mice. Figure 44A shows Masson's trichrome staining images of the hearts of MI model mice treated with Ab3 or an IgG control. These images were taken one month after IR surgery. Each row represents a series of cross-sectional images of the mouse hearts at different cross-sectional depths. As shown, cardiac infarct size was visibly smaller in the Ab3-treated group compared with the IgG control group. Figure 44B shows immunohistochemical staining visualizing CD11b, a macrophage marker, in the cardiac tissue of MI mice treated with Ab3 or IgG. These images were taken one month after IR surgery. As shown, macrophage infiltration in cardiac tissue was reduced in the Ab3-treated group compared with the IgG control group, indicating that the level of tissue damage and inflammation in cardiac tissue was reduced after anti-Sdc2 treatment. Figure 44C shows 2,3,5-triphenyltetrazolium chloride (TTC) staining images of the hearts of MI model mice treated with Ab3 or IgG control. These images were taken 24 hours after IR surgery, and Figure 44D shows quantification of infarct size from this study. As shown, cardiac infarct size was significantly smaller in the group receiving Ab3 treatment compared to the group receiving the IgG control.

[0077] [Figure 45]This figure illustrates that treatment with polyclonal anti-Sdc2 antibody (Ab3) reduced endothelial permeability in cardiac tissue of MI model mice 24 and 72 hours after MI by IR surgery. In particular, Figure 45A shows quantification of endothelial permeability measured using an FITC-dextran permeability assay 24 hours after PI surgery. Mice received an IV injection of FITC-dextran (70 Kda molecular weight) 24 hours after surgery and were then euthanized 1 hour after dextran injection. Mice were then perfused with 30 ml of PBS, and cardiac samples were collected and lysed to quantify FITC-dextran extravasation (using a fluorescent plate reader). As shown, endothelial permeability in mouse cardiac tissue was significantly reduced in the Ab3-treated group compared to the IgG control group. Figure 45B shows images and quantification of vascular leakage measured using Evans Blue. Mice were intravenously injected via the tail vein with Evans Blue, which binds to albumin, 72 hours after surgery and allowed to circulate for 1 hour before extravasation. The top panel shows actual photographs of the heart of an MI mouse taken 72 hours after surgery and after Evans Blue injection. Vascular leakage in the heart is observed when blood vessels begin to leak proteins, and thus Evans Blue, which binds to albumin, resulting in a bluish coloration of the cardiac tissue. The bottom panel shows quantification of vascular leakage measured from the area at risk of infarction and resting myocardium in this study (the Y-axis indicates the amount of leaked Evans Blue).

[0078] [Figure 46]This figure illustrates that treatment with polyclonal anti-Sdc2 antibody (Ab3) significantly reduced the induction of postinfarction ventricular tachycardia (VT) in MI mice. Figure 46A shows the VT duration in mice treated with Ab3 or IgG under normokalemic and hypokalemic conditions. Figure 46B shows that Ab3-treated mice, in contrast to IgG-treated mice, did not have a prolonged action potential duration (APD) under hypokalemic conditions. Figure 46C shows that more benign arrhythmias were induced in Ab3-treated mice compared with IgG-treated mice. These data indicate that anti-Sdc2 antibody treatment significantly increased the threshold for VT induction. Notably, an increased number of stimuli was required to induce VT or fibrillation (VF) in the anti-Sdc2 antibody-treated group, and the VT cycle length of induced VT was longer in the anti-Sdc2 antibody-treated group after programmed stimulation was observed. These animals were less prone to postinfarction ventricular arrhythmias and exhibited more benign arrhythmias.

[0079] [Figure 47] Plasma levels (pg / ml) of various biomarkers measured by ELISA 24 to 72 hours after an episode of induced MI in groups of mice receiving anti-Sdc2 antibody (Ab3) treatment or IgG control are shown. As shown, GM-CSF, MIG, eotaxin (CCL11), IL-3, IL-6, TNF-α, and MCP1 (CCL2) were identified as systemic biomarkers for AMI treatment. DETAILED DESCRIPTION OF THE INVENTION

[0080] 6. Detailed Description 6.1 Definition Various publications, articles, and patents are cited or described in the background and throughout this specification. All applications, publications, patents, and other references, GenBank citations, and ATCC citations cited herein are incorporated by reference in their entirety. Any discussion of documents, acts, materials, devices, articles, and the like which has been included in the specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items form part of the prior art with respect to any invention disclosed or claimed.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0082] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In case of conflict, the present specification, including definitions, will control.

[0083] The articles "a," "an," and "the" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. That is, these terms include plural referents unless the context clearly dictates otherwise. By way of example, "an element" means one element or more than one element.

[0084] As used herein, the terms "about" and "approximately," when referring to a measurable value, such as an amount, time period, etc., mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1% or less of a given value or range.

[0085] A disease or disorder is "alleviated" if the severity of a symptom of the disease or disorder, the frequency with which such symptoms are experienced by a patient, or both, are reduced.

[0086] As used herein, the connective term "and / or" between multiple listed elements is understood to encompass both individual and combined alternatives. For example, when two elements are connected by "and / or," the first alternative refers to the applicability of the first element without the second element. The second alternative refers to the applicability of the second element without the first element. The third alternative refers to the applicability of both the first and second elements. Any one of these alternatives is understood to fall within the meaning and thus meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the alternatives is also understood to fall within the meaning and thus meets the requirements of the term "and / or." Additionally, unless expressly stated to the contrary, "or" refers to an inclusive or, not an exclusive or. For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0087] The term "antibody," as used herein, refers to an immunoglobulin molecule that specifically binds to an antigen. An antibody can be an intact immunoglobulin from natural or recombinant sources, or it can be an immunoreactive portion or fragment of an intact immunoglobulin. The terms "antibody," "immunoglobulin," or "Ig" are used interchangeably herein and are used in the broadest sense, specifically to encompass, for example, individual anti-Sdc2 monoclonal antibodies (including agonist, antagonist, neutralizing, full-length, or intact monoclonal antibodies), anti-Sdc2 antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies, so long as they exhibit the desired biological activity), single-chain anti-Sdc2 antibodies, and fragments of anti-Sdc2 antibodies, as described below. Antibodies can be human, humanized, chimeric, and / or affinity matured, as well as antibodies from other species, such as mouse and rabbit. The term "antibody" is intended to include polypeptide products of B cells within the immunoglobulin class of polypeptides that are capable of binding to a specific molecular antigen and are composed of a pair of two identical polypeptide chains, each pair having one heavy chain (approximately 50-70 kDa) and one light chain (approximately 25 kDa), with the amino-terminal portion of each chain containing a variable region of about 100 to about 130 amino acids or more, and the carboxy-terminal portion of each chain containing a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2nd ed. 1995) and Kuby, Immunology (3rd ed. 1997). In certain embodiments, specific molecular antigens can be bound by antibodies provided herein that contain Sdc2 polypeptides, Sdc2 fragments, or Sdc2 epitopes. Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments of any of the above (e.g., antigen-binding fragments such as Sdc2-binding fragments), which refer to portions of antibody heavy or light chain polypeptides that retain some or all of the binding activity of the antibody from which the fragment is derived.Non-limiting examples of functional fragments (e.g., antigen-binding fragments such as Sdc2-binding fragments) include single-chain Fvs (scFvs) (including, e.g., monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab)2 fragments, F(ab')2 fragments, disulfide-linked Fvs (dsFvs), Fd fragments, Fv fragments, diabodies, triabodies, tetrabodies, and minibodies. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, e.g., antigen-binding domains or molecules containing an antigen-binding site that binds to an Sdc2 antigen (e.g., one or more CDRs of an anti-Sdc2 antibody). Such antibody fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (1989), Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995), Huston et al., 1993, Cell Biophysics 22:189-224, Pluckthun and Skerra, 1989, Meth. Enzymol. 178:497-515, and Day, Advanced Immunochemistry (2d ed. 1990). Anti-Sdc2 antibodies can be agonist or antagonist antibodies. Antagonist antibodies against Sdc2, including antibodies that inhibit Sdc2 activity, are described herein.

[0088] As used herein, the term "antibody" is used broadly and includes immunoglobulins or antibody molecules, including monoclonal or polyclonal human, humanized, composite, and chimeric antibodies, as well as antibody fragments. Generally, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen. Antibody structure is well known. Immunoglobulins can be assigned to five major classes (i.e., IgA, IgD, IgE, IgG, and IgM) depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subclassified as isotypes: IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Thus, the antibodies provided herein can be of any of the five major classes or corresponding subclasses. In specific embodiments, the antibodies provided herein are IgG1, IgG2, IgG3, or IgG4. Antibody light chains of vertebrate species can be assigned to one of two clearly distinct types, namely, kappa and lambda, based on the amino acid sequence of their constant domains. Thus, the antibodies provided herein, in certain embodiments, may contain a kappa light chain constant domain. The antibodies provided herein may also, in certain embodiments, contain a lambda light chain constant domain. According to certain embodiments, the antibodies provided herein comprise heavy and / or light chain constant regions derived from a rat or human antibody. In certain embodiments, the constant regions are human constant regions.

[0089] In addition to heavy and light chain constant domains, antibodies contain antigen-binding regions consisting of a light chain variable region (VL) and a heavy chain variable region (VH), each of which contains three domains: complementarity-determining region 1 (CDR1), CDR2, and CDR3. A "CDR" refers to one of the three hypervariable regions (HCDR1, HCDR2, or HCDR3) within the non-framework regions of an immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (LCDR1, LCDR2, or LCDR3) within the non-framework regions of an antibody VL β-sheet framework. Thus, a CDR is a variable region sequence flanked by framework region sequences. CDR regions are well known to those skilled in the art and have been defined, for example, by Kabat as the most hypervariable regions within antibody variable (V) domains (Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have also been structurally defined by Chothia as residues that are not part of the conserved β-sheet framework and therefore can adopt different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terms are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. Exemplary CDR region sequences are illustrated herein, for example, in the tables provided in the Examples below. The positions of CDRs within standard antibody variable regions have been determined by comparison of numerous structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Because the number of residues within hypervariable regions varies in different antibodies, additional residues relative to the standard positions are conventionally numbered a, b, c, etc. next to the residue number in the standard variable region numbering scheme (Al-Lazikani et al., supra (1997)). Such nomenclature is similarly well known to those skilled in the art.

[0090] The light chain variable region CDR1 domain is herein referred to interchangeably as LCDR1 or VL CDR1. The light chain variable region CDR2 domain is herein referred to interchangeably as LCDR2 or VL CDR2. The light chain variable region CDR3 domain is herein referred to interchangeably as LCDR3 or VL CDR3. The heavy chain variable region CDR1 domain is herein referred to interchangeably as HCDR1 or VH CDR1. The heavy chain variable region CDR2 domain is herein referred to interchangeably as HCDR2 or VH CDR2. The heavy chain variable region CDR1 domain is herein referred to interchangeably as HCDR3 or VH CDR3.

[0091] As used herein, the terms "hypervariable region," "HVR," or "HV," such as VH or VL, refer to the regions of an antibody variable region that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six hypervariable regions: three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3). Several hypervariable region descriptive methods are in use and are encompassed herein. The "Kabat" CDR is based on sequence variability and is the most commonly used (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). "Chothia" instead refers to the location of a structural loop (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When numbered using the Kabat numbering convention, the end of the Chothia CDR-HCDR1 loop varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; and if both 35A and 35B are present, the loop ends at 34). The "AbM" hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag). The "Contact" hypervariable regions are based on an analysis of available complex crystal structures.

[0092] Recently, a universal numbering system, the ImMunoGeneTics (IMGT) Information System®, has been developed and widely adopted (Lafranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003)). IMGT is a comprehensive information system specialized for immunoglobulins (IGs), T-cell receptors (CRs), and major histocompatibility complexes (MHCs) of humans and other vertebrates. Herein, CDRs are referred to both by their amino acid sequence and their location within the light or heavy chain. Because the "location" of CDRs within the structure of immunoglobulin variable domains is conserved across species and occurs in structures called loops, CDR and framework residues can be readily identified by using a numbering system that aligns variable domain sequences according to structural features. This information can be used to graft and replace CDR residues from one immunoglobulin into an acceptor framework, typically derived from a human antibody. An additional numbering system (AHon) was developed by Honegger and Pluckthun, J. Mol. Biol. 309:657-670 (2001). Correspondence between numbering systems, including, for example, Kabat numbering and the IMGT specific numbering system, is well known to those skilled in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). The exemplary system presented herein combines Kabat and Chothia. [Table 1]

[0093] The hypervariable regions may comprise "extended hypervariable regions" as follows: 24-36 or 24-34 (LCDR1), 46-56 or 50-56 (LCDR2), and 89-97 or 89-96 (LCDR3) for VL, and 26-35 or 26-35A (HCDR1), 50-65 or 49-65 (HCDR2), and 93-102, 94-102, or 95-102 (HCDR3) for VH. CDR sequences reflecting each of the above numbering schemes are provided herein, including in the tables in the Examples section below.

[0094] The term "constant region" or "constant domain" refers to the carboxy-terminal portions of the light and heavy chains that are not directly involved in binding an antibody to an antigen but exhibit various effector functions, such as interaction with Fc receptors. This term refers to the portion of an immunoglobulin molecule that contains the antigen-binding site and has a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region. The constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0095] The term "framework" or "FR" residues are those variable domain residues that flank the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those hypervariable region or variable domain residues other than CDR residues.

[0096] The terms "variable region," "variable domain," "V region," or "V domain" refer to a portion of an antibody light or heavy chain, generally located at the amino terminus of the light or heavy chain, approximately 120-130 amino acids in length for heavy chains and approximately 100-110 amino acids in length for light chains, and are used to determine the binding and specificity of each particular antibody for its particular antigen. The variable region of a heavy chain may be referred to as "VH." The variable region of a light chain may be referred to as "VL." The term "variable" refers to the fact that the sequences of certain segments of variable regions vary significantly among antibodies. The V regions mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not uniformly distributed throughout the 110-amino acid span of the variable region. Instead, V regions consist of less variable (e.g., relatively invariant) stretches of approximately 15-30 amino acids called framework regions (FRs) separated by shorter regions of greater variability (e.g., hypervariable) called "hypervariable regions," each approximately 9-12 amino acids in length. Each heavy-chain and light-chain variable region contains four FRs, which largely adopt a β-sheet configuration and are connected by three hypervariable regions, which form loops connecting, and in some cases, forming part of, the β-sheet structure. The hypervariable regions in each chain, along with hypervariable regions from other chains, are held in close proximity by the FRs and contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed. 1991)). The constant regions are not directly involved in binding the antibody to the antigen, but exhibit various effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The sequences of the variable regions vary significantly among different antibodies. In a specific embodiment, the variable regions are human variable regions.

[0097] The terms "variable region residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering system used for the heavy or light chain variable regions of the compilation of antibodies in Kabat et al., supra. When using this numbering system, the actual linear amino acid sequence may contain fewer amino acids depending on truncation of the FRs or CDRs of the variable domain, or additional amino acids depending on insertions into the FRs or CDRs. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 (residue 52a according to Kabat) and three inserted residues after residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody's sequence with the "standard" Kabat-numbered sequence at the regions of homology. The Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The "EU numbering system" or "EU index" is generally used when referring to residues within an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). "EU index as in Kabat" refers to the residue numbering of a human IgG1 EU antibody. Other numbering systems are described, for example, by AbM, Chothia, Contact, IMGT, and AHon, as noted above.

[0098] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations. The monoclonal antibodies provided herein may be produced by hybridoma methods, phage display techniques, single lymphocyte gene cloning techniques, or recombinant DNA methods. For example, monoclonal antibodies may be produced by hybridomas comprising B cells obtained from a transgenic non-human animal, such as a transgenic mouse or rat, whose genome includes human heavy chain and light chain transgenes.

[0099] As used herein, the term "antigen-binding fragment" refers to an antibody fragment, such as, for example, a diabody, Fab, Fab', F(ab'), Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (dsdiabody), single-chain antibody molecule (scFv), single-domain antibody (sdAb) scFv dimer (bivalent diabody), multispecific antibody formed from a portion of an antibody comprising one or more CDRs, camelized single-domain antibody, nanobody, domain antibody, bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise the complete antibody structure. An antigen-binding fragment can bind to the same antigen as the parent antibody or parent antibody fragment. According to certain embodiments, the antigen-binding fragment comprises a light chain variable region, a light chain constant region, and the Fd segment of a heavy chain. According to other specific embodiments, the antigen-binding fragment comprises Fab and F(ab'). In certain embodiments, the antigen-binding fragment exhibits at least one, if not some or all, of the biological functions attributed to an intact antibody, where the function includes at least binding to a target antigen (e.g., an Sdc2-binding fragment or an Sdc2-binding fragment).

[0100] As used herein, the term "single-chain antibody" refers to a conventional single-chain antibody in the art that comprises a heavy chain variable region and a light chain variable region linked by a short peptide of about 15 to about 20 amino acids. As used herein, the term "single-domain antibody" refers to a conventional single-domain antibody in the art that comprises a heavy chain variable region and a heavy chain constant region, or comprises only a heavy chain variable region.

[0101] As used herein, the term "multispecific antibody" refers to an antibody comprising a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In one embodiment, the first and second epitopes do not overlap or substantially do not overlap. In one embodiment, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In one embodiment, the multispecific antibody comprises a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody is a bispecific, trispecific, or tetraspecific antibody molecule.

[0102] As used herein, the term "bispecific antibody" refers to a multispecific antibody that binds to no more than two epitopes or two antigens. Bispecific antibodies are characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope (e.g., an epitope on the Sdc2 antigen) and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In one embodiment, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In one embodiment, a bispecific antibody comprises heavy and light chain variable domain sequences that have binding specificity for a first epitope and heavy and light chain variable domain sequences that have binding specificity for a second epitope. In one embodiment, a bispecific antibody comprises a half antibody, or fragment thereof, that has binding specificity for a first epitope and a half antibody, or fragment thereof, that has binding specificity for a second epitope. In one embodiment, the bispecific antibody comprises an scFv or fragment thereof that has binding specificity for a first epitope and an scFv or fragment thereof that has binding specificity for a second epitope.

[0103] The terms "antibody that specifically binds to Sdc2," "antibody that specifically binds to an Sdc2 epitope," and similar terms are also used interchangeably herein and refer to an antibody that specifically binds to an Sdc2 polypeptide (e.g., human Sdc2, such as a human Sdc2 polypeptide, antigen, or epitope), such as an Sdc2 antigen, or fragment, or epitope. An antibody that specifically binds to Sdc2 (e.g., human Sdc2) may bind to the extracellular domain of Sdc2 or a peptide derived from the extracellular domain. An antibody that specifically binds to Sdc2 (e.g., human Sdc2) may bind to the Dep-1 binding region of Sdc2. An antibody that specifically binds to an Sdc2 antigen (e.g., human Sdc2) may cross-react with related antigens (e.g., cynomolgus monkey Sdc2). In certain embodiments, an antibody that specifically binds to an Sdc2 antigen does not cross-react with other antigens. Antibodies that specifically bind to the Sdc2 antigen can be identified, for example, by immunoassays, Biacore®, or other techniques known to those skilled in the art. An antibody specifically binds to the Sdc2 antigen if it binds to the Sdc2 antigen with higher affinity than any cross-reactive antigens, as measured using laboratory techniques such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). Typically, a specific or selective response is at least twice the background signal or noise, and may exceed background by more than 10 times. For a discussion of antibody specificity, see, for example, Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989). An antibody that "binds to an antigen of interest" (e.g., a target antigen such as Sdc2) is one that binds to the antigen with sufficient affinity so that it is useful as a therapeutic agent in targeting cells or tissues expressing the antigen and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody to a "non-target" protein is less than about 10% of the binding of the antibody to its specific target protein, as determined, for example, by fluorescence-activated cell sorting (FACS) analysis or RIA.With respect to the binding of an antibody to a target molecule, the terms "specific binding," "specifically binds to," or "specific for" a particular polypeptide or epitope on a particular polypeptide target refer to binding that is measurably different from nonspecific interactions. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which is generally a molecule of similar structure that lacks binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, e.g., excess unlabeled target. In this case, specific binding is indicated when binding of the labeled target to the probe is competitively inhibited by excess unlabeled target. The terms "anti-Sdc2 antibody" and "antibody that binds Sdc2" refer to an antibody that can bind to Sdc2 with sufficient affinity such that the antibody is useful, for example, as a diagnostic agent when targeting Sdc2. The terms "specific binding," "specifically binding to," or "being specific for" a particular polypeptide or epitope on a particular polypeptide target, as used herein, refer to binding where a molecule binds to a particular polypeptide or an epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes. In certain embodiments, antibodies that bind to Sdc2 have a dissociation constant (K) of 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM or less. D In certain embodiments, an anti-Sdc2 antibody binds to an epitope of Sdc2 that is conserved between Sdc2 from different species (e.g., between human Sdc2 and cynomolgus monkey Sdc2). In certain embodiments, an antibody that "specifically binds to Sdc2" binds to Sdc2, preferably human Sdc2, at a concentration of 1×10 -8 M or less, 5×10 -9 M or less, 1×10 -9 M or less, 5×10 -10 M or less, or 1 x 10 -10 M or less, such as 1 x 10 -7 This refers to an antibody that binds with a KD of M or less.

[0104] The term "KD" refers to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). The KD value of an antibody can be determined using methods in the art in light of the present disclosure. For example, the KD of an antibody can be determined by using surface plasmon resonance, such as by using a biosensor system, e.g., a Biacore® system, or by using biolayer interferometry technology, such as an Octet RED96 system. The smaller the KD value of an antibody, the higher the affinity with which the antibody binds to a target antigen.

[0105] An "intact" antibody is one that contains, in addition to the antigen-binding site, a CL and at least a heavy chain constant region, CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, an intact antibody has one or more effector functions. In this regard, whether the antibody is an antibody fragment or an intact immunoglobulin, the antibody comprises a variable region, including a heavy chain variable region and a light chain variable region, which determine antigenicity. Antibodies are typically tetramers of immunoglobulin molecules. Antibodies can exist in a variety of forms, including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab, and F(ab)2, as well as single-chain antibodies (scFv) and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, scFv antibodies, and multispecific antibodies formed from antibody fragments.

[0106] The terms "anti-syndecan-2 antibody," "Sdc2 antibody," and related terms refer to an antibody that specifically binds to syndecan-2 under physiological conditions.

[0107] "Antibody heavy chain," as used herein, refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformation. The antibody heavy chain comprises a heavy chain variable region and a heavy chain constant region.

[0108] "Antibody light chain," as used herein, refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. α and β light chains refer to the two major antibody light chain isotypes. An antibody light chain comprises a light chain variable region and a light chain constant region. Together, the light chain variable region(s) and heavy chain variable region(s) of an antibody determine the antigenicity of the antibody.

[0109] As used herein, the term "synthetic antibody" refers to an antibody produced using recombinant DNA technology, such as, for example, an antibody expressed by a CHO cell as described herein. The term should also be taken to mean an antibody produced by synthesis of a DNA molecule encoding the antibody, which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, where the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence techniques that are available and well known in the art.

[0110] The term "coronavirus disease 2019" (COVID-19), as used herein, refers to the disease initially caused by infection of a subject with the novel 2019 coronavirus. The novel 2019 coronavirus is also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is initially caused by infection with SARS-CoV-2, which is characterized by eliciting a severe immune response in a subpopulation of individuals. The immune response to the SARS-CoV-2 virus and cells infected by it, combined with damage to lung cells caused by the SARS-CoV-2 virus itself, can result in acute respiratory distress syndrome in a subset of patients. COVID-19 may thereby require intubation, mechanical ventilation, and / or the use of a heart and lung bypass machine in a further subset of patients.

[0111] As used herein, the term "heterologous peptide" refers to any peptide, polypeptide, or protein whose sequence is selected so that the product of the fusion of this sequence has a sequence that differs from the wild-type sequences that flank the peptide to which it is fused.

[0112] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of a pharmaceutically acceptable carrier and at least one useful compound. A pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques for administering compounds exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, intraocular, pulmonary, and topical administration. The term "composition" is intended to encompass a product that optionally contains specified components (e.g., antibodies provided herein) in specified amounts.

[0113] As used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency for use in animals, and more particularly for use in humans, or listed in the United States Pharmacopeia, the European Pharmacopeia, or other generally recognized pharmacopeia. The term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not neutralize the biological activity or properties of a compound and is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0114] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a substance within or to a patient so that it may perform its intended function. Typically, such a construct is carried or transported from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds provided herein, and not harmful to the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible materials used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds provided herein and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compounds provided herein.For example, other additional ingredients that may be included in the pharmaceutical compositions used in the methods provided herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0115] As used herein, "syndecan-2," "Sdc2," "Sdc-2," "SDC-2," and similar terms are used interchangeably and refer to the protein encoded by the syndecan-2 gene (Sdc2). In some embodiments, the human Sdc2 and mouse Sdc2 proteins each comprise the following amino acid sequence: Human MRRAWILLTLGLVACVSAESRAELTSDKDMYLDNSSIEEASGVYPIDDDDYASASGSGADEDVESPELTTSRPLPKILLTSAAPKVETTTLNIQNKIPAQTKSPEETDKEKVHLSDSERKMDPAEEDTNVYTEKHSDSLFKRTEVLAAVIAGGVIGFLFAIFLILLLVYRMRKKDEGSYDLGERKPSSAAYQKAPTKEFYA (SEQ ID NO: 25) mouse MQRAWILLTLGLMACVSAETRTELTSDKDMYLDNSSIEEASGVYPIDDDDYSSASGSGADEDIESPVLTTSQLIPRIPLTSAASPKVETMTLKTQSITPAQTESPEETDKEEVDISEAEEKLGPAIKSTDVYTEKHSDNLFKRTEVLAAVIAGGVIGFLFAIFLILLLVYRMRKKDEGSYDLGERKPSSAAYQKAPTKEFYA (SEQ ID NO: 26)

[0116] As used herein, the term "syndecan-2 extracellular domain" or "Sdc-2 ECD" refers to a peptide having the sequence of the extracellular domain of syndecan-2, either isolated or linked to a heterologous peptide, and including its associated heparan sulfate chains. In certain embodiments, the extracellular domain of syndecan-2 may be derived from human, mouse, or porcine syndecan-2 protein. As a non-limiting example, the amino acid sequence of the extracellular domain of human syndecan-2 is as follows: MYLDNSSIEE ASGVYPIDDD DYASASGSGA DEDVESPELT TSRPLPKILL TSAAPKVETT TLNIQNKIPA QTKSPEETDK EKVHLSDSER KMDPAEEDTN VYTEKHSDSL FKRTEVLAAV IAGGVIGFLF AIFLILL (SEQ ID NO: 27)

[0117] As used herein, "Density-Enhanced Phophatease-1" or "Dep-1," unless otherwise indicated, refers to any native Dep-1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses unprocessed Dep-1 as well as any form of Dep-1 resulting from processing within a cell. The term also encompasses naturally occurring variants of Dep-1, such as splice variants or allelic variants. The amino acid sequence of an exemplary human Dep-1 is as follows:

[0118] The term "binding protein" refers to a protein comprising a portion (e.g., one or more binding regions, such as CDRs) that binds to Sdc2, including human and / or cynomolgus monkey Sdc2, and optionally a scaffold or framework portion (e.g., one or more scaffold or framework regions) that enables the binding portion to adopt a conformation that promotes binding of the binding protein to an Sdc2 polypeptide, fragment, or epitope. Examples of such binding proteins include antibodies, such as human antibodies, humanized antibodies, chimeric antibodies, recombinant antibodies, single-chain antibodies, diabodies, triabodies, tetrabodies, Fab fragments, F(ab')2 fragments, IgD antibodies, IgE antibodies, IgM antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, or IgG4 antibodies, and fragments thereof. Binding proteins may also include alternative protein scaffolds or artificial scaffolds, for example, with grafted CDRs or CDR derivatives. Such scaffolds include, but are not limited to, antibody-derived scaffolds containing mutations introduced to stabilize the three-dimensional structure of the binding protein, as well as fully synthetic scaffolds containing, for example, biocompatible polymers. See, for example, Korndorfer et al., 2003, Proteins: Structure, Function, and Bioinformatics 53(1):121-29, and Roque et al., 2004, Biotechnol. Prog. 20:639-54. In addition, peptide antibody mimics ("PAMs"), as well as scaffolds based on antibody mimics that utilize fibronectin components as scaffolds, can be used. In the context of the present disclosure, binding proteins are characterized by, for example, a dissociation constant (K D ) is 10 -7 In some embodiments, a binding protein (e.g., an antibody) is said to specifically or selectively bind to Sdc2 if it has a binding affinity of about 10 M or less. -7 M~about 10 -12 K of M D In certain embodiments, the binding protein (e.g., antibody) can specifically bind to Sdc2 at K D is 10-8 M or less or K D is 10 -9 In one embodiment, a binding protein (e.g., an antibody) can specifically bind to Sdc2 with high affinity if it has a mAb density of 1×10 M or less, as measured by Biacore®. -9 M~10×10 -9 K of M D In another embodiment, the binding protein (e.g., antibody) can specifically bind to purified human Sdc2 at a concentration of 0.1 x 10 as measured by KinExA™ (Sapidyne, Boise, ID). -9 M~1×10 -9 K of M D In yet another embodiment, the binding protein (e.g., antibody) can specifically bind to purified human Sdc2 at a concentration of 0.1 x 10 -9 M~10×10 -9 K of M D In certain embodiments, the binding protein (e.g., antibody) specifically binds to human Sdc2 expressed on cells at a concentration of 0.1 x 10 -9 M~1×10 -9 K of M D In some embodiments, the binding protein (e.g., antibody) specifically binds to human Sdc2 expressed on cells at a concentration of 1×10 -9 M~10×10 -9 K of M D In certain embodiments, the binding protein (e.g., antibody) specifically binds to human Sdc2 expressed on cells at a concentration of about 0.1 x 10 -9 M, approx. 0.5×10 -9 M, about 1 x 10 -9 M, about 5 x 10 -9 M, about 10 x 10 -9 M, or K in any range or interval thereof D In yet another embodiment, the binding protein (e.g., antibody) specifically binds to human Sdc2 expressed on cells at a concentration of 0.1 x 10 -9 M~10×10 -9 K of M DIn certain embodiments, the binding protein (e.g., antibody) can specifically bind to cynomolgus monkey Sdc2 expressed on cells at a concentration of 0.1 x 10 -9 M~1×10 -9 K of M D In some embodiments, the binding protein (e.g., antibody) specifically binds to cynomolgus monkey Sdc2 expressed on cells at a concentration of 1×10 -9 M~10×10 -9 K of M D In certain embodiments, the binding protein (e.g., antibody) specifically binds to cynomolgus monkey Sdc2 expressed on cells at about 0.1 x 10 -9 M, approx. 0.5×10 -9 M, about 1 x 10 -9 M, about 5 x 10 -9 M, about 10 x 10 -9 M, or K in any range or interval thereof D It specifically binds to cynomolgus monkey Sdc2 expressed on cells in vivo.

[0119] An "antigen" is a predetermined antigen to which an antibody can selectively bind. A target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide.

[0120] The terms "antigen-binding fragment," "antigen-binding domain," "antigen-binding region," and similar terms refer to a portion of an antibody that contains the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., CDRs).

[0121] The terms "binding" or "association" refer to interactions between molecules, including, for example, forming a complex. The interaction can be a non-covalent interaction, including, for example, hydrogen bonding, ionic bonding, hydrophobic interactions, and / or van der Waals interactions. A complex can also include the association of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the overall non-covalent interaction between a single antigen-binding site on an antibody and a single epitope on a target molecule, such as Sdc2, is the affinity of the antibody or functional fragment for that epitope. The dissociation rate (k) of an antibody for a monovalent antigen is off ) versus association rate (k on ) ratio (k off / k on ) is the dissociation constant K, which is inversely related to affinity D It is. K D The lower the value, the higher the affinity of the antibody. D The value of k varies with different antibody and antigen complexes. on and k off The dissociation constant K of the antibodies provided herein depends on both D Avidity can be determined using any of the methods provided herein or any other method known to those skilled in the art. Affinity at one binding site does not necessarily reflect the true strength of the interaction between an antibody and an antigen. When a complex antigen containing multiple repeating antigenic determinants, such as multivalent Sdc2, contacts an antibody containing multiple binding sites, antibody interaction with the antigen at one site increases the probability of reaction at a second site. The strength of multiple interactions between such a multivalent antibody and an antigen is called avidity. An antibody's avidity may be a better measure of its binding ability than the affinity of its individual binding sites. For example, as is sometimes found in the case of pentameric IgM antibodies, high avidity can compensate for low affinity. Although pentameric IgM antibodies may have lower affinity than IgG, the high avidity of IgM resulting from its multivalency allows them to effectively bind antigens.

[0122] When used in the context of anti-Sdc2 antibodies (e.g., antibodies and binding proteins that bind to Sdc2 and compete for the same epitope or binding site on a target), the term "compete" refers to competition as determined by an assay in which the antibody (or binding fragment) under study prevents or inhibits specific binding of a reference molecule (e.g., a reference antigen-binding protein such as a reference ligand or reference antibody) to a common antigen (e.g., Sdc2 or a fragment thereof). Many types of competitive binding assays can be used to determine whether a test antibody competes with a reference antibody for binding to Sdc2 (e.g., human Sdc2). Examples of assays that can be used include solid-phase direct or indirect RIA, solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahl et al., 1983, Methods in Enzymology 9:242-53), solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-19), solid-phase direct labeling assay, solid-phase direct sandwich assay (see, e.g., Harlow and Lane, Antibodies, A Laboratory Manual (1988)), solid-phase direct labeling RIA using I-125 label (see, e.g., Morel et al., 1988, Mol. Immunol. 25:7-15), and direct labeling RIA (Moldenhauer et al., 1988, J. Immunol. 25:7-15). (e.g., Sdc2, such as human Sdc2) bound to a solid surface, or cells bearing either an unlabeled test antigen-binding protein (e.g., a test anti-Sdc2 antibody) or a labeled reference antigen-binding protein (e.g., a reference anti-Sdc2 antibody). Competitive inhibition can be measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen-binding protein. Typically, the test antigen-binding protein is present in excess.Antibodies identified by competitive assays (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and / or antibodies that bind to an adjacent epitope sufficiently close to the epitope bound by the reference antibody that steric hindrance occurs. Further details regarding methods for determining competitive binding are described herein. Typically, when a competing antibody protein is present in excess, it inhibits specific binding of the reference antibody to a common antigen by at least 30%, e.g., 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more.

[0123] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to Sdc2 is substantially free of antibodies that do not bind to Sdc2). In addition, an isolated antibody is substantially free of cellular material or other contaminating proteins and / or other components from the cell or tissue source from which the antibody is derived, or, if chemically synthesized, substantially free of chemical precursors or other chemicals. The language "substantially free of cellular material" includes preparations of antibody in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced. Accordingly, an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 25%, 20%, 15%, 10%, 5%, or 1% (by dry weight) of heterologous protein (also referred to herein as "contaminating protein"). In certain embodiments, when an antibody is recombinantly produced, it is substantially free of culture medium, e.g., culture medium represents less than about 20%, 15%, 10%, 5%, or 1% of the volume of the protein preparation. In certain embodiments, when an antibody is produced by chemical synthesis, it is substantially free of chemical precursors or other chemicals, e.g., the antibody is separated from chemical precursors or other chemicals involved in the synthesis of the protein. Thus, such antibody preparations have less than about 30%, 25%, 20%, 15%, 10%, 5%, or 1% (by dry weight) of chemical precursors or compounds other than the antibody of interest. Contaminating components may include, but are not limited to, materials that would interfere with therapeutic use of the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In certain embodiments, the antibody is purified to (1) greater than 95% by weight of antibody, such as 96%, 97%, 98%, or 99%, as determined by the Lowry method (Lowry et al., 1951, J. Bio. Chem. 193:265-75); (2) sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a rotating cup sequencer; or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver staining.Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. In certain embodiments, the antibodies provided herein are isolated.

[0124] The term "fusion protein," as used herein, refers to a polypeptide comprising the amino acid sequence of an antibody and the amino acid sequence of a heterologous polypeptide or protein (e.g., a polypeptide or protein that is not normally part of an antibody (e.g., a non-anti-Sdc2 antigen-binding antibody)). The term "fusion," when used with respect to Sdc2 or an anti-Sdc2 antibody, refers to the association of a peptide or polypeptide, or a fragment, variant, and / or derivative thereof, with a heterologous peptide or polypeptide. In certain embodiments, a fusion protein retains the biological activity of Sdc2 or an anti-Sdc2 antibody. In certain embodiments, a fusion protein comprises an Sdc2 antibody VH region, VL region, VH CDRs (one, two, or three VH CDRs), and / or VL CDRs (one, two, or three VL CDRs), and the fusion protein binds to an Sdc2 epitope, Sdc2 fragment, and / or Sdc2 polypeptide.

[0125] The term "heavy chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 50 to 70 kDa, the amino-terminal portion of which contains a variable region of approximately 120 to 130 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The constant region can be one of five different types (e.g., isotypes) designated alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ) based on the amino acid sequence of the heavy chain constant region. Individual heavy chains vary in size, with α, δ, and γ containing approximately 450 amino acids, and μ and ε containing approximately 550 amino acids. When combined with light chains, these different types of heavy chains result in five well-known classes (e.g., isotypes) of antibodies: IgA, IgD, IgE, IgG, and IgM, respectively, including the four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0126] The term "light chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 25 kDa, the amino-terminal portion of which contains a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types of light chains, designated kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. The light chain may be a human light chain.

[0127] As used herein, the term "host" refers to an animal, such as a mammal (e.g., a human).

[0128] As used herein, the term "host cell" refers to a cell containing a nucleic acid molecule provided herein. A "host cell" can be any type of cell, for example, a primary cell, a cultured cell, or a cell from a cell line. In one embodiment, a "host cell" is a cell transfected with a nucleic acid molecule provided herein. In another embodiment, a "host cell" is the progeny or potential progeny of such a transfected cell. The progeny of a cell may or may not be identical to the parent cell due to mutations or environmental influences that may occur in subsequent generations, or due to integration of the nucleic acid molecule into the host cell genome. As used herein, the term "host cell" refers to a specific subject cell into which a nucleic acid molecule can be transfected, and the progeny or potential progeny of such a cell. The progeny of such a cell may not be identical to the parent cell into which the nucleic acid molecule was transfected due to mutations or environmental influences that may occur in subsequent generations, or due to integration of the nucleic acid molecule into the host cell genome.

[0129] As used herein, the term "expression" refers to the biosynthesis of a gene product. The term includes transcription of a gene into RNA. The term also includes translation of RNA into one or more polypeptides, and further includes all naturally occurring post-transcriptional and post-translational modifications. The expressed antibody can be in the cytoplasm of a host cell, in an extracellular environment such as the growth medium of a cell culture, or anchored to the cell membrane.

[0130] As used herein, the terms "peptide," "polypeptide," or "protein" may refer to a molecule composed of amino acids and recognized as a protein by those skilled in the art. Conventional one-letter or three-letter codes for amino acid residues are used herein. The terms "peptide," "polypeptide," and "protein" may be used interchangeably herein to refer to polymers of amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that are modified, either naturally or by intervention, e.g., disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, e.g., conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, e.g., unnatural amino acids), as well as other modifications known in the art.

[0131] The term "immune cell" is art-recognized and, as used herein, refers to any cell involved in host defense mechanisms, such as cells that produce pro-inflammatory cytokines and cells involved in tissue damage and / or disease pathogenesis. Examples of immune cells include, but are not limited to, T cells, B cells, natural killer cells, neutrophils, mast cells, macrophages, antigen-presenting cells (APCs), basophils, and eosinophils.

[0132] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for naturally occurring mutations that may be present in minor amounts, and each monoclonal antibody typically recognizes a single epitope on an antigen. In certain embodiments, a "monoclonal antibody," as used herein, is an antibody produced by a single hybridoma or other cell, and the antibody binds only to an Sdc2 epitope, as determined, for example, by ELISA or other antigen-binding or competitive binding assays known in the art. The term "monoclonal" is not limited to any particular method for producing the antibody. For example, monoclonal antibodies useful in the present disclosure can be prepared by the hybridoma method first described by Kohler et al., 1975, Nature 256:495, or can be made using recombinant DNA methods in bacterial or eukaryotic animal or plant cells (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using the techniques described, for example, in Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J. Mol. Biol. 222:581-97. Other methods for preparing clonal cell lines and the monoclonal antibodies expressed thereby are well known in the art. See, for example, Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed. 2002). Exemplary methods for producing monoclonal antibodies are provided in the Examples herein.

[0133] The term "naturally occurring," when used in reference to biological materials such as nucleic acid molecules, polypeptides, host cells, etc., refers to those found in nature and which have not been manipulated, modified, and / or altered (e.g., isolated, purified, selected) by humans.

[0134] As used herein, the term "human antibody" refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human, produced using any technique known in the art. This definition of a human antibody includes intact or full-length antibodies, fragments thereof, and / or antibodies comprising at least one human heavy and / or light chain polypeptide. This definition of a human antibody specifically excludes humanized antibodies, which comprise non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol. 227:381; Marks et al., 1991, J. Mol. Biol. 222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1:755-68). Also available for preparing human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985), Boerner et al., 1991, J. Immunol. 147(1):86-95, and van Dijk and van de Winkel, 2001, Curr. Opin. Pharmacol. 5:368-74. Human antibodies can be prepared by administering antigen to transgenic animals, e.g., mice, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66; Bruggemann and Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58; and U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, e.g., Li et al., 2006, Proc. Natl. Acad. Sci. USA 103:3557-62, regarding human antibodies generated via human B-cell hybridoma technology.

[0135] "Fully human" refers to an immunoglobulin, such as an antibody or antigen-binding fragment thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequence of an antibody), where the entire molecule is of human origin or consists of an amino acid sequence identical to the human form of the antibody.

[0136] As used herein, "humanized" and "chimeric" antibodies, or antigen-binding fragments thereof (such as Fv, Fab, Fab', F(ab')2, or other antigen-binding subsequences of antibodies), refer to immunoglobulins that contain minimal sequence derived from non-human sources. In most cases, humanized and chimeric immunoglobulins are immunoglobulins of human origin in which complementarity-determining region (CDR) residues are replaced with those from a non-human species such as mouse, rat, or rabbit possessing the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized and chimeric antibodies or antigen-binding fragments thereof may comprise residues that are found neither in the recipient human antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and optimize antibody performance. Generally, humanized and chimeric antibodies or their antigen-binding fragments comprise substantially all or at least one, and typically two, variable domains, with all or substantially all of the CDR regions corresponding to those of a non-human immunoglobulin and all or substantially all of the FR regions being those of a human immunoglobulin consensus sequence. The World Health Organization (WHO) International Nonproprietary Name (INN) Expert Group defined the requirements for an antibody of non-human origin to be considered "humanized." According to the guidelines, comparison of candidate antibodies to human sequences should be performed via the International Immunogenetics Information System® (IMGT®) DomainGapAlign tool (imgt.org). This tool queries the IMGT® database of antibody germline variable region genes, generating alignment scores only for germline sequence variable region exons, thus omitting CDR3 and portions of the J region from the analysis.For an antibody to be "humanized," in addition to being "closer to human than other species," the top "hit" must be human and the identity to the human sequence must be at least 85%; otherwise, the antibody will be designated as "chimeric." For further details, see Jones et al., Nature, 321:522-525, 1986; Reichmann et al., Nature, 332:323-329, 1988; Presta, Curr. Op. Struct. Biol., 2:593-596, 1992.

[0137] As used herein, the term "chimeric antibody" refers to an antibody in which the amino acid sequences of the immunoglobulin molecule are derived from two or more species. The variable regions of both the light and heavy chains often correspond to the variable regions of antibodies from one mammalian species (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capacity, while the constant regions correspond to the sequences of antibodies from another mammalian species (e.g., human) to avoid eliciting an immune response in that species. In some embodiments, the antibody comprises portions of the heavy and / or light chains that are identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) are identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567 and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55).

[0138] As used herein, the term "humanized antibody" refers to a non-human antibody that has been modified to increase its sequence similarity to human antibodies, such that the antibody's antigen-binding properties are retained but its antigenicity in humans is reduced. "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies comprising a human immunoglobulin (e.g., recipient antibody) in which native CDR residues have been replaced by residues from a corresponding CDR (e.g., donor antibody) of a non-human species, such as mouse, rat, rabbit, or non-human primate, having the desired specificity, affinity, and capacity. In some cases, one or more FR region residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may contain residues that are not found in the recipient antibody or donor antibody. These modifications are made to further refine antibody performance. A humanized antibody heavy or light chain may comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. In certain embodiments, a humanized antibody comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1988, Nature 332:323-29; Presta, 1992, Curr. Op. Struct. Biol. 2:593-96; Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; U.S. Patent Nos. 6,800,738, 6,719,971, 6,639,055, 6,407,213, and 6,054,297.

[0139] An "affinity matured" antibody is one that has one or more modifications (e.g., amino acid sequence variations, including changes, additions, and / or deletions) in one or more of its HVRs that result in improved affinity of the antibody for antigen compared to a parent antibody that does not have those modification(s). Affinity matured antibodies may have nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For reviews, see Hudson and Souriau, 2003, Nature Medicine 9:129-34; Hoogenboom, 2005, Nature Biotechnol. 23:1105-16; Quiroz and Sinclair, 2010, Revista Ingeneria Biomedia 4:39-51.

[0140] A "blocking" or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds. For example, a blocking or antagonist antibody can substantially or completely inhibit the biological activity of the antigen.

[0141] An "agonist" antibody is one that elicits a response, e.g., a response that mimics at least one of the functional activities of a polypeptide of interest. Agonist antibodies include antibodies that are ligand mimetics, e.g., where a ligand binds to a cell surface receptor and binding induces cell signaling or activity through an intercellular cell signaling pathway, and the antibody induces similar cell signaling or activation.

[0142] "Binding affinity" generally refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., a binding protein such as an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a binding molecule X for its binding partner Y is generally determined by the dissociation constant (K D) Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies generally bind antigens slowly and tend to dissociate easily, whereas high affinity antibodies generally bind antigens faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present disclosure. Specific illustrative embodiments include the following. In one embodiment, "K" is used to measure affinity. D " or "K D The "K value" can be measured by assays known in the art, for example, binding assays. D can be measured, for example, in an RIA performed using the Fab version of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). D or K D The "on-rate" or "rate of association" or "association rate" or "k" value can also be measured by using a surface plasmon resonance assay by Biacore®, for example, using a Biacore® TM-2000 or Biacore® TM-3000, or by biolayer interferometry, for example, using an Octet® QK384 system. on " can also be determined by the same surface plasmon resonance or biolayer interferometry methods described above, for example, using a Biacore® TM-2000 or Biacore® TM-3000 or Octet® QK384 system.

[0143] The phrases "substantially similar" or "substantially the same" are used by those skilled in the art to determine the value (e.g., K DA "value" indicates a sufficiently high similarity between two numerical values ​​(e.g., one associated with an antibody of the present disclosure and the other associated with a reference antibody) such that a difference between the two values ​​is considered to have little or no biological and / or statistical significance within the context of a biological property measured by the value of the reference antibody. For example, the difference between the two values ​​can be less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, or less than about 5% as a function of the value of the reference antibody.

[0144] As used herein, the phrases "substantially increased," "substantially reduced," or "substantially different" refer to a difference between two numerical values ​​(e.g., one associated with an antibody of the present disclosure and the other associated with a reference antibody) that is sufficiently high that one of skill in the art would consider the difference between the two values ​​to have statistical significance within the context of the biological property measured by the values. For example, the difference between the two values ​​can be greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or greater than about 50% as a function of the value of the reference antibody.

[0145] The terms "inhibition" or "inhibiting" as used herein refer to partial (1%, 2%, 5%, 10%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, etc.) or complete (i.e., 100%) inhibition.

[0146] "Antibody effector functions" refer to the biological activities attributable to the Fc region of an antibody (e.g., a native sequence Fc region or an amino acid sequence variant Fc region) and vary with the antibody isotype. Examples of antibody effector functions include, but are not limited to, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0147] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, including, for example, native-sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the Fc region of a human IgG heavy chain is often defined to extend from an amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification or by recombinantly engineering a nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition may include an antibody population with all K447 residues removed, an antibody population without the K447 residue removed, and an antibody population having a mixture of antibodies with and without the K447 residue.

[0148] A "functional Fc region" possesses an "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and the like. Such effector functions generally require that the Fc region be combined with a binding region or domain (e.g., an antibody variable region or domain), and can be assessed using a variety of assays as disclosed.

[0149] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature, and has not been manipulated, modified, and / or altered (e.g., isolated, purified, selected, or combined with other sequences such as variable region sequences) by human beings. Native sequence human IgG1 Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes), native sequence human IgG2 Fc regions, native sequence human IgG3 Fc regions, and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0150] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification (e.g., substitution, addition, or deletion). In certain embodiments, a variant Fc region has at least one amino acid substitution compared to a native-sequence Fc region or the Fc region of a parent polypeptide, e.g., about 1 to about 10 amino acid substitutions, or about 1 to about 5 amino acid substitutions in a native-sequence Fc region or the Fc region of a parent polypeptide. A variant Fc region herein may have at least about 80% homology to a native-sequence Fc region and / or the Fc region of a parent polypeptide, or at least about 90% homology thereto, e.g., at least about 95% homology thereto.

[0151] The term "variant," when used with respect to Sdc2 or anti-Sdc2 antibodies, can refer to a peptide or polypeptide that contains one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) amino acid substitutions, deletions, and / or additions relative to the native or unmodified sequence. For example, an Sdc2 variant can result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) changes in the amino acid sequence of native Sdc2. Also, by way of example, anti-Sdc2 antibody variants can result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) changes to the amino acid sequence of a native or previously unmodified anti-Sdc2 antibody. Variants can be naturally occurring, such as alleles or splice variants, or can be artificially constructed. Polypeptide variants can be prepared from corresponding nucleic acid molecules encoding the variants. In certain embodiments, Sdc2 variants or anti-Sdc2 antibody variants retain at least Sdc2 or anti-Sdc2 antibody functional activity, respectively. In certain embodiments, anti-Sdc2 antibody variants bind to Sdc2 and / or are antagonists of Sdc2 activity. In certain embodiments, anti-Sdc2 antibody variants bind to Sdc2 and / or are agonists of Sdc2 activity. In certain embodiments, the variants are encoded by single nucleotide polymorphism (SNP) variants in nucleic acid molecules encoding Sdc2 or anti-Sdc2 antibody VH or VL regions or subregions, such as one or more CDRs.

[0152] As used herein, the term "vector" is a replicon into which another nucleic acid segment may be operatively inserted so as to bring about the replication or expression of the segment.

[0153] The term "vector" refers to a substance used to carry or contain a nucleic acid sequence, including, for example, a nucleic acid sequence encoding an anti-Sdc2 antibody described herein, for introducing a nucleic acid sequence into a host cell. Vectors that can be used include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, and may contain a selection sequence or selection marker for stable integration into a host cell chromosome. In addition, a vector may contain one or more selection marker genes and appropriate expression control sequences. Selection marker genes that can be included, for example, confer resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not present in the culture medium. Expression control sequences may include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, as are well known in the art. When two or more nucleic acid molecules (e.g., both antibody heavy and light chains, or both antibody VH and VL) are to be coexpressed, both nucleic acid molecules can be inserted, for example, into a single expression vector or into separate expression vectors. In the case of single vector expression, the encoding nucleic acids may be operably linked to one common expression control sequence or to different expression control sequences, such as one inducible promoter and one constitutive promoter. Introduction of nucleic acid molecules into host cells can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blot or polymerase chain reaction (PCR) amplification of mRNA, immunoblotting for expression of gene products, or other analytical methods suitable for testing the expression of the introduced nucleic acid sequence or its corresponding gene product. It will be understood by those skilled in the art that the nucleic acid molecule will be expressed in an amount sufficient to produce the desired product (e.g., the anti-Sdc2 antibody described herein), and it will further be understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0154] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted immunoglobulins bound to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to specifically bind to antigen-bearing target cells and subsequently cytotoxically kill the target cells. These antibodies "arm" the cytotoxic cells and are essential for such killing. NK cells, the primary cells for mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is known (see, e.g., Ravetch and Kinet, 1991, Annu. Rev. Immunol. 9:457-92). To assess the ADCC activity of a molecule of interest, an in vitro ADCC assay (see, e.g., U.S. Patent Nos. 5,500,362 and 5,821,337) can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or additionally, the ADCC activity of a molecule of interest can be assessed in vivo, for example, in an animal model (see, e.g., Clynes et al., 1998, Proc. Natl. Acad. Sci. USA 95:652-56). Antibodies with little or no ADCC activity can be selected for use.

[0155] "Antibody-dependent cellular phagocytosis" or "ADCP" refers to the destruction of target cells via monocyte- or macrophage-mediated phagocytosis, when immunoglobulins bound to Fc receptors (FcRs) present on certain phagocytes (e.g., neutrophils, monocytes, and macrophages) enable these phagocytes to specifically bind to antigen-bearing target cells and subsequently kill them. To assess the ADCP activity of a molecule of interest, an in vitro ADCP assay (e.g., Bracher et al., 2007, J. Immunol. Methods 323:160-71) can be performed. Phagocytic cells useful for such assays include peripheral blood mononuclear cells (PBMCs), purified monocytes derived from PBMCs, or mononuclearly differentiated U937 cells. Alternatively, or additionally, the ADCP activity of the molecule of interest can be assessed in vivo, for example, in an animal model (see, e.g., Wallace et al., 2001, J. Immunol. Methods 248:167-82). Antibodies with little or no ADCP activity can be selected for use.

[0156] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. An exemplary FcR is a native-sequence human FcR. Further exemplary FcRs are those that bind IgG antibodies (e.g., gamma receptors) and include receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains (see, e.g., Daeron, 1997, Annu. Rev. Immunol. 15:203-34). Various FcRs are known (see, e.g., Ravetch and Kinet, 1991, Annu. Rev. Immunol. 9:457-92; Capel et al., 1994, Immunomethods 4:25-34; and de Haas et al., 1995, J. Lab. Clin. Med. 126:330-41). Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein. This term also includes FcRn, the neonatal receptor responsible for the transfer of maternal IgG to the fetus (see, e.g., Guyer et al., 1976, J. Immunol. 117:587-93; and Kim et al., 1994, Eu. J. Immunol. 24:2429-34). Antibody variants with improved or diminished binding to FcRs have been described (see, e.g., WO 2000 / 42072, U.S. Patent Nos. 7,183,387, 7,332,581, and 7,335,742; Shields et al. 2001, J. Biol. Chem. 9(2):6591-604).

[0157] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate subclass) that binds its cognate antigen. To assess complement activation, a CDC assay (e.g., Gazzano-Santoro et al., 1996, J. Immunol. Methods 202:163) can be performed. Polypeptide variants with altered Fc region amino acid sequences (polypeptides with variant Fc regions) and increased or decreased C1q binding ability have been described (see, e.g., U.S. Patent No. 6,194,551; WO 1999 / 51642; Idusogie et al., 2000, J. Immunol. 164:4178-84). Antibodies with little or no CDC activity can be selected for use.

[0158] An Sdc2 polypeptide "extracellular domain" or "ECD" refers to a form of an Sdc2 polypeptide that is essentially free of transmembrane and cytoplasmic domains. For example, an Sdc2 polypeptide ECD may have less than 1% of such transmembrane and / or cytoplasmic domains, and may have less than 0.5% of such domains.

[0159] The term "identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. "Percent (%) amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment across the full length of the sequences being compared.

[0160] The terms "identical" or "percent identity" in the context of two or more polypeptide sequences (e.g., Sdc2 antibodies) or nucleic acid sequences thereof refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same when compared and aligned for maximum correspondence, as determined using one of the following sequence comparison algorithms or by visual inspection.

[0161] For sequence comparison, typically, one sequence serves as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated as necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence based on the designated program parameters.

[0162] Optimal alignment of sequences for comparison can be determined, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), the similarity search method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or visual inspection (see generally, Current Protocols in Molecular Biology, F.M.A.usubel et al., eds., Current Protocols, a joint venture between Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., (1995) This can be performed by the Ausubel method (see Supplement).

[0163] Examples of algorithms suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves identifying high-scoring sequence pairs (HSPs) by first identifying short words W in the query sequence that match or meet some positive threshold score T when aligned with words of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits serve as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased.

[0164] Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues, always >0) and N (penalty score for mismatching residues, always <0). For amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. Extension of the word hits in each direction is halted when: the cumulative alignment score falls by a quantity X from its maximum achieved value; the accumulation of one or more negative-scoring residue alignments causes the cumulative score to fall below zero; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).

[0165] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, for example, Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the minimum total probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered to be similar to a reference sequence if the minimum total probability in the comparison between the test nucleic acid and the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

[0166] A further indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.

[0167] A "modification" of an amino acid residue / position refers to a change in the primary amino acid sequence compared to the starting amino acid sequence, which change results from a change in the sequence involving that amino acid residue / position. For example, typical modifications include substitution of the residue with another amino acid (e.g., a conservative or non-conservative substitution), insertion of one or more (e.g., generally less than 5, 4, or 3) amino acids adjacent to that residue / position, and / or deletion of that residue / position.

[0168] An "epitope" is a site on the surface of an antigen molecule, such as a localized region on the surface of an antigen, such as an Sdc2 polypeptide or Sdc2 polypeptide fragment, to which a single antibody molecule binds. It is capable of binding to one or more antigen-binding regions of an antibody, has antigenic or immunogenic activity, and is capable of eliciting an immune response in an animal, such as a mammal (e.g., a human). An epitope with immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal. An epitope with antigenic activity is a portion of a polypeptide to which an antibody binds, as determined by any method known in the art, including, for example, immunoassays. An antigenic epitope is not necessarily immunogenic. Epitopes often consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and have specific three-dimensional structural characteristics and specific charge characteristics. Antibody epitopes can be linear or conformational epitopes. Linear epitopes are formed by a continuous sequence of amino acids in a protein. Conformational epitopes are formed by amino acids that are discontinuous in the protein sequence but come together when the protein folds into its three-dimensional structure. Induced epitopes are formed when the three-dimensional structure of a protein is in an altered conformation, such as after activation or binding of another protein or ligand. In certain embodiments, the Sdc2 epitope is a three-dimensional surface feature of the Sdc2 polypeptide. In other embodiments, the Sdc2 epitope is a linear feature of the Sdc2 polypeptide. Generally, an antigen may have several or many different epitopes and react with many different antibodies.

[0169] If two antibodies recognize the same, overlapping, or adjacent epitopes in three-dimensional space, the antibodies bind to the "epitope," "essentially the same epitope," or "the same epitope" as a reference antibody. The most widely used and rapid method for determining whether two antibodies bind to the same, overlapping, or adjacent epitopes in three-dimensional space is a competitive assay, which can be configured in several different formats, for example, using either labeled antigen or labeled antibody. In some assays, the antigen is immobilized on a 96-well plate or expressed on a cell surface, and the ability of an unlabeled antibody to block the binding of the labeled antibody is measured using radioactive, fluorescent, or enzymatic labels.

[0170] "Epitope mapping" is the process of identifying the binding sites, or epitopes, of antibodies on their target antigens. "Epitope binning" is the process of grouping antibodies based on the epitopes they recognize. More specifically, epitope binning includes methods and systems for distinguishing the epitope recognition characteristics of different antibodies using competitive assays combined with computational processes to cluster antibodies based on their epitope recognition characteristics, identifying antibodies with different binding specificities.

[0171] An "effective amount" of a delivery vehicle is an amount sufficient to effectively bind or deliver a compound. An "effective amount" is generally an amount sufficient to reduce the severity and / or frequency of symptoms, eliminate symptoms and / or underlying causes, prevent the occurrence of symptoms and / or underlying causes, and / or ameliorate or repair damage caused by or associated with a disease, disorder, or condition, including, for example, Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)). In some embodiments, an effective amount is a therapeutically effective amount or a prophylactically effective amount.

[0172] As used herein, the term "therapeutically effective amount" refers to an amount of an agent (e.g., an antibody provided herein or any other agent described herein) sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder, or condition, and / or its associated symptoms, such as Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)). A "therapeutically effective amount" of a substance / molecule / agent of the present disclosure (e.g., an anti-Sdc2 antibody) may vary depending on factors such as the individual's medical condition, age, sex, and weight, as well as the ability of the substance / molecule / agent to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the substance / molecule / agent. In certain embodiments, the term "therapeutically effective amount" refers to an amount of an antibody or other agent (e.g., a drug) effective to "treat" a disease, disorder, or condition in a subject or mammal.

[0173] A "prophylactically effective amount" is an amount of a pharmaceutical composition that, when administered to a subject, has the intended prophylactic effect, e.g., preventing, delaying, or reducing the likelihood of onset (or recurrence) of a disease, disorder, condition, or associated symptom(s), e.g., Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)). Typically, although not necessarily, a prophylactically effective amount may be less than the therapeutically effective amount, since a prophylactic dose is used in a subject prior to or at an earlier stage of a disease, disorder, or condition. A complete therapeutic or prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations.

[0174] "Chronic" administration refers to administering an agent(s) in a continuous mode (e.g., over a period of days, weeks, months, or years), as opposed to an acute mode, to maintain the initial therapeutic effect (activity) over an extended period of time. "Intermittent" administration is treatment that is cyclic in nature, rather than continuous without interruption.

[0175] As used herein, "carrier" refers to a pharmaceutically acceptable carrier, excipient, or stabilizer that is nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, physiologically acceptable carriers are pH-buffered aqueous solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citric acid, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., less than about 10 amino acid residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. The term "carrier" can also refer to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), excipient, or vehicle. Such carriers, including pharmaceutical carriers, can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the composition (e.g., pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable excipients (e.g., pharmaceutical excipients) include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. The compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.Oral compositions containing formulations may contain standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington and Gennaro, Remington's Pharmaceutical Sciences (18th ed. 1990). Compositions containing pharmaceutical compounds may contain anti-Sdc2 antibodies, for example, in isolated or purified form, together with a suitable amount of carrier.

[0176] "Polyclonal antibody," as used herein, refers to an antibody population generated in an immunogenic response to a protein with many epitopes, and thus includes a variety of different antibodies directed to the same or different epitopes within the protein. Methods for producing polyclonal antibodies are known in the art (see, e.g., Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed. 2002)).

[0177] An "isolated nucleic acid" is a nucleic acid, e.g., RNA, DNA, or mixed nucleic acid, that has been substantially separated from other genomic DNA sequences and proteins or complexes, such as ribosomes and polymerases, that naturally accompany the native sequence. An "isolated" nucleic acid molecule is one that is separated from other nucleic acid molecules that are present in the nucleic acid molecule's natural source. Furthermore, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium if produced by recombinant techniques, or substantially free of chemical precursors or other chemicals if chemically synthesized. In certain embodiments, one or more nucleic acid molecules encoding an antibody described herein are isolated or purified. This term encompasses nucleic acid sequences that have been removed from their naturally occurring environment, including recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biologically synthesized by heterologous systems. A substantially pure molecule can include a molecule in isolated form.

[0178] As used herein, the term "polynucleotide," which is synonymously referred to as "nucleic acid molecule," "nucleotide," or "nucleic acid," refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA, or modified RNA or DNA. "Polynucleotide" includes single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is a mixture of single- and double-stranded regions. This includes, but is not limited to, hybrid molecules containing DNA and RNA, which may be single-stranded or, more typically, double-stranded, or may be a mixture of single- and double-stranded regions. Additionally, "polynucleotide" refers to triple-stranded regions containing RNA or DNA, or both RNA and DNA. The term polynucleotide also includes DNA or RNA containing one or more modified bases and DNA or RNA with backbones modified for stability or other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. Various modifications can be made to DNA and RNA, and thus "polynucleotide" encompasses chemically, enzymatically, or metabolically modified forms of polynucleotides typically found in nature, as well as chemical forms of DNA and RNA characteristic of viruses and cells. "Polynucleotide" also encompasses relatively short nucleic acid chains, often referred to as oligonucleotides. "Polynucleotide" and "nucleic acid" are used interchangeably herein to refer to polymers of nucleotides of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Polynucleotides may contain modified nucleotides, such as methylated nucleotides and their analogs. "Oligonucleotide," as used herein, refers to a short, synthetic polynucleotide that is generally single-stranded, generally, but not necessarily, less than about 200 nucleotides in length. The terms "oligonucleotide" and "polynucleotide" are not mutually exclusive. The above description of polynucleotides is equally and fully applicable to oligonucleotides. Cells that produce the anti-Sdc2 antibodies of the present disclosure can include parent hybridoma cells, as well as bacterial and eukaryotic host cells into which nucleic acid encoding the antibody has been introduced. Suitable host cells are disclosed below.

[0179] Unless otherwise specified, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5'-end, and the left-hand direction of a double-stranded polynucleotide sequence is referred to as the 5'-direction. The 5' to 3' addition direction of a nascent RNA transcript is referred to as the transcription direction, and the region of the sequence on the DNA strand that is 5' to the 5' end of the RNA transcript and has the same sequence as the RNA transcript is referred to as the "upstream sequence," and the region of the sequence on the DNA strand that is 3' to the 3' end of the RNA transcript and has the same sequence as the RNA transcript is referred to as the "downstream sequence."

[0180] The terms "prevent," "preventing," and "prevention" refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptom(s) (e.g., AMD).

[0181] The term "prophylactic agent" refers to any agent that can completely or partially inhibit the onset, recurrence, progression, or spread of a disease, e.g., Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)) and / or symptoms associated therewith in a subject. In certain embodiments, the term "prophylactic agent" refers to an anti-Sdc2 antibody described herein.

[0182] As used herein, a "prophylactically effective serum titer" is a serum titer of an Sdc2 antibody, e.g., an Sdc2 antibody described herein, in a subject (e.g., a human) that completely or partially inhibits the onset, recurrence, progression, or spread of a disease, disorder, or condition in the subject, e.g., Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)) and / or symptoms associated therewith.

[0183] In certain embodiments, a "therapeutically effective serum titer" is a serum titer of an Sdc2 antibody, e.g., an Sdc2 antibody described herein, in a subject (e.g., a human) that reduces the severity, duration, and / or symptoms associated with an Sdc2-mediated disease, disorder, or condition in the subject.

[0184] The term "recombinant antibody" refers to an antibody prepared, expressed, generated, or isolated by recombinant means. A recombinant antibody can be an antibody expressed using a recombinant expression vector transfected into a host cell, an antibody isolated from a recombinant combinatorial antibody library, an antibody isolated from an animal (e.g., a mouse or a cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see, e.g., Taylor et al., 1992, Nucl. Acids Res. 20:6287-95), or an antibody prepared, expressed, generated, or isolated by any other means, including splicing of immunoglobulin gene sequences into other DNA sequences. Such recombinant antibodies can have variable and constant regions that comprise those derived from human germline immunoglobulin sequences (see, e.g., Kabat et al., supra). However, in certain embodiments, such recombinant antibodies are subjected to in vitro mutagenesis (or, when transgenic animals for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally exist within the human antibody germline repertoire in vivo.

[0185] The term "serum titer" refers to the average serum titer in a subject from multiple samples (e.g., at multiple time points), or in a population of at least 10, at least 20, at least 40 subjects, up to about 100, 1000, or more.

[0186] The term "side effect" encompasses unwanted and / or adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Unwanted effects are not necessarily harmful. Adverse effects from a therapy (e.g., a prophylactic or therapeutic agent) can be harmful, uncomfortable, or dangerous. Examples of side effects include diarrhea, cough, gastroenteritis, wheezing, nausea, vomiting, anorexia, abdominal cramps, fever, pain, weight loss, dehydration, alopecia, difficulty breathing, insomnia, dizziness, mucositis, nerve and muscle effects, fatigue, dry mouth, loss of appetite, rash or swelling at the site of administration, flu-like symptoms such as fever, chills, and fatigue, gastrointestinal problems, and allergic reactions. Additional unwanted effects experienced by patients are numerous and known in the art. Many are described in the Physician's Desk Reference (68th ed. 2014).

[0187] The terms "subject," "patient," "individual," and the like are used interchangeably. As used herein, in certain embodiments, a subject is a mammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkeys and humans). In particular embodiments, a subject is a human. In one embodiment, a subject is a mammal (e.g., a human) having a disease, disorder, or condition. In another embodiment, a subject is a mammal (e.g., a human) at risk for developing a disease, disorder, or condition, such as an Sdc2-associated disease or disorder (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)).

[0188] "Substantially all" refers to at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.

[0189] The term "therapeutic agent" refers to any agent that can be used to treat, prevent, or alleviate a disease, disorder, or condition, including the treatment, prevention, or alleviation of one or more symptoms of a disease, disorder, or condition, e.g., Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)) and / or symptoms associated therewith. In certain embodiments, a therapeutic agent refers to an anti-Sdc2 antibody described herein.

[0190] The term "therapy" refers to any protocol, method, and / or agent that can be used to prevent, manage, treat, and / or ameliorate a disease, disorder, or condition, for example, an Sdc2-associated disease and disorder (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)). In certain embodiments, the terms "therapies" and "therapy" refer to biological, supportive, and / or other therapies known to those of skill in the art, such as healthcare professionals, that are useful in preventing, managing, treating, and / or ameliorating a disease, disorder, or condition, for example, an Sdc2-associated disease and disorder (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)).

[0191] The term "detectable probe" refers to a composition that provides a detectable signal. This term includes, but is not limited to, any fluorophore, chromophore, radiolabel, enzyme, antibody or antibody fragment, etc. that provides a detectable signal through its activity.

[0192] The term "detectable agent" refers to a substance that can be used to confirm the existence or presence of a desired molecule, such as an anti-Sdc2 antibody described herein, in a sample or subject. A detectable agent can be a substance that can be visualized or otherwise determined and / or measured (e.g., by quantification).

[0193] The term "diagnostic agent" refers to a substance administered to a subject that aids in the diagnosis of a disease, disorder, or condition. Such substances can be used to localize, identify, and / or define the process that causes the disease. In certain embodiments, a diagnostic agent comprises a substance conjugated to an anti-Sdc2 antibody described herein that, when administered to a subject or contacted with a sample from a subject, aids in the diagnosis of a disease, e.g., an Sdc2-associated disease or disorder (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)).

[0194] The term "encoding nucleic acid" or grammatical equivalents, when used with respect to a nucleic acid molecule, refers to a nucleic acid molecule, in its native state or when manipulated by methods well known to those of skill in the art, that can be transcribed to produce mRNA, which is then translated into a polypeptide and / or fragment thereof. The antisense strand is the complementary strand of such a nucleic acid molecule, and a coding sequence can be deduced therefrom.

[0195] The term "excipient" refers to an inert substance commonly used as a diluent, vehicle, preservative, binder, or stabilizer, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkylsulfonates, caprylates, etc.), surfactants (e.g., SDS, polysorbates, nonionic surfactants, etc.), sugars (e.g., sucrose, maltose, trehalose, etc.), and polyols (e.g., mannitol, sorbitol, etc.). See also Remington and Gennaro, Remington's Pharmaceutical Sciences (18th ed. 1990), which is incorporated herein by reference in its entirety.

[0196] The term "fragment," as used herein in the context of a peptide or polypeptide, refers to a peptide or polypeptide that comprises less than the full-length amino acid sequence. Such fragments can result, for example, from truncation at the amino terminus, truncation at the carboxy terminus, and / or internal deletion of a residue(s) from the amino acid sequence. Fragments can result, for example, from alternative RNA splicing or from in vivo protease activity. In certain embodiments, an Sdc2 fragment or anti-Sdc2 antibody fragment comprises at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 30 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino acid residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, or at least 10 contiguous amino acid residues of the amino acid sequence of an Sdc2 polypeptide or anti-Sdc2 antibody. Contiguous amino acid residues include at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, or at least 950 contiguous amino acid residues. In certain embodiments, a fragment of an Sdc2 polypeptide or anti-Sdc2 antibody retains at least one, at least two, at least three, or more functions of the polypeptide or antibody.

[0197] As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or amelioration of the progression, severity, and / or duration of a disease or condition resulting from the administration of one or more therapies. Treating can be determined by assessing whether there is a decrease, alleviation, and / or alleviation of one or more symptoms associated with the underlying disease, such that the patient experiences improvement, even though the patient may still be suffering from the underlying disease. The term "treating" includes both disease management and cure. As used herein, "treating a disease or disorder" means reducing the frequency with which the symptoms of the disease or disorder are experienced by the patient. Disease and disorder are used interchangeably herein. As used herein, the terms "treatment" or "treating" encompass prophylaxis and / or therapy. Thus, the compositions and methods provided herein are not limited to therapeutic applications and can be used for prophylactic applications. Thus, "treating" or "treatment" of a state, disorder, or condition includes (i) preventing or delaying the onset of clinical symptoms of the state, disorder, or condition in a subject who may be affected by or susceptible to the state, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition; (ii) inhibiting the state, disorder, or condition, i.e., arresting or reducing the onset of the disease or at least one clinical or subclinical symptom thereof; or (iii) alleviating the disease, i.e., causing regression of the state, disorder, or condition, or at least one of its clinical or subclinical symptoms. As used herein, the terms "treat," "treating," and "treatment" are all intended to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease or disorder, which may, but is not necessarily, discernible in the subject.The terms "treat," "treating," and "treatment" can also refer to causing regression, preventing progression, or at least slowing the progression of a disease, disorder, or condition. In certain embodiments, "treat," "treating," and "treatment" refer to alleviating, preventing the onset or onset of, or reducing the duration of one or more symptoms associated with a disease, disorder, or condition, such as a tumor, more preferably a cancer. In certain embodiments, "treat," "treating," and "treatment" refer to preventing the recurrence of a disease, disorder, or condition. In certain embodiments, "treat," "treating," and "treatment" refer to increasing the survival of a subject having a disease, disorder, or condition. In certain embodiments, "treat," "treating," and "treatment" refer to eliminating a disease, disorder, or condition in a subject.

[0198] The terms "manage," "managing," and "management" refer to the beneficial effect a subject derives from a therapy (e.g., a prophylactic or therapeutic agent) that does not result in a cure of the disease. In certain embodiments, a subject is administered one or more therapies (e.g., a prophylactic or therapeutic agent, e.g., an antibody provided herein) to "manage" one or more symptoms of a disease, e.g., Sdc2-associated diseases and disorders (e.g., stroke (e.g., ischemic stroke), inflammatory eye disorders (e.g., AMD), and cardiovascular disorders (e.g., myocardial infarction)), to prevent the progression or worsening of the disease.

[0199] "Administering" or "administration" refers to the act of injecting or otherwise physically delivering an exogenous substance (e.g., an anti-Sdc2 antibody described herein) to a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When a disease, disorder, condition, or symptom thereof is being treated, administration of the substance typically occurs after the onset of the disease, disorder, condition, or symptom thereof. When a disease, disorder, condition, or symptom thereof is being prevented, administration of the substance typically occurs before the onset of the disease, disorder, condition, or symptom thereof.

[0200] As used herein in the context of a polypeptide, the term "analog" refers to a polypeptide that has a similar or identical function to an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody, but does not necessarily contain a similar or identical amino acid sequence of an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody, or a similar or identical structure of an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody.A polypeptide having a similar amino acid sequence refers to a polypeptide that satisfies at least one of the following: (a) a polypeptide having an amino acid sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody provided herein; (b) a polypeptide that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody provided herein under stringent conditions. Fragments, or polypeptides encoded by nucleotide sequences that hybridize to a nucleotide sequence encoding an anti-Sdc2 antibody (or a VH or VL region thereof), at least 5 amino acid residues, at least 10 amino acid residues, at least 15 amino acid residues, at least 20 amino acid residues, at least 25 amino acid residues, at least 30 amino acid residues, at least 40 amino acid residues, at least 50 amino acid residues, at least 60 amino acid residues, at least 70 amino acid residues, at least 80 amino acid residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 125 amino acid residues, or at least 150 amino acid residues (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (2001), and Maniatis et al., Molecular Cloning: A Laboratory Manual (1982)), or (c) a polypeptide encoded by a nucleotide sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to a nucleotide sequence encoding an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody (or a VH or VL region thereof) described herein.A polypeptide having a structure similar to an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody provided herein refers to a polypeptide having a similar secondary, tertiary, or quaternary structure to an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody provided herein. The structure of a polypeptide can be determined by methods known to those skilled in the art, including, but not limited to, X-ray crystallography, nuclear magnetic resonance, and crystallographic electron microscopy.

[0201] In the context of polypeptides, the term "derivative" as used herein refers to a polypeptide comprising the amino acid sequence of an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an antibody that binds to an Sdc2 polypeptide, which has been altered by the introduction of amino acid substitutions, deletions, or additions. The term "derivative" as used herein also refers to an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an antibody that binds to an Sdc2 polypeptide, which has been chemically modified, for example, by the covalent attachment of any type of molecule to the polypeptide. For example, but not limited to, an Sdc2 polypeptide, a fragment of an Sdc2 polypeptide, or an anti-Sdc2 antibody may be chemically modified by, for example, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, chemical cleavage, formulation, metabolic synthesis of tunicamycin, conjugation to cellular ligands or other proteins, etc. Derivatives are modified in a manner that differs from the naturally occurring or starting peptide or polypeptide, either in the type or location of the attached molecule. Derivatives further include deletion of one or more chemical groups naturally present on the peptide or polypeptide. Furthermore, derivatives of Sdc2 polypeptides, fragments of Sdc2 polypeptides, or anti-Sdc2 antibodies can contain one or more non-classical amino acids. Polypeptide derivatives have a similar or identical function as the Sdc2 polypeptides, fragments of Sdc2 polypeptides, or anti-Sdc2 antibodies provided herein.

[0202] The peptide sequences described herein are written according to the usual convention with the N-terminal region of the peptide on the left and the C-terminal region on the right. Although isomeric forms of amino acids are known, unless expressly indicated otherwise, it is the L-form of the amino acid.

[0203] 6.2 Generation of human therapeutic antibodies Due to immune recognition of such foreign mouse- or rat-derived proteins, the therapeutic use of humanized and fully human antibodies is preferable to the use of antibodies with mouse or rat sequence regions (e.g., variable and / or constant regions), which may result in rapid clearance of the antibody or the generation of an immune response against the antibody by the recipient subject. While it is possible to isolate individual antigen-specific plasma B cells from human subjects and recent advances in high-throughput cell sorting and sequencing technologies have made this approach more feasible, it remains expensive and time-consuming. Several other strategies have been developed for rapidly producing fully human or mostly human antibodies against defined antigens for clinical development, including humanized and synthetic phage display.

[0204] "Humanization" is the process by which antibodies generated in non-human animal models (e.g., mice) and screened for appropriate function and affinity are converted to primarily human sequences. Typically, this process involves cloning antigen specificities to confer amino acid sequences (e.g., complementarity-determining regions (CDRs)) onto fully human heavy and light chain frameworks. In this way, the resulting primarily human hybrid antibodies retain the antigen-binding function conferred by the original mouse sequences. Exploratory studies involving humanized antibodies benefit from the ease of working with small animal models for handling and immunization with desired antigens. In certain embodiments, a mouse antibody generation platform utilizing several inbred strains (e.g., the PentaMice™ platform) was used to generate a wide variety of antibody clones against human, porcine, and mouse Sdc2 proteins. Those clones that passed screening were humanized for further development.

[0205] Another strategy for rapidly producing antigen-specific, fully human antibodies is the use of filamentous phage display libraries. Here, large libraries of scFv or Fab antibodies are produced by high-throughput cloning methods and engineered onto the coat protein of filamentous phage particles, such that each viral particle displays a single, unique antibody clone. The library of phage particles is then screened for high-affinity binding to the antigen of interest via panning. In certain embodiments, fully human anti-Sdc2 antibody and scFv clones screened from a phage display library (e.g., the XOMA phage display platform) containing naive scFv clones are provided.

[0206] 6.3 Anti-syndecan-2 antibody The present invention is based, in part, on the discovery of one or more anti-syndecan-2 antibodies that modulate syndecan-2 signaling, including inhibiting syndecan-2 signaling, activating syndecan-2 signaling (i.e., in the absence of an agonist), or enhancing syndecan-2 signaling in the presence of an agonist. In some embodiments, the antibody or antigen-binding fragment thereof may bind to the extracellular region of syndecan-2, more specifically, the region of the extracellular domain of syndecan-2 to which Dep-1 binds. The anti-syndecan-2 antibody may thereby inhibit or activate syndecan-2 signaling. In some embodiments, the antibody or antigen-binding fragment thereof may block or enhance Dep-1 internalization without directly targeting the Dep-1-binding site of Sdc2. In some embodiments, the antibody or antigen-binding fragment thereof may bind to the Sdc2 extracellular domain and promote endothelial cell junction stabilization, thereby inhibiting vascular permeability. The present invention is also based in part on the discovery that modulation of syndecan-2 can be used to treat diseases whose etiology is determined by vascular leakage or edema formation, including, inter alia, acute respiratory distress syndrome (ARDS).

[0207] In one aspect, provided herein are antibodies that bind to Sdc2. In some embodiments, the syndecan-2 protein to which the antibody or antigen-binding fragment thereof binds is of human, mouse, or porcine origin. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to an epitope shared by human, mouse, and porcine syndecan-2 proteins, or any combination thereof (i.e., human and mouse, mouse and pig, or pig and human).

[0208] In certain aspects, provided herein are anti-syndecan-2 antibodies or antigen-binding fragments thereof, compositions comprising the anti-syndecan-2 antibodies or antigen-binding fragments thereof, and methods of using them. In some embodiments, the antigen-binding fragment is selected from the group consisting of a Fab, a single-chain variable fragment (scFv), or a single-domain antibody. In further embodiments, the antibody is a full-length antibody. In yet further embodiments, the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a fully human antibody or antigen-binding fragment thereof.

[0209] Regarding anti-syndecan-2 antibodies or antigen-binding fragments thereof, and compositions comprising such antibodies or antigen-binding fragments, various embodiments provide anti-syndecan-2 antibodies or antigen-binding fragments thereof, which comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least 80% sequence identity to at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity to at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24.

[0210] In one embodiment, the amino acid sequence contained within the heavy chain variable region has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity, or 100% sequence identity, to at least one selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23. In one embodiment, the heavy chain variable region consists of an amino acid sequence having at least 95% sequence identity to at least one selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23. In various embodiments herein, the amino acid sequence of the heavy chain variable region has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity, or 100% sequence identity, to at least one selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23.

[0211] In one embodiment, the amino acid sequence contained within the light chain variable region has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity, or 100% sequence identity, to at least one selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. In one embodiment, the light chain variable region consists of an amino acid sequence having at least 95% sequence identity to at least one selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. In various embodiments herein, the amino acid sequence of the light chain variable region has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity, or 100% sequence identity, to at least one selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24.

[0212] In another embodiment, the amino acid sequence of the heavy chain variable region is selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, and the amino acid sequence of the light chain variable region is selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. In an additional embodiment, the heavy chain variable region consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, and the light chain variable region consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. In another embodiment, the amino acid sequences contained within the heavy chain variable region and the amino acid sequences contained within the light chain variable region are selected from the group consisting of SEQ ID NOs: 1 and 2, 3 and 4, 5 and 6, 7 and 8, and 9 and 10, respectively. In additional embodiments, the heavy and light chain variable regions consist of SEQ ID NOs: 1 and 2, 3 and 4, 5 and 6, 7 and 8, or 9 and 10, respectively.

[0213] In one embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof is IgA, IgD, IgE, IgG, or IgM. In one embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof is IgG1 or IgG4. In one embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof is IgG4. In one embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof is an IgE subclass containing a point mutation. In one embodiment, the point mutation in IgG4 is serine 228 to proline (S228P), which strengthens the disulfide bond in the core-hinge region.

[0214] In one embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof is selected from the group consisting of a full-length antibody, a Fab, and a single-chain variable fragment (scFv). In some embodiments, the anti-syndecan-2 antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some embodiments, the anti-syndecan-2 antibody or antigen-binding fragment thereof is fully human.

[0215] In another embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 1, and the light chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 2. In another embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7, and the light chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8. In another embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11, and the light chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. In another embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 13, and the light chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 14. In another embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 15, and the light chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 16. In another embodiment, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 17, and the light chain constant region comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 18.

[0216] In another aspect, a single-chain variable fragment (scFv) is provided comprising an antigen-binding domain that specifically binds to an epitope of syndecan-2 (Sdc2) protein, wherein the antigen-binding domain comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity to at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity to at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24.

[0217] In various embodiments, the anti-syndecan-2 antibody or antigen-binding fragment thereof further comprises a post-translational modification. Non-limiting examples of post-translational modifications include myristoylation, palmitoylation, stearoylation, glycosylation, the addition of heparan sulfate chains, and combinations thereof. A non-limiting example of glycosylation is the addition of heparan sulfate chains to the anti-syndecan-2 antibody.

[0218] Provided herein are anti-Sdc2 antibodies or antigen-binding fragments thereof, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, and compositions comprising the antibodies. Methods for producing the antibodies and methods for using the antibodies to treat diseases are also provided. The antibodies disclosed herein possess one or more desirable functional properties, including, but not limited to, high affinity binding to Sdc2 or high specificity for Sdc2. In certain embodiments, the antibodies disclosed herein are capable of treating or preventing a disease or disorder when administered to a subject alone or in combination with other therapies.

[0219] In one aspect, provided herein is an antibody that binds to Sdc2. In some embodiments, the antibody comprises a heavy chain variable region and a light chain variable region. In some embodiments, the Sdc2 antibody is a single domain antibody or nanobody. In some embodiments, the Sdc2 antibody is not a single domain antibody or nanobody. In some embodiments, the Sdc2 antibody is a humanized antibody. In certain embodiments, the Sdc2 antibody is a fully human antibody.

[0220] In one embodiment, the present disclosure provides anti-Sdc2 antibodies that may be used herein as therapeutic agents. In another embodiment, the present disclosure provides anti-Sdc2 antibodies that may be used herein as diagnostic agents. Exemplary antibodies include polyclonal, monoclonal, humanized, human, bispecific, and heteroconjugate antibodies, as well as variants thereof with improved affinity or other properties.

[0221] In certain embodiments, provided herein are Sdc2 antibodies comprising the VH region, VL region, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 of any one of the antibodies described herein. In some embodiments, provided herein are Sdc2 antibodies comprising the VH region of any one of the antibodies described herein. In some embodiments, provided herein are Sdc2 antibodies comprising the VL region of any one of the antibodies described herein. In some embodiments, provided herein are Sdc2 antibodies comprising the VH region of any one of the antibodies described herein and the VL region of any one of the antibodies described herein. In some embodiments, provided herein are Sdc2 antibodies comprising the VH CDR1, VH CDR2, and VH CDR3 of any one of the antibodies described herein. In some embodiments, provided herein are Sdc2 antibodies comprising the VL CDR1, VL CDR2, and VL CDR3 of any one of the antibodies described herein. In some embodiments, provided herein are Sdc2 antibodies that comprise the VH CDR1, VH CDR2, and VH CDR3 of any one of the antibodies described herein, and the VL CDR1, VL CDR2, and VL CDR3 of any one of the antibodies described herein. Representative VH and VL amino acid sequences, including the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 amino acid sequences of the anti-Sdc2 antibodies provided herein, are provided in Tables 1 and 3-8 below.

[0222] Thus, in some embodiments, an isolated antibody or functional fragment thereof provided herein comprises one, two, and / or three heavy chain CDRs and / or one, two, and / or three light chain CDRs from: (a) antibody 20-H19-AB, (b) antibody TP-43327F, (c) antibody TP-43329F, (d) antibody 8-G17-A, (e) antibody 6-N03-A, (f) antibody R3-P3-C11, (g) antibody R4M-P3-E06, (h) antibody R3-P3-E09, (i) antibody R3-P1-C02, (j) antibody R3-P3-A12, (k) antibody R4M-P3-A12, or (l) antibody R4M-P1-A10, as shown in Tables 1 and 3-8 below.

[0223] In some embodiments, the antibody specifically binds to Sdc2. In some embodiments, Sdc2 is present on the surface of endothelial cells. In some embodiments, Sdc2 is present on the surface of neuronal cells.

[0224] In some embodiments, the antibody is a humanized antibody. In certain embodiments, the antibody is an IgG antibody. In other embodiments, the IgG antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In one embodiment, the IgG antibody is an IgG1 antibody. In one embodiment, the IgG antibody is an IgG2 antibody. In one embodiment, the IgG antibody is an IgG3 antibody. In one embodiment, the IgG antibody is an IgG4 antibody. In some embodiments, the antibody is a bispecific antibody. In certain embodiments, the antibody is multivalent. In other embodiments, the antibody is capable of binding to at least three antigens. In some embodiments, the antibody is capable of binding to at least five antigens.

[0225] In certain embodiments, Sdc2 antibodies are provided that are intact antibodies. In other embodiments, Sdc2 antibodies are provided that are antigen-binding fragments of Sdc2 antibodies. In some embodiments, the antigen-binding fragments of Sdc2 antibodies are functional fragments.

[0226] In some embodiments, the antigen-binding fragment is a diabody. In some embodiments, the antigen-binding fragment is a Fab. In some embodiments, the antigen-binding fragment is a Fab'. In some embodiments, the antigen-binding fragment is a F(ab')2. In some embodiments, the antigen-binding fragment is an Fv fragment. In some embodiments, the antigen-binding fragment is a disulfide-stabilized Fv fragment (dsFv). In some embodiments, the antigen-binding fragment is a (dsFv)2. In some embodiments, the antigen-binding fragment is a bispecific dsFv (dsFv-dsFv'). In some embodiments, the antigen-binding fragment is a disulfide-stabilized diabody (dsdiabody). In some embodiments, the antigen-binding fragment is a single-chain antibody molecule (scFv). In some embodiments, the antigen-binding fragment is a single-domain antibody (sdAb). In some embodiments, the antigen-binding fragment is an scFv dimer (bivalent diabody). In some embodiments, the antigen-binding fragment is a multispecific antibody formed from portions of an antibody comprising one or more CDRs. In some embodiments, the antigen-binding fragment is a camelized single domain antibody. In some embodiments, the antigen-binding fragment is a nanobody. In some embodiments, the antigen-binding fragment is a domain antibody. In some embodiments, the antigen-binding fragment is a bivalent domain antibody. In some embodiments, the antigen-binding fragment is an antibody fragment that binds to an antigen but does not comprise the complete antibody structure.

[0227] In certain embodiments, the Sdc2 antibody comprises a VH region and a VL region. In some embodiments, the Sdc2 antibody is a single-chain antibody. In some embodiments, the Sdc2 antibody is a single-domain antibody. In some embodiments, the Sdc2 antibody is a nanobody. In certain embodiments, the Sdc2 antibody is a VHH antibody. In certain embodiments, the Sdc2 antibody is a llama antibody. In some embodiments, the Sdc2 antibody is not a single-chain antibody. In some embodiments, the Sdc2 antibody is not a single-domain antibody. In some embodiments, the Sdc2 antibody is not a nanobody. In certain embodiments, the Sdc2 antibody is not a VHH antibody. In certain embodiments, the Sdc2 antibody is not a llama antibody. In some embodiments, the Sdc2 antibody is a multispecific antibody. In other embodiments, the Sdc2 is a bispecific antibody. In certain embodiments, the multispecific antibody comprises an antigen-binding fragment of an Sdc2 antibody provided herein. In other embodiments, the bispecific antibody comprises an antigen-binding fragment of an Sdc2 antibody provided herein. In some embodiments, the Sdc2 antibody is an agonist antibody. In certain embodiments, the Sdc2 antibody activates T cells. In other embodiments, the Sdc2 antibody is an antagonist antibody. In certain embodiments, the Sdc2 antibody inactivates T cells. In some embodiments, the Sdc2 antibody blocks T cell activation. In some embodiments, the Sdc2 antibody modulates T cell activity. In some embodiments, the Sdc2 antibody neither activates nor inactivates T cell activity. In certain embodiments, the T cell is a human T cell.

[0228] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are numbered according to the Kabat numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are numbered according to the Chothia numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are numbered according to an exemplary numbering system. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are numbered according to the Contact numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are according to the IMGT numbering system. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are according to the AbM numbering system. Exemplary sets of six CDRs (VH CDR1-3 and VL CDR1-3) for particular antibody embodiments are provided herein. Other sets of CDRs are contemplated and are within the scope of the antibody embodiments provided herein.

[0229]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone 20-H19-AB.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 61, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 62. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 31, 32, and 33, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 34, 35, and 36, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 37, 38, and 39, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 40, 41, and 42, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 43, 44, and 45, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 46, 47, and 48, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 49, 50, and 51, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 52, 53, and 54, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 55, 56, and 57, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 58, 59, and 60, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 61. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 62. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 61, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 62. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 61. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 62. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 61, and (ii) a VL having the amino acid sequence of SEQ ID NO: 62. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 63.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 64. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 63, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 64. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 63. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 64. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 63, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 64.

[0230]

[0013] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone TP-43327F.

[0014] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 95, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 96. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 65, 66, and 67, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 68, 89, and 70, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 71, 72, and 73, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 74, 75, and 76, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 77, 78, and 79, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 80, 81, and 82, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 83, 84, and 85, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 86, 87, and 88, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 89, 90, and 91, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 92, 93, and 94, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 95. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 96. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 95, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 96. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 95. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 96. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 95, and (ii) a VL having the amino acid sequence of SEQ ID NO: 96. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 97.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 98. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 97, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 98. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 97. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 98. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 97, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 98.

[0231]

[0013] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone TP-43329F.

[0014] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 129, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 130. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 99, 100, and 101, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 102, 103, and 104, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 105, 106, and 107, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 108, 109, and 110, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 111, 112, and 113, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 114, 115, and 116, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 117, 118, and 119, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 120, 121, and 122, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 123, 124, and 125, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 126, 127, and 128, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 129. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 130. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 129, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 130. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 129. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 130. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 129, and (ii) a VL having the amino acid sequence of SEQ ID NO: 130.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 131. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 132. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 131, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 132. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 131. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 132. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 131, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 132.

[0232]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone 8-G17A.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 163, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 164. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 133, 134, and 135, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 137, and 138, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 139, 140, and 141, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 142, 143, and 144, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 145, 146, and 147, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 148, 149, and 150, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 151, 152, and 153, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 154, 155, and 156, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 157, 158, and 159, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 160, 161, and 162, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 163. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 164. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 163, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 164. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 163. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 164. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 163, and (ii) a VL having the amino acid sequence of SEQ ID NO: 164.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 165. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 166. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 165, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 166. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 165. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 166. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 165, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 166.

[0233]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone 6-N03-A.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 197, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 198. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 167, 168, and 169, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 170, 171, and 172, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 173, 174, and 175, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 176, 177, and 178, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 179, 180, and 181, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 182, 183, and 184, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 185, 186, and 187, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 188, 189, and 190, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 191, 192, and 193, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 194, 195, and 196, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 197. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 198. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 197, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 198. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 197. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 198. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 197, and (ii) a VL having the amino acid sequence of SEQ ID NO: 198.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 199. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 200. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 199, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 200. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 199. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 200. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 199, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 200.

[0234]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone R3-P3-C11.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 231, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 232. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 201, 202, and 203, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 204, 205, and 206, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 207, 208, and 209, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 210, 211, and 212, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 213, 214, and 215, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 216, 217, and 218, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 219, 220, and 221, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 222, 223, and 224, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 225, 226, and 227, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 228, 229, and 230, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 231. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 232. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 231, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 232. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 231. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 232. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 231, and (ii) a VL having the amino acid sequence of SEQ ID NO: 232.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 233. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 234. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 233, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 234. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 233. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 234. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 233, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 234.

[0235]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone R4M-P3-E06.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 265, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 266. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 235, 236, and 237, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 238, 239, and 240, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 241, 242, and 243, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 244, 245, and 246, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 247, 248, and 249, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 250, 251, and 252, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 253, 254, and 255, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 256, 257, and 258, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 259, 260, and 261, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 262, 263, and 264, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 265. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 266. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 265, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 266. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 265. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 266. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 265, and (ii) a VL having the amino acid sequence of SEQ ID NO: 266.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 267. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 268. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 267, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 268. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 267. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 268. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 267, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 268.

[0236]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone R3-P3-E09.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 299, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 300. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 269, 270, and 271, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 272, 273, and 274, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 275, 276, and 277, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 278, 279, and 280, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 281, 282, and 283, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 284, 285, and 286, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 287, 288, and 289, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 290, 292, and 292, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 293, 294, and 295, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 296, 297, and 298, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 299. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 300. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 299, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 300. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 299. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 300. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 299, and (ii) a VL having the amino acid sequence of SEQ ID NO: 300.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 301. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 302. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 301, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 302. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 301. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 302. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 301, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 302.

[0237]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone R3-P1-C02.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 333, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 334. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 303, 304, and 305, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 306, 307, and 308, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 309, 310, and 311, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 312, 313, and 314, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 315, 316, and 317, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 318, 319, and 320, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 321, 322, and 323, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 324, 325, and 326, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 327, 328, and 329, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 330, 331, and 332, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 333. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 334. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 333, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 334. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 333. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 334. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 333, and (ii) a VL having the amino acid sequence of SEQ ID NO: 334.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 335. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 336. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 335, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 336. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 335. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 336. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 335, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 336.

[0238]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone R3-P3-A12.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 367, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 368. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 337, 338, and 339, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 340, 341, and 342, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 343, 344, and 345, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 346, 347, and 348, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 349, 350, and 351, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 352, 353, and 354, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 355, 356, and 357, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 358, 359, and 360, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 361, 362, and 363, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 364, 365, and 366, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 367. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 368. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 367, and (ii) a VL having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 368. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 367. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 368. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH having the amino acid sequence of SEQ ID NO: 367, and (ii) a VL having the amino acid sequence of SEQ ID NO: 368.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 369. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 370. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 369, and (ii) a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 370. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 369. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 370. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 369, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 370.

[0239]

[0010] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody that binds to Sdc2 is antibody clone R4M-P3-A12.

[0011] In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, of the VH having the amino acid sequence of SEQ ID NO: 401, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, of the VL having the amino acid sequence of SEQ ID NO: 402. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 371, 372, and 373, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 374, 375, and 376, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 377, 378, and 379, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 380, 381, and 382, ​​respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 383, 384, and 385, respectively, and (ii) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 386, 387, and 388, respectively.In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 389, 390, and 391, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein the antibody comprises (i) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 395, 396, and 397, respectively, and (ii) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 398, 399, and 400, respectively. In one aspect, provided herein is an antibody that binds to Sdc2, wherein ...

Claims

1. (a.) (i) VH having the amino acid sequence of SEQ ID NO: 61, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 62, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (b.) (i) VH having the amino acid sequence of SEQ ID NO: 95, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 96, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (c.) (i) VH having the amino acid sequence of SEQ ID NO: 129, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 130, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (d.) (i) VH having the amino acid sequence of SEQ ID NO: 163, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 164, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (e.) (i) VH having the amino acid sequence of SEQ ID NO: 197, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 198, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (f.) (i) VH having the amino acid sequence of SEQ ID NO: 231, and VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, and (ii) VL having the amino acid sequence of SEQ ID NO: 232, and VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, (g.) (i) VH having the amino acid sequence of SEQ ID NO: 265, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 266, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (h.) (i) VH having the amino acid sequence of SEQ ID NO: 299, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 300, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (i.) (i) VH having the amino acid sequence of SEQ ID NO: 333, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 334, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (j.) (i) VH having the amino acid sequence of SEQ ID NO: 367, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 368, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. (k.) (i) VH having the amino acid sequence of SEQ ID NO: 401, and VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively, and (ii) VL having the amino acid sequence of SEQ ID NO: 402, and VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively, or (l.) (i) VH having the amino acid sequence of SEQ ID NO: 435, and including VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of VH CDR1, VH CDR2, and VH CDR3, respectively; and (ii) VL having the amino acid sequence of SEQ ID NO: 436, and including VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of VL CDR1, VL CDR2, and VL CDR3, respectively. An antibody that binds to Sdc2, including, Hereinafter, the antibody is characterized in that the amino acid sequences of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are determined by the Kabat numbering system, Chothia numbering system, AbM numbering system, Contact, or IMGT numbering system.

2. (I.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 31, 32, and 33, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 34, 35, and 36, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 37, 38, and 39, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 40, 41, and 42, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 43, 44, and 45, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 46, 47, and 48, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 49, 50, and 51 respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 52, 53, and 54 respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 55, 56, and 57 respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 58, 59, and 60 respectively, (II.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 65, 66, and 67, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 68, 89, and 70, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 71, 72, and 73, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 74, 75, and 76, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 77, 78, and 79, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 80, 81, and 82, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 83, 84, and 85 respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 86, 87, and 88 respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 89, 90, and 91 respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 92, 93, and 94 respectively, (III.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 99, 100, and 101, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 102, 103, and 104, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 105, 106, and 107, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 108, 109, and 110, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 111, 112, and 113, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 114, 115, and 116, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 117, 118, and 119, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 120, 121, and 122, respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 123, 124, and 125, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 126, 127, and 128, respectively. (IV.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 133, 134, and 135, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 136, 137, and 138, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 139, 140, and 141, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 142, 143, and 144, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 145, 146, and 147, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 148, 149, and 150, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 151, 152, and 153, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 154, 155, and 156, respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 157, 158, and 159, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 160, 161, and 162, respectively. (V.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 167, 168, and 169, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 170, 171, and 172, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 173, 174, and 175, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 176, 177, and 178, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 179, 180, and 181 respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 182, 183, and 184 respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 185, 186, and 187, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 188, 189, and 190, respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 191, 192, and 193, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 194, 195, and 196, respectively. (VI.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 201, 202, and 203, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 204, 205, and 206, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 207, 208, and 209, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 210, 211, and 212, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 213, 214, and 215, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 216, 217, and 218, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 219, 220, and 221 respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 222, 223, and 224 respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 225, 226, and 227, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 228, 229, and 230, respectively. (VII.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 235, 236, and 237, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 238, 239, and 240, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 241, 242, and 243, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 244, 245, and 246, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 247, 248, and 249, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 250, 251, and 252, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 253, 254, and 255, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 256, 257, and 258, respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 259, 260, and 261 respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 262, 263, and 264 respectively, (VIII.) (A) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 269, 270, and 271 respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 272, 273, and 274 respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 275, 276, and 277 respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 278, 279, and 280 respectively, (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 281, 282, and 283, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 284, 285, and 286, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 287, 288, and 289, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 290, 292, and 292, respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 293, 294, and 295, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 296, 297, and 298, respectively. (IX.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 303, 304, and 305, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 306, 307, and 308, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 309, 310, and 311, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 312, 313, and 314, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 315, 316, and 317, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 318, 319, and 320, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 321, 322, and 323 respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 324, 325, and 326 respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 327, 328, and 329, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 330, 331, and 332, respectively. (X.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 337, 338, and 339, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 340, 341, and 342, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 343, 344, and 345, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 346, 347, and 348, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 349, 350, and 351, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 352, 353, and 354, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 355, 356, and 357, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 358, 359, and 360, respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 361, 362, and 363, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 364, 365, and 366, respectively. (XI.) (A) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 371, 372, and 373, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 374, 375, and 376, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 377, 378, and 379, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 380, 381, and 382, ​​respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 383, 384, and 385, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 386, 387, and 388, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 389, 390, and 391 respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 392, 393, and 394 respectively, or (E) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 395, 396, and 397, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 398, 399, and 400, respectively, or (XII.) (A) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 405, 406, and 407, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 408, 409, and 410, respectively. (B) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 411, 412, and 413, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 414, 415, and 416, respectively. (C) (i) VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 417, 418, and 419, respectively, and (ii) VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 420, 421, and 422, respectively. (D) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 423, 424, and 425, respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 426, 427, and 428, respectively, or (E) (i) VH containing VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs. 429, 430, and 431 respectively, and (ii) VL containing VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs. 432, 433, and 434 respectively. The antibody according to claim 1, comprising:

3. (a.) (i) VH having the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 62 or an amino acid sequence having at least 95% identity to said amino acid sequence, (b.) (i) VH having the amino acid sequence of SEQ ID NO: 95 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 96 or an amino acid sequence having at least 95% identity with said amino acid sequence, (c.) (i) VH having the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence having at least 95% identity with said amino acid sequence, (d.) (i) VH having the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence having at least 95% identity to said amino acid sequence, (e.) (i) VH having the amino acid sequence of SEQ ID NO: 197 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 198 or an amino acid sequence having at least 95% identity to said amino acid sequence, (f.) (i) VH having the amino acid sequence of SEQ ID NO: 231 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence having at least 95% identity with said amino acid sequence, (g.) (i) VH having the amino acid sequence of SEQ ID NO: 265 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 266 or an amino acid sequence having at least 95% identity to said amino acid sequence, (h.) (i) VH having the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence having at least 95% identity to said amino acid sequence, (i) VH having the amino acid sequence of SEQ ID NO: 333 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence having at least 95% identity to said amino acid sequence, (j.) (i) VH having the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence having at least 95% identity to said amino acid sequence, (k.) (i) VH having the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 402 or an amino acid sequence having at least 95% identity to said amino acid sequence, (l.) (i) VH having the amino acid sequence of SEQ ID NO: 435 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) VL having the amino acid sequence of SEQ ID NO: 436 or an amino acid sequence having at least 95% identity to said amino acid sequence. The antibody according to claim 1 or 2, comprising:

4. (a.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence having at least 95% identity to said amino acid sequence, (b.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence having at least 95% identity to said amino acid sequence, (c) (i) a heavy chain having the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence having at least 95% identity with said amino acid sequence, (d.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence having at least 95% identity to said amino acid sequence, (e.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 199 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 200 or an amino acid sequence having at least 95% identity with said amino acid sequence, (f.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence having at least 95% identity with said amino acid sequence, (g.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 267 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 268 or an amino acid sequence having at least 95% identity to said amino acid sequence, (h.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 301 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence having at least 95% identity to said amino acid sequence, (i) (i) a heavy chain having the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) a light chain having the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence having at least 95% identity to said amino acid sequence, (j.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence having at least 95% identity with said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 370 or an amino acid sequence having at least 95% identity with said amino acid sequence, (k.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 403 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 404 or an amino acid sequence having at least 95% identity to said amino acid sequence, (l.) (i) A heavy chain having the amino acid sequence of SEQ ID NO: 437 or an amino acid sequence having at least 95% identity to said amino acid sequence, and (ii) A light chain having the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence having at least 95% identity to said amino acid sequence. The antibody according to claim 1 or 2, comprising:

5. (a) The antibody is an IgG antibody, and / or (b) The antibody contains a kappa light chain or a lambda light chain, and / or (c) The antibody is a humanized antibody or a fully human antibody, and / or (d.) The antibody is a monoclonal antibody, and / or (e.) The antibody specifically binds to Sdc2, and / or (f.) The Sdc2 is present on the surface of endothelial cells or nerve cells, and / or (g.) The antibody is polyvalent, and / or (h.) The antibody is a multispecific antibody. The antibody according to claim 1 or 2.

6. A pharmaceutical composition comprising the antibody according to claim 1 or 2, and a pharmaceutically acceptable carrier.

7. A method for preparing the pharmaceutical composition described in claim 6, comprising combining the antibody with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition.

8. One or more nucleic acids encoding the antibody according to claim 1 or 2.

9. One or more vectors comprising one or more nucleic acids as described in claim 8.

10. A host cell comprising one or more vectors as described in claim 9.

11. A kit comprising (i) one or more vectors according to claim 9 and packaging therefor, or (ii) an antibody according to claim 1 or 2 and packaging therefor.

12. An in vitro method for reducing vascular cell permeability, comprising contacting vascular cells with the antibody described in claim 1 or 2.

13. The in vitro method according to claim 12, wherein the vascular cells are endothelial cells.

14. The in vitro method according to claim 12, wherein the endothelial cells are VEGFA-induced endothelial cells, and the method comprises contacting the endothelial cells with the antibody before, during, or after contacting the endothelial cells with VEGFA.

15. An antibody according to claim 1 or 2 for use in a method for reducing vascular permeability, vascular leakage, or endothelial permeability in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

16. The antibody for use according to claim 15, wherein the subject has a disease that is caused in whole or in part by cells expressing Sdc2.

17. An antibody according to claim 1 or 2 for use in a method for preventing, treating or modulating a disease caused in whole or in part by cells expressing Sdc2, comprising administering an effective amount of the antibody to a subject (e.g., a human).

18. (a) The cells are endothelial cells, and / or (b) The disease is related to vascular permeability or vascular leakage. The antibody for use according to claim 17.

19. The aforementioned disease, (a.) Acute respiratory distress syndrome (ARDS) (b) A neurological disorder in which the blood-brain barrier (BBB) ​​is altered or destroyed, (c) Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, traumatic brain injury, epilepsy, multiple sclerosis, cardiovascular disease, myocardial infarction, congestive heart failure, blunt traumatic injury, peripheral vascular disease, lymphedema, POEMS syndrome, childhood capillary leak syndrome, adult capillary leak syndrome, hydrocephalus, inflammation-related edema, inflammatory disease, systemic lupus erythematosus, rheumatoid arthritis, cardiovascular disease, neovascular eye disease, age-related macular degeneration (AMD), diabetic retinopathy, stroke, ischemic stroke, hemorrhagic stroke, or cancer. The antibody for use according to claim 17.

20. An antibody according to claim 1 or 2 for use in a method for treating stroke in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

21. An antibody according to claim 1 or 2 for use in a method for treating ischemic stroke in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

22. The antibody for use according to claim 21, wherein the subject has a brain lesion region associated with the ischemic stroke.

23. An antibody according to claim 1 or 2 for use in a method for treating hemorrhagic stroke in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

24. An antibody according to claim 1 or 2 for use in a method for reducing ocular inflammation in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

25. An antibody according to claim 1 or 2 for use in a method for treating neovascular eye disease in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

26. An antibody according to claim 1 or 2 for use in a method for treating diabetic retinopathy in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

27. An antibody according to claim 1 or 2 for use in a method for treating AMD in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

28. An antibody according to claim 1 or 2 for use in a method for treating cardiovascular disease in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

29. An antibody according to claim 1 or 2 for use in a method for treating congestive heart failure in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

30. An antibody according to claim 1 or 2 for use in a method for treating myocardial infarction in a subject, comprising administering an effective amount of the antibody to the subject (e.g., a human).

31. The antibody for use according to claim 30, wherein the subject is a human being who has suffered from myocardial infarction or is at risk of developing myocardial infarction.

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