Fusion protein and uses thereof

Abstract

Provided herein are fusion proteins and methods for engineered cell therapy. In aspects, a fusion protein provided herein is administered in combination with an engineered cell therapy, for use in treating a disease, e.g., a proliferative disease, e.g., a cancer, e.g., an autoimmune disease.

Description

FUSION PROTEIN AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 490,966, filed March 17, 2023, the entire contents of which is incorporated herein by this reference.SUMMARY

[0002] In some aspects, described herein is an antibody or an antigen binding fragment thereof that specifically binds to a truncated epithelial growth factor receptor (EGFR) and does not specifically bind to a full-length EGFR.

[0003] In some aspects, described herein is an antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR, comprising at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 3 amino acid modifications.

[0004] In some aspects, described herein is an antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR, comprising at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 257, 258, 260, 262, 188, 193, 225, 230, 254-256, 259, or 261, with from 0 to 3 amino acid modifications.

[0005] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acidmodifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications.

[0006] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 190, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 195, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 226, 227, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 231, 232, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 263, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 264, 270, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 265, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 268, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 273, and 261, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 194, 273, and 262, respectively, each with 0 to 3 amino acid modifications.

[0007] In some aspects, described herein is an antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR, comprising at least one light chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 15 with from 0 to 3 amino acid modifications.

[0008] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications.

[0009] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising: (a) a heavy chain that comprises a heavy chain variable (VH) domain, and (b) a light chain that comprises a light chain variable (VL) domain, wherein the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273 with from 0 to 3 amino acid modifications, and wherein the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 15 with from 0 to 3 amino acid modifications.

[0010] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as setforth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications.

[0011] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 190, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 195, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 226, 227, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 231, 232, and 230, respectively,each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 263, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 264, 270, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 265, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 268, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 273, and 261, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 194, 273, and 262, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications.

[0012] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein: CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth inSEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234,respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; or CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications.

[0013] In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1),CDRL2, and CDRL3, and wherein: CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 190, and 188, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 195, and 193, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 226, 227, and 225, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 231, 232, and 230, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 263, 269, and 254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 255, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acidmodifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 256, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 259, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 264, 270, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 265, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 268, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 273, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; or CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 273, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications.

[0014] In any one of the foregoing or related aspects, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain that comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, 381, 383, or 384. In some cases, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, 381, 383, or 384, with from 0 to 5 amino acid modifications. In some cases, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) domain that comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205. In some cases, the antibody or antigenbinding fragment thereof comprises a light chain variable (VL) domain that comprises an amino acidsequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205, with from 0 to 5 amino acid modifications. In some cases, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein: (a) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (b) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:(c) the VH domain comprises an amino acid sequence having at least 90%,95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (d) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (e) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (f) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (g) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 202, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 204; (h) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 203, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205; (i) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 235, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205; (j) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the aminoacid sequence as set forth in SEQ ID NO: 236, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (k) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 276, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (1) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 277, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (m) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 278, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (n) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 279, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (o) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 282, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (p) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 283, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (q) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 284, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (r) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 374, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (s) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 375, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (t) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 376, andthe VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (u) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 377, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (v) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 378, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (w) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 379, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (x) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 381, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (y) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 383, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; or (z) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 384, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385. In some cases, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein: (a) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 280, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (b) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 281, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (c) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 285, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (d) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 373, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (e) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 380, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence asset forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (f) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 382, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (g) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 202, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 204, with from 0 to 5 amino acid modifications; (h) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 203, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 205, with from 0 to 5 amino acid modifications; (i) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 235, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 205, with from 0 to 5 amino acid modifications; or (j) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 236, with from 0 to 5 amino acid modifications, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (k) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 276, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (1) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 277, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (m) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 278, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (n) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 279, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (o) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 282, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (p) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 283, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (q) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 284, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (r) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 374, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (s) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 375, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (t) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 376, with from 0 to 5 amino acidmodifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (u) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 377, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (v) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 378, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (w) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 379, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (x) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 381, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (y) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 383, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; or (z) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 384, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications. In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain that comprises a heavy chain variable (VH) domain, and wherein the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, or 381-384. In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain, and wherein the VH domain comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, or 381-384, with from 0 to 5 amino acid modifications. In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a light chain that comprises a light chain variable (VL) domain, and wherein the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205. In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a light chain that comprises a light chain variable (VL) domain, and wherein the VL domain comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205, with from 0 to 5 amino acid modifications. In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein theheavy chain comprises a heavy chain variable (VH) domain, and the light chain comprises a light chain variable (VL) domain, wherein: (a) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (b) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (c) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (d) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (e) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (f) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (g) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 202, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 204; or (h) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 203, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205; (i) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 235, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205; (j) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 236, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (k) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 276, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (1) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 277, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (m) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 278, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (n) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 279, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (o) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 282, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (p) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 283, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (q) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 284, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (r) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 374, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (s) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 375, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (t) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 376, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acidsequence as set forth in SEQ ID NO: 385; (u) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 377, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (v) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 378, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (w) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 379, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (x) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 381, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (y) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 383, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; or (z) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 384, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385. In some aspects, described herein is an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain and the light chain comprises a light chain variable (VL) domain, wherein: the VH and VL domains comprise the sequence of SEQ ID NOs: 280 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 281 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 285 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 373 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 380 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 382 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 202 and 204, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 203 and 205, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 235 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 236 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 276 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 277 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 278 and 237, respectively; the VH and VL domains comprise the sequence ofSEQ ID NOs: 279 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 282 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 283 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 284 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 374 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 375 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 376 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 377 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 378 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 379 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 381 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 383 and 385, respectively; or the VH and VL domains comprise the sequence of SEQ ID NOs: 384 and 385, respectively.

[0015] In any one of the foregoing or related aspects, the antibody or antigen binding fragment thereof does not specifically bind to a full-length EGFR. In some cases, the truncated EGFR comprises an EGFR extracellular region domain III of the full-length EGFR. In some cases, the truncated EGFR comprises at least a N-terminus of the EGFR extracellular region domain III. In some cases, the truncated EGFR comprises residue R310 or K311 numbered according to SEQ ID NO: 218. In some cases, the truncated EGFR comprises residues R310 and K311 numbered according to SEQ ID NO: 218. In some cases, the truncated EGFR comprises at least portion of a signal peptide at the N-terminus. In some cases, the signal peptide is a GM-CSFR alpha chain signal sequence as set forth in SEQ ID NO: 413. In some cases, the truncated EGFR comprises a C-terminal portion of the signal peptide. In some cases, the C-terminal portion of the signal peptide consists of three amino acids Leu-Ile-Pro. In some cases, the antibody or antigen-binding fragment thereof specifically binds to amino acids of the C-terminal portion of the signal peptide. In some cases, the antibody or antigen-binding fragment thereof specifically binds to amino acids of the three amino acids Leu-Ile-Pro. In some cases, the antibody or antigen-binding fragment thereof specifically binds to amino acids at the N-terminus of the truncated EGFR. In some cases, the antibody or antigen-binding fragment thereof specifically binds to amino acid at position R310 and / or amino acid at position K311, the positions numbered according to SEQ ID NO: 218. In some cases, the truncated EGFR lacks a membrane distal EGF -binding domain of the full-length EGFR, or a cytoplasmic signaling tail of the full-length EGFR, or both. In some cases, the truncated EGFR lacks both the membrane distal EGF- binding domain and the cytoplasmic signaling tail. In some cases, the truncated EGFR lacks EGFR extracellular domain I of the full-length EGFR, EGFR extracellular domain II of the full-length EGFR, or both. In some cases, the truncated EGFR lacks EGFR extracellular domain I of the full-length EGFR, EGFR extracellular domain II of the full-length EGFR, and the cytoplasmic signaling tail of the full- length EGFR. In some cases, the truncated EGFR comprises EGFR extracellular domain III of the full- length EGFR and EGFR extracellular domain IV of the full-length EGFR. In some cases, the truncated EGFR comprises transmembrane domain of the full-length EGFR, EGFR extracellular domain III of the full-length EGFR, and EGFR extracellular domain IV of the full-length EGFR. In some cases, the full-length EGFR is a human EGFR. In some cases, the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 216, 219, 222, 239, or 415. In some cases, the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 239 or 415. In some cases, the truncated EGFR is encoded by a polynucleotide comprising a nucleic acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 217 or 416. In some cases, said antibody or antigen-binding fragment thereof binds to the truncated EGFR with a KD of less than lOOOnM, 800nM, 500nM, 200 nM, 150 nM, 100 nM, 80 nM, 60 nM, 50 nM, 40 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, or 1 nM, as determined by surface plasmon resonance (SPR) at 37°C. In some cases, said antibody or antigen-binding fragment thereof binds to the truncated EGFR with a KD of less than 10 nM, as determined by surface plasmon resonance (SPR) at 37°C. In some cases, said antibody or antigen-binding fragment thereof binds to the truncated EGFR with a KD of less than 2 nM, as determined by surface plasmon resonance (SPR) at 37°C. In some cases, said antibody or antigen-binding fragment thereof, at lOOnM concentration, does not specifically bind to (a) the full-length EGFR, as determined by surface plasmon resonance (SPR) at 37°C; or (b) cells that express the full-length EGFR and do not express the truncated EGFR, as determined by flow cytometry binding at 4°C. In some cases, said antibody or antigen-binding fragment thereof binds to cells expressing the truncated EGFR with a EC50 of less than lOOOnM, 800nM, 500nM, 200 nM, 150 nM, 100 nM, 80 nM, 60 nM, 50 nM, 40 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, or 1 nM, as determined by flow cytometry binding at 4°C. In some cases, the antibody or antigenbinding fragment thereof is an IgG, an IgM, an IgE, an IgA, or an IgD molecule, or is derived from one of these. In some cases, the antibody is a monoclonal antibody. In some cases, the antibody is a human or humanized antibody. In some cases, the antibody is a chimeric antibody. In some cases, is selected from the group consisting of: scFv, sc(Fv)2, dsFv, Fab, Fab', (Fab')2, a diabody, a triabody, a minibody, a sdAb, and a Variable New Antigen Receptors (VNARs). In some cases, the antibody or antigen-binding fragment thereof is bi-specific or multi-specific.

[0016] In some aspects, described herein is a fusion protein comprising: (i) a first moiety comprising the antibody or antigen binding fragment thereof described herein; and (ii) a second moiety comprising a polypeptide that modulates activation or inhibition of a cell. In some cases, the fusion protein selectively activates a cell that expresses the truncated EGFR with 10-fold or greater potency as compared to activation of a cell that does not express the truncated EGFR. In some cases, the cell is an immune cell. In some cases, the potency is measured by a pSTAT5 or a pSTAT3 activation assay. In some cases, the second moiety comprises a cytokine, a chemokine, a growth factor, or a second antibody or antigenbinding fragment thereof. In some cases, the second moiety comprises IL-2, IL-7, IL-10, IL-15, and IL- 21, or a functional fragment thereof, or a variant thereof, or any combinations thereof. In some cases, the second moiety comprises an IL-2 polypeptide, or a functional fragment thereof, or a variant thereof. In some cases, the IL-2 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-2Rapolypeptide having an amino acid sequence of SEQ ID NO: 2, compared to the binding affinity of the wild-type IL-2 polypeptide with an amino acid sequence of SEQ ID NO: 1. In some cases, the IL-2 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-2RP polypeptide having an amino acid sequence of SEQ ID NO: 3, and / or reduced binding affinity by at least about 50% to an IL- 2Ry polypeptide having an amino acid sequence of SEQ ID NO: 4 compared to the binding affinity of the wild-type IL-2 polypeptide with an amino acid sequence of SEQ ID NO: 1. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 1 with one or more amino acid substitutions relative to SEQ ID NO: 1, and wherein the one or more substitution(s) comprise substitution(s) at positions of SEQ ID NO: 1 selected from the group consisting of: QI 1, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, 192, T123, Q126, S127, 1129, and S130. In some cases, the one or more substitution(s) comprise an F42A or F42K amino acid substitution relative to SEQ ID NO: 1. In some cases, the one or more substitution(s) further comprise an R38A, R38D, R38E, E62Q, E68A, E68Q, E68K, or E68R amino acid substitution relative to SEQ ID NO: 1. In some cases, the one or more substitution(s) further comprise an H16E, H16D, D20N, M23A, M23R, M23K, S87K, S87A, D84L, D84N, D84V, D84H, D84Y, D84R, D84K, N88A, N88G, N88S, N88T, N88R, N88I, N88D, V91A, V91T, V91E, I92A, E95S, E95A, E95R, T123A, T123E, T123K, T123Q, Q126A, Q126S, Q126T, Q126E, S127A, S127E, S127K, or S127Q amino acid substitution relative to SEQ ID NO: 1. In some cases, the one or more substitution(s) further comprise the amino acid mutation Cl 25 A relative to SEQ ID NO: 1. In some cases, the IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1 with one of the following sets of amino acid substitutions (relative to the sequence of SEQ ID NO: 1): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F42A, and N88S; R38E, F42A, and N88A; R38E, F42A, and N88G; R38E, F42A, and N88D; R38E, F42A, and V91E; R38E, F42A, and D84H; R38E, F42A, and D84K; R38E, F42A, and D84R; H16D, R38E and F42A; H16E, R38E and F42A; R38E, F42A and Q126S; R38D, F42A and N88S; R38D, F42A and N88A; R38D, F42A and N88G; R38D, F42A and N88D; R38D, F42A and V91E; R38D, F42A, and D84H; R38D, F42A, and D84K; R38D, F42A, and D84R; H16D, R38D and F42A; H16E, R38D and F42A; R38D, F42A and Q126S; R38A, F42K, and N88S; R38A, F42K, and N88A; R38A, F42K, and N88G; R38A, F42K, and N88D; R38A, F42K, and V91E; R38A, F42K, and D84H; R38A, F42K, and D84K; R38A, F42K, and D84R; H16D, R38A, and F42K; H16E, R38A, and F42K; R38A, F42K, and Q126S; F42A, E62Q, and N88S; F42A, E62Q, and N88A; F42A, E62Q, and N88G; F42A, E62Q, and N88D; F42A, E62Q, and V91E; F42A, E62Q, and D84H; F42A, E62Q, and D84K; F42A, E62Q, and D84R; H16D, F42A, and E62Q; H16E, F42A, and E62Q; F42A, E62Q, and Q126S; R38E, F42A, and C125A; R38D, F42A, and C125A; F42A, E62Q, and C125A; R38A, F42K, and C125A; R38E, F42A, N88S, and C125A; R38E, F42A, N88A, and Cl 25 A; R38E, F42A, N88G, and Cl 25 A; R38E, F42A, N88D, and Cl 25 A; R38E, F42A, V91E, and C125A; R38E, F42A, D84H, and C125A; R38E, F42A, D84K, and C125A; R38E, F42A, D84R, and C125A; H16D, R38E, F42A, and C125A; H16E, R38E, F42A, and C125A; R38E, F42A, C125A and Q126S; R38D, F42A, N88S, and C125A; R38D, F42A, N88A, and C125A; R38D, F42A, N88G, and Cl 25 A; R38D, F42A, N88D, and Cl 25 A; R38D, F42A, V91E, and Cl 25 A; R38D,F42A, D84H, and C125A; R38D, F42A, D84K, and C125A; R38D, F42A, D84R, and C125A; H16D, R38D, F42A, and C125A; H16E, R38D, F42A, and C125A; R38D, F42A, C125A, and Q126S; R38A, F42K, N88S, and C125A; R38A, F42K, N88G, and C125A; R38A, F42K, N88D, and C125A; R38A, F42K, N88A, and C125A; R38A, F42K, V91E, and C125A; R38A, F42K, D84H, and C125A; R38A, F42K, D84K, and C125A; R38A, F42K, D84R, and C125A; H16D, R38A, F42K, and C125A; H16E, R38A, F42K, and C125A; R38A, F42K, C125A and Q126S; F42A, E62Q, N88S, and C125A; F42A, E62Q, N88A, and C125A; F42A, E62Q, N88G, and C125A; F42A, E62Q, N88D, and C125A; F42A, E62Q, V91E, and C125A; F42A, E62Q, and D84H, and C125A; F42A, E62Q, and D84K, and C125A; F42A, E62Q, and D84R, and C125A; H16D, F42A, and E62Q, and C125A; H16E, F42A, E62Q, and C125A; F42A, E62Q, C125A and Q126S; F42A, N88S, and C125A; F42A, N88A, and C125A; F42A, N88G, and C125A; F42A, N88D, and C125A; F42A, V91E, and C125A; F42A, D84H, and C125A; F42A, D84K, and C125A; F42A, D84R, and C125A; H16D, F42A, and C125A; H16E, F42A, and C125A; and F42A, C125A and Q126S. In some cases, the IL-2 polypeptide comprises an amino acid sequence that is at least about 85% identical to a sequence selected from the group consisting of SEQ ID NOs: 11-90 and 137-185. In some cases, said IL-2 polypeptide comprises a sequence that is at least about 75% identical to a sequence selected from the group consisting of SEQ ID NOs: 43, 48, 52, 49, and 156. In some cases, the fusion protein comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 386-412. In some cases, the second moiety comprises an IL-7 polypeptide, or a functional fragment thereof, or a variant thereof. In some cases, the IL-7 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-7Ra polypeptide comprising the amino acid sequence of SEQ ID NO: 94, compared to binding affinity of a wild-type IL-7 polypeptide comprising the amino acid sequence of SEQ ID NO: 91 to the IL-7Ra polypeptide. In some cases, the IL-7 polypeptide comprises the sequence of SEQ ID NO: 91, with one or more substitutions relative to SEQ ID NO: 91. In some cases, the one or more substitutions are at positions selected from the positions: K10, QI 1, S14, V15, V18, Q22, L35, N36, D74, L77, L80, K81, E84, 188, R133, Q136, E137, T140, and N143, and K144, numbered according to SEQ ID NO: 91 . In some cases, the substitution in position K81 is K81A and the substitution in position T140 is T140A. In some cases, the second moiety comprises an IL-10 polypeptide, or a functional fragment thereof, or a variant thereof. In some cases, the IL- 10 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-lORa polypeptide comprising the amino acid sequence of SEQ ID NO: 96, compared to binding affinity of a wild-type IL-10 polypeptide comprising the amino acid sequence of SEQ ID NO: 95 to the IL-lORa polypeptide. In some cases, the IL- 10 polypeptide exhibits increased binding affinity by at least about 50% to an IL-10RP polypeptide comprising the amino acid sequence of SEQ ID NO: 97, compared to binding affinity of a wild-type IL- 10 polypeptide comprising the amino acid sequence of SEQ ID NO: 95 to the IL-10RP polypeptide. In some cases, the IL-10 polypeptide comprises the sequence of SEQ ID NO: 95, with one or more substitution relative to SEQ ID NO: 95. In some cases, the IL- 10 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 99-112. In some cases, the IL-10polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 362- 372. In some cases, the second moiety comprises an IL-21 polypeptide, or a functional fragment thereof, or a variant thereof. In some cases, the IL-21 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-21R polypeptide comprising the amino acid sequence of SEQ ID NO: 93, compared to binding affinity of a wild-type IL-21 polypeptide comprising the amino acid sequence of SEQ ID NO: 92 or SEQ ID NO: 115 to the IL-21R polypeptide. In some cases, the IL-21 polypeptide comprises the sequence of SEQ ID NO: 115, with one or more substitution relative to SEQ ID NO: 115. In some cases, the substitution in one or more positions are selected from the positions: R5, 18, R9, Rl l, Q12, 114, D15, D18, Q19, Y23, R65, S70, K72, K73, K75, R76, K77, S80, QI 16, and KI 17, wherein the position numbering is number according to the amino acid sequence of SEQ ID NO: 115. In some cases, the IL-21 polypeptide comprises a polypeptide sequence having at least 80% sequence identity to SEQ ID NO: 115, wherein the IL-21 polypeptide has an isoelectric point that is at least about 0.6 units to about 5 units lower, compared to that of a wild-type IL-21 protein having a sequence of SEQ ID NO: 115. In some cases, the isoelectric point of SEQ ID NO: 115 is about 9.42. In some cases, the IL-21 polypeptide has an isoelectric point of about 7.12 to about 8.72. In some cases, the polypeptide provides an improved exposure compared to the wild-type IL-21 protein, as measured by at least about 1.5 times greater under the curve (AUC) for the polypeptide, relative to that of the wild-type IL-21, when administered to a subject, at equivalent concentrations. In some cases, the IL-21 polypeptide comprises a mutation at one or more positions selected from the group consisting of: K56, T81, N82, A83, G84, R85, R86, Q87, K88, H89, R90, L91, and T92 of SEQ ID NO: 115. In some cases, the IL-21 polypeptide further comprises a mutation at a position selected from the group consisting of: R5, 18, R9, R11, Q12, 114, D15, D18, Q19, Y23, R65, S70, K72, K73, K75, R76, K77, S80, QI 16, and KI 17 of SEQ ID NO: 115. In some cases, the amino acid sequence of the IL-21 polypeptide is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to a sequence selected from the group consisting of SEQ ID NOs: 116, 118-129, and 286-303. In some cases, the amino acid sequence of the IL- 21 polypeptide is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to a sequence selected from the group consisting of SEQ ID NO: 130-135 and 304-361. In some cases, the first moiety and the second moiety are directly linked. In some cases, the first moiety and the second moiety are linked via a linker. In some cases, the linker comprises the sequence (GGGS)xGn, (GGGGS)xGn, or (GGGGGS)xGn, S(GGGS)xGn, S(GGGGS)xGn, or S(GGGGGS)xGn, wherein x=l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and wherein n=0, 1, 2 or 3. In some cases, the linker comprises the sequence GGGGSGGGGSGGGGS or SGGGGSGGGGSGGGGS. In some cases, the antibody or antigen binding fragment thereof comprises: two heavy chain polypeptides, each comprising a structure according to formula [I], from N-terminus to C-terminus: VH-CH1- hinge-CH2-CH3 [I], and two light chain polypeptides, each comprising a structure according to formula [II], from N-terminus to C-terminus: VL-CL [II], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody F c domain, wherein VL is the VL domain, and wherein CL is an antibodyconstant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of the CH3 domain of one of the two heavy chain polypeptides. In some cases, the antibody or antigen binding fragment thereof comprises: a first heavy chain polypeptide comprising a structure according to formula [I], from N-terminus to C-terminus: VH-CHl-hinge-CH2-CH3 [I], a light chain polypeptide comprising a structure according to formula [II], from N-terminus to C-terminus: VL-CL [II], and a second heavy chain polypeptide comprising a structure according to formula [III], from N-terminus to C-terminus: hinge-CH2-CH3 [III], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide. In some cases, the antibody or antigen binding fragment thereof comprises: a first heavy chain polypeptide comprising a structure according to formula [I], from N-terminus to C-terminus: VH-CHl-hinge-CH2-CH3 [I], a light chain polypeptide comprising a structure according to formula [II], from N-terminus to C-terminus: VL-CL[II], and a second heavy chain polypeptide comprising a structure according to formula [III], from N- terminus to C-terminus: hinge-CH2-CH3 [III], wherein VH is the VH domain, whereinCHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the C-terminus of the second moiety is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide. In some cases, the antibody or antigen binding fragment thereof comprises: a first heavy chain polypeptide comprising a structure according to formula [I], from N-terminus to C-terminus: VH-CHl-hinge-CH2-CH3 [I], a light chain polypeptide comprising a structure according to formula [II], from N-terminus to C-terminus: VL-CL [II], and a second heavy chain polypeptide comprising a structure according to formula [III], from N-terminus to C-terminus: hinge-CH2-CH3 [III], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide. In some cases, one or both of the antibody heavy chain polypeptides comprise(s) the following amino acid substitutions in the CH2 domain: L234A, L235A, and G237A, numbered according to EU numbering. In some cases, the first moiety comprises two antibody heavy chain polypeptides, and wherein one of the antibody heavy chain polypeptides comprises amino acid substitutions S354C and T366W in the CH3 domain, numbered according to EU numbering, and another of the antibody heavy chain polypeptides comprises amino acid substitutions Y349C, T366S, L368A and Y407V in the CH3 domain, numbered according to EU numbering.

[0017] In some cases, first moiety comprises one or two antibody heavy chain polypeptides and one or two antibody light chain polypeptides. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain; (b) a second polypeptide chain comprising a VH domain; (c) a thirdpolypeptide chain comprising a VH domain; and (d) a fourth polypeptide chain comprising a VL domain; wherein the VH domains and VL domains comprise CDRs that specifically bind to the truncated EGFR and does not specifically bind to a full-length EGFR, wherein the second polypeptide chain or the third polypeptide chain is linked to the second moiety via a linker. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively. In some cases, the fusion protein comprises: (a) the VL domain of the first polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or (ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (b) the VH domain of the second polypeptide chain comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, or (ii) an amino acid sequence as set forth in SEQ ID NO: 280, with from 0 to 5 amino acid modifications; (c) the VH domain of the third polypeptide chain comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, or (ii) an amino acid sequence as set forth in SEQ ID NO: 280, with from 0 to 5 amino acid modifications; and (d) the VL domain of the fourth polypeptide chain comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or (ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acidmodifications. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, (c) athird polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, (c) athird polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively. In some cases, the fusion protein comprises (a) the VL domain of the first polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or (ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications; (b) the VH domain of the second polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, or (ii) an amino acid sequence as set forth in SEQ ID NO: 281, with from 0 to 5 amino acid modifications; (c) the VH domain of the third polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, or (ii) an amino acid sequence as set forth in SEQ ID NO: 281, with from 0 to 5 amino acid modifications; and (d) the VL domain of the fourth polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or (ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3,wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively. In some cases, the fusion protein comprises (a) the VL domain of the first polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or (ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (b) the VH domain of the second polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, or (ii) an amino acid sequence as set forth in SEQ ID NO: 285, with from 0 to 5 amino acid modifications; (c) the VH domain of the third polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, or (ii) an amino acid sequence as set forth in SEQ ID NO: 285, with from 0 to 5 amino acid modifications; and (d) the VL domain of the fourth polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or (ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively; and (d)a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively. In some cases, the fusion protein comprises (a) the VL domain of the first polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or (ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications; (b) the VH domain of the second polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, or (ii) an amino acid sequence as set forth in SEQ ID NO: 373, with from 0 to 5 amino acid modifications; (c) the VH domain of the third polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, or (ii) an amino acid sequence as set forth in SEQ ID NO: 373, with from 0 to 5 amino acid modifications; and (d) the VL domain of the fourth polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or (ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein theCDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively. In some cases, the fusion protein comprises (a) the VL domain of the first polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or (ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (b) the VH domain of the second polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, or (ii) an amino acid sequence as set forth in SEQ ID NO: 380, with from 0 to 5 amino acid modifications; (c) the VH domain of the third polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, or (ii) an amino acid sequence as set forth in SEQ ID NO: 380, with from 0 to 5 amino acid modifications; and (d) the VL domain of the fourth polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or (ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, (c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively. In some cases, the first moiety comprises (a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively; (b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, (c) a thirdpolypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively; and (d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively. In some cases, the fusion protein comprises (a) the VL domain of the first polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or (ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; (b) the VH domain of the second polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, or (ii) an amino acid sequence as set forth in SEQ ID NO: 382, with from 0 to 5 amino acid modifications; (c) the VH domain of the third polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, or (ii) an amino acid sequence as set forth in SEQ ID NO: 382, with from 0 to 5 amino acid modifications; and (d) the VL domain of the fourth polypeptide comprises (i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or (ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications. In some cases, the first moiety comprises a single chain antibody or single chain variable fragment (scFv), wherein the scFv comprises a VH domain and a VL domain, wherein: (a) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (b) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (c) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (d) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (e) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequenceidentity to the amino acid sequence as set forth in SEQ ID NO: 385; (f) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385. In some cases, the first moiety comprises a diabody wherein the diabody comprises two VH domains and two VL domains, wherein: (a) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (b) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237; (c) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (d) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238; (e) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; (f) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385. In some cases, the first moiety comprises a single domain antibody or a VHH antibody comprising a VH domain that comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, or 382. In some cases, the second moiety comprises an IL-2 polypeptide having an amino acid sequence that is at least about 99% identical to the sequence of SEQ ID NOs: 52 or 156. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%,97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 386; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 387 or 388; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 404; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 387 or 388; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 390; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 391 or 392; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 405; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 391 or 392; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 393; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 394 or 395; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the aminoacid sequence as set forth in SEQ ID NO: 396. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 406; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 394 or 395; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 397; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 398 or 399; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 407; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 398 or 399; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 400; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 401 or 402; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth inSEQ ID NO: 408; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 401 or 402; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 412; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 410 or 411; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403. In some cases, the fusion protein comprises (a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403; (b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 409; (c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 410 or 411; and (d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403.In some aspects, described herein are one or more polynucleotides encoding polypeptides capable of forming the fusion protein described herein. In some cases, at least one of the one or more polynucleotides is a messenger RNA (mRNA).

[0018] In some aspects, described herein are one or more polynucleotides encoding polypeptides capable of forming the antibody or antigen-binding fragment thereof described herein. In some cases, at least one of the one or more polynucleotides is a messenger RNA (mRNA).

[0019] In some aspects, described herein is a vector comprising the one or more nucleotide sequences encoding polypeptides capable of forming the fusion protein described herein, or the antibody or antigenbinding fragment thereof described herein.

[0020] In some aspects, described herein a host cell comprising the one or more polynucleotides described herein or the vector described herein.

[0021] In some aspects, described herein is a method comprising culturing the host cell described herein under conditions for production of the fusion protein, or the antibody or antigen-binding fragment thereof.

[0022] In some aspects, described herein is a pharmaceutical composition comprising the fusion protein described herein, and / or the one or more polynucleotides described herein, or the antibody or antigen binding fragment thereof of described herein, and at least one of: a pharmaceutically acceptableexcipient, carrier, or diluent, or any combination thereof. In some cases, the pharmaceutical composition comprises further comprising a population of engineered cells. In some cases, the population of engineered cells comprises engineered cells that express the truncated EGFR. In some cases, the engineered cells that express the truncated EGFR further express a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof. In some cases, the engineered cells that express the truncated EGFR comprise the fusion protein described herein and / or the one or more polynucleotides encoding the fusion protein. In some aspects, described herein is a cell therapy kit comprising the pharmaceutical composition described herein, and instructions specified for administering the pharmaceutical composition to a subject.

[0023] In some cases, the cell therapy kit further comprising a pharmaceutical composition that comprises a population of engineered cells and instructions specified for administering the population of engineered cells to the subject.

[0024] In any one of the foregoing or related aspects, the pharmaceutical composition that comprises the fusion protein and the pharmaceutical composition that comprises the population of engineered cells are for sequential or simultaneous administration. In some cases, the pharmaceutical composition that comprises the antibody or antigen binding fragment thereof is administered after the pharmaceutical composition that comprises the population of engineered cells.

[0025] In some aspects, described herein is a cell therapy kit comprising a pharmaceutical composition that comprises a population of engineered cells and instructions specified for administering the population of engineered cells to the subject, wherein the population of engineered cells comprises engineered cells comprising the fusion protein described herein and / or the one or more polynucleotides encoding the fusion protein. In some cases, the population of engineered cells comprises engineered cells that express the truncated EGFR. In some cases, the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

[0026] In some aspects, described herein is a method of treating a disease or condition in a subject, the method comprising administering to the subject (a) (i) the fusion protein described herein or (ii) the one or more polynucleotides encoding the fusion protein described herein; or (b)(i) the antibody or antigenbinding fragment thereof described herein or (ii) the one or more polynucleotides encoding the antibody or antigen-binding fragment thereof described herein.

[0027] In some aspects, described herein is a method of treating a disease or condition in a subject, the method comprising administering to the subject a population of engineered cells that expresses the truncated EGFR, and wherein the population of engineered cells that expresses the truncated EGFR (i) expresses the fusion protein described herein and / or (ii) comprises the one or more polynucleotides encoding the fusion protein described herein.

[0028] In some aspects, described herein is a method of treating a disease or condition in a subject, the method comprising administering to the subject a therapeutic regimen comprising: (a) an engineered celltherapy that comprises a population of engineered cells that expresses the truncated EGFR and (b)(i) the fusion protein described herein or (ii) the one or more polynucleotides encoding the fusion protein described herein. In some cases, the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

[0029] In any one of the foregoing or related aspects, the population of engineered cells that expresses the truncated EGFR expresses the fusion protein described herein. In some cases, the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof. In some cases, the population of engineered cells that expresses the truncated EGFR comprises the one or more polynucleotides encoding the fusion protein described herein. In some cases, the population of engineered cells comprises tumor infdtrating lymphocytes (TILs) autologous to the subject, wherein the TILs have been engineered to express the truncated EGFR. In some cases, the subject has received administration of the engineered cell therapy that comprises a population of engineered cells prior to the administration of the fusion protein or the one or more polynucleotides, or is scheduled to receive administration of the engineered cell therapy within a period of time after the administration of the fusion protein or the one or more polynucleotides. In some cases, the fusion protein results in an increase in expansion and / or proliferation of the population of the engineered cells, as compared to the expansion and / or proliferation of a population of otherwise same cells that do not express the truncated EGFR. In some cases, the fusion protein results in an increased in vivo persistence of the population of engineered cells, as compared to the in vivo persistence of a population of otherwise same cells that do not express the truncated EGFR. In some cases, the fusion protein results in an increase in activation, effector function, expansion and / or proliferation of the population of engineered cells, as compared to the activation, effector function, expansion and / or proliferation of the population of engineered cells, when administered without the fusion protein. In some cases, the activation, effector function, expansion and / or proliferation takes place in vivo or in vitro. In some cases, the fusion protein results in an increased in vivo persistence of the population of the engineered cells, as compared to the in vivo persistence of the population of engineered cells, when administered without the fusion protein. In some cases, the in vivo persistence of the population of engineered cells comprises a period of about 15 days, about 30 days to about a year. In some cases, the fusion protein reduces a rate and / or extent of exhaustion of the population of the engineered cells, as compared to the rate and / or extent of exhaustion of the population of engineered cells, when administered without the fusion protein. In some cases, the fusion protein results in selective potentiation of the engineered cells, allowing enhanced specific enrichment of the population of the engineered cells, as compared to specific enrichment of a population of engineered cells when administered with the second moiety alone. In some cases, the fusion protein does not increase count of Treg cells in a biological sample isolated from the subject, as compared to the count of Treg cells in a biological sample isolated from a subject who has been administered the second moiety alone. In some cases, the biological sample is at least one of: a tumor biopsy or peripheral blood.In some cases, the subject is previously administered a pre-conditioning regimen. In some cases, administering the fusion protein or the one or more polynucleotides allows for reduction in at least one of: severity or duration of the pre-conditioning regimen. In some cases, pre-conditioning regimen is used to decrease the endogenous lymphocyte population so as to allow a population of the engineered cell to expand. In some cases, the method eliminates the need for administering, or minimizes the severity of, a pre-conditioning regimen prior to administering an engineered cell therapy. In some cases, the subject has not been administered the pre-conditioning regimen. In some cases, the fusion protein is administered within or within about 2 days, 3 days, 6 days, 12 days, 15 days, 30 days, 60 days or 90 days following administration of the engineered cell therapy. In some cases, the fusion protein is administered about 2 days, 3 days, 6 days, 12 days, 15 days, 30 days, 60 days or 90 days or more prior to administration of the engineered cell therapy. In some cases, the fusion protein is administered simultaneously with administering the engineered cell therapy. In some cases, an effective dose of the engineered cells in the therapeutic regimen is lower than that of a reference therapeutic regimen that comprises administering the engineered cells but does not comprise administering the fusion protein. In some cases, the effective dose of the engineered cells in the therapeutic regimen is at least about 1.5x to about lOOOx lower than the effective dosage of the engineered cell in the reference therapeutic regimen.

[0030] In some aspects, described herein is a method of treating a disease or condition in a subject, the method comprising administering to the subject a therapeutic regimen comprising: (a) an engineered cell therapy that comprises a population of engineered cells that expresses the truncated EGFR and (b)(i) the antibody or antigen-binding fragment thereof described herein or (ii) the one or more polynucleotides encoding the antibody or antigen-binding fragment thereof described herein. In some cases, the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof. In some cases, the subject is scheduled to receive administration of the engineered cell therapy within a period of time after the administration of antibody or antigen-binding fragment thereof or the one or more polynucleotides. In some cases, the antibody or antigen-binding fragment thereof alone results in (a) a decrease in expansion and / or proliferation of the population of the engineered cells, as compared to the expansion and / or proliferation of a population of otherwise same cells that do not express the truncated EGFR; and / or (b) a decrease in vivo persistence of the population of engineered cells, as compared to the in vivo persistence of a population of otherwise same cells that do not express the truncated EGFR.

[0031] In some aspects, the fusion protein described herein, the one or more polynucleotides encoding the fusion protein described herein, the antibody or antigen-binding fragment thereof described herein or the one or more polynucleotides encoding the antigen-binding fragment thereof described herein, for use in treating a disease or condition a subject in need thereof.

[0032] In any one of the foregoing or related aspects, the fusion protein or the one or more polynucleotides is administered to the subject simultaneously or sequentially with an engineered cell therapy that comprises a population of engineered cells that expresses the truncated EGFR.

[0033] In any one of the foregoing or related aspects, the fusion protein or the one or more polynucleotides is administered to the subject via an engineered cell therapy that comprises a population of engineered cells that (a) expresses the truncated EGFR and (b)(i) expresses the fusion protein and / or (ii) comprises the one or more polynucleotides.

[0034] In any one of the foregoing or related aspects, the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

[0035] In some aspects, described herein is use of the fusion protein described herein or one or more polynucleotides encoding the fusion protein described herein in the manufacture of a medicament for treating a disease or a condition. In some cases, the disease or condition comprises cancer, chronic infection, autoimmune disease or immune-mediated disorder.

[0036] In some aspects, described herein is a method of enriching or expanding a population of engineered cells that expresses the truncated EGFR, the method comprising: contacting the population of engineered cells with the fusion protein described herein or the one or more polynucleotides encoding the fusion protein described herein.

[0037] In some aspects, described herein is a method of reducing or eliminating a population of engineered cells that expresses the truncated EGFR, the method comprising: contacting the population of engineered cells with the antibody or antigen-binding fragment thereof described herein.

[0038] In any one of the foregoing or related aspects, the population of engineered cells is present in vitro.

[0039] In any one of the foregoing or related aspects, the population of engineered cells is present in vivo in a subject, and the method comprises administering the fusion protein or the one or more polynucleotides, or the antibody or antigen-binding fragment thereof to the subject.

[0040] In any one of the foregoing or related aspects, the administration of the fusion protein described herein or the one or more polynucleotides encoding the fusion protein results in an increase in activation, effector function, expansion and / or proliferation of the population of engineered cells generated in vivo, as compared to the activation, effector function, expansion and / or proliferation of the population of the engineered cells generated in vivo, when the subject is not administered the fusion protein or the one or more polynucleotides.

[0041] In any one of the foregoing or related aspects, the administration of the fusion protein described herein or the one or more polynucleotides encoding the fusion protein results in an increase in persistence of the population of engineered cells generated in vivo, as compared to the persistence of the population of the engineered cells generated in vivo, when the subject is not administered the fusion protein or the one or more polynucleotides.

[0042] In any one of the foregoing or related aspects, the administration of the fusion protein described herein or the one or more polynucleotides encoding the fusion protein reduces a rate and / or extent of exhaustion of the population of engineered cells generated in vivo, as compared to the rate and / or extentof exhaustion of the population of the engineered cell generated in vivo, when administered without the fusion protein or the one or more polynucleotides.

[0043] In any one of the foregoing or related aspects, the administration of the fusion protein described herein or the one or more polynucleotides encoding the fusion protein results in selective potentiation of the engineered cells generated in vivo, allowing enhanced specific enrichment of a population of the engineered cells generated in vivo, as compared to specific enrichment of a population of engineered cells when administered with the second moiety alone.

[0044] In any one of the foregoing or related aspects, the administration of the fusion protein described herein or the one or more polynucleotides encoding the fusion protein does not increase count of Treg cells in a biological sample isolated from the subject, as compared to the count of Treg cells in a biological sample isolated from a subject who has been administered the second moiety alone, wherein the subject has cancer, and optionally wherein the biological sample is at least one of: a tumor biopsy or peripheral blood.

[0045] In any one of the foregoing or related aspects, the persistence of the population of engineered cells comprises a period of at least about 30 days to about a year.

[0046] In any one of the foregoing or related aspects, the population of engineered cells comprises at least one of: a T cell expressing a T cell receptor (a TCR-T cell), a gamma delta T cell, a pluripotent stem cell derived T cell, or an induced pluripotent stem cell derived T cell, a natural killer cell (NK cell), a pluripotent stem cell derived NK cell, or an induced pluripotent stem cell (iPSC) derived NK cell, a T cell engineered to express a chimeric antigen receptor (a CAR-T cell), a T cell engineered to express a chimeric autoantibody receptor (a CAAR-T cell), a macrophage engineered to express a chimeric antigen receptor (a CAR-M cell), a B cell engineered to express a chimeric antigen receptor (a CAR-B cell), a CD8-positive T cell, a CD4-positive T cell, a cytotoxic T cell, a tumor infiltrating lymphocyte, a CAR- NK cell, a gamma delta T cell, a myeloid cell, a hematopoietic lineage cell, a hematopoietic stem and progenitor cell (HSC), a hematopoietic multipotent progenitor cell (MPP), a pre-T cell progenitor cell, a T cell progenitor cell, a NK cell progenitor cell.

[0047] In any one of the foregoing or related aspects, the population of engineered cells comprises T cells engineered to express a chimeric antigen receptor, an engineered T cell receptor, or both.

[0048] In any one of the foregoing or related aspects, the T cells comprises CD8-positive T cells, CD4- positive T cells, cytotoxic T cells, tumor infdtrating lymphocytes.

[0049] In any one of the foregoing or related aspects, the population of engineered cells comprises a T cell engineered to express a chimeric antigen receptor (a CAR-T cell), wherein the chimeric antigen receptor targets an antigen expressed by a cancer cell. In some cases, the chimeric antigen receptor targets CD19 or B-cell maturation antigen (BCMA).

[0050] In any one of the foregoing or related aspects, the subject has a cancer.

[0051] In any one of the foregoing or related aspects, the cancer is acute lymphoblastic leukemia(ALL) (including non T cell ALL), acute myeloid leukemia, B cell prolymphocytic leukemia, B cell acute lymphoid leukemia (“BALL”), blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloid leukemia, chronic or acute leukemia, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia, Hodgkin's Disease, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma (NHL), plasma cell proliferative disorder (including asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, plasmacytomas (including plasma cell dyscrasia; solitary myeloma; solitary plasmacytoma; extramedullary plasmacytoma; and multiple plasmacytoma), POEMS syndrome (also known as Crow-Fukase syndrome; Takatsuki disease; and PEP syndrome), primary mediastinal large B cell lymphoma (PMBC), small cell- or a large cell -follicular lymphoma, splenic marginal zone lymphoma (SMZL), systemic amyloid light chain amyloidosis, T cell acute lymphoid leukemia (“TALL”), T cell lymphoma, transformed follicular lymphoma, or Waldenstrom macroglobulinemia, Mantlecell lymphoma (MCL), Transformed follicular lymphoma (TFL), Primary mediastinal B cell lymphoma (PMBCL), Multiple myeloma, Hairy cell lymphoma / leukemia, lung cancer, small-cell lung cancer, non-small cell lung (NSCL) cancer, bronchioloalveolar cell lung cancer, squamous cell cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, head and neck cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, thyroid cancer, uterine cancer, gastrointestinal cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, endometrial carcinoma, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the cervix, carcinoma of the vagina, vulval cancer, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, bladder cancer, liver cancer, hepatoma, hepatocellular cancer, cervical cancer, salivary gland carcinoma, biliary cancer, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenoma and Ewings sarcoma, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers.

[0052] In any one of the foregoing or related aspects, the subject has undergone B cell aplasia.

[0053] In any one of the foregoing or related aspects, further comprising administering to the subject aT cell therapy, cancer vaccine, chemotherapeutic agent, or immune checkpoint inhibitor (ICI). In some cases, the ICI is an inhibitor of PD-1, PD-L1, or CTLA-4.

[0054] In any one of the foregoing or related aspects, the T cell therapy comprises a chimeric antigen receptor (CAR)-based T cell therapy, a tumor-infiltrating lymphocyte (TIL)-based therapy, or a therapy with T cells bearing a transduced TCR.

[0055] In any one of the foregoing or related aspects, the subject has an autoimmune disease or an immune-mediated disorder, optionally a B-cell mediated autoimmune disease.

[0056] In any one of the foregoing or related aspects, the population of engineered cells comprises a T cell engineered to express a chimeric antigen receptor (a CAR-T cell), wherein the chimeric antigen receptor targets an antigen expressed by an autoreactive immune cell. In some cases, the chimeric antigen receptor targets CD19, CD20, CD22, CD7, or B-cell maturation antigen (BCMA).

[0057] In any one of the foregoing or related aspects, the population of engineered cells comprises T cells engineered to express a chimeric autoantibody receptor. In some cases, the chimeric autoantibody receptor targets a B cell membrane -bound autoantibody. In some cases, the B cell membrane-bound autoantibody is anti-DSG3 B cell receptor (BCR).

[0058] In any one of the foregoing or related aspects, the population of engineered cells comprises regulatory T (Treg) cells. In some cases, the Treg cells are autologous to the subject and are engineered ex vivo to express the truncated EGFR. In some cases, the Treg cells are engineered to express a chimeric antigen receptor (CAR-Treg). In some cases, the Treg cells are obtained via engineering CD4+ and / or CD3+ T cells to express FoxP3, a chimeric antigen receptor, and the truncated EGFR. In some cases, the CD4+ and / or CD3+ T cells are contacted with a nucleic acid carrier comprising a nucleic acid that expresses FoxP3 and a nucleic acid that expresses the chimeric antigen receptor and the truncated EGFR ex vivo. In some cases, the chimeric antigen receptor of the Treg cells targets an HLA-A2 MHC complex (optionally HLAA2*02), CD83, CD19, insulin, glucose-dependent insulinotropic polypeptide receptor (GIPR), HiP2, a citrullinated protein (optionally citrullinated vimentin), myelin oligodendrocyte glycoprotein, myelin basic protein (MBP), Ganglioside D3, 2,4,6-trinitrophenol (TNP), carcinoembryonic antigen (CEA), IL-23 R, Factor VIII (FVIII), or AAV Capsid. In some cases, Treg cells comprise CD4+CD25+ Treg cells, natural Treg cells (nTreg), induced Treg cells (iTreg), CD8+CD45RClow / - Treg cells, CD4+ FoxP3+ Treg cells, or CD3+ Treg cells.

[0059] In any one of the foregoing or related aspects, the autoimmune disease or immune-mediated disorder comprises systemic lupus erythematosus (SLE), refractory antisynthetase syndrome, myasthenia gravis, neuromyelitis optica spectrum disorder (NMOSD), Sjogren’s syndrome (SS), Scleroderma, immune nephritis, pemphigus vulgaris (PV), idiopathic inflammatory myopathies, and systemic sclerosis.

[0060] In any one of the foregoing or related aspects, the autoimmune disease or immune-mediated disorder comprises graft-versus-host disease (GvHD), Type 1 Diabetes, Rheumatoid Arthitis, Multiple Sclerosis, Vitiligo, Inflammatory Bowel Disease, asthma, hemophilia, and Immune Response to Gene Therapies.

[0061] In any one of the foregoing or related aspects, the autoimmune disease or immune-mediated disorder comprises Acquired aplastic anemia, Agammaglobulinemia, primary, Alopecia areata, Ankylosing spondylitis (AS), Antiphospholipid syndrome (APS), Autoimmune Addison’s disease (AAD), Autoimmune autonomic ganglionopathy (AAG), Autoimmune encephalitis | acute disseminated encephalomyelitis (ADEM), Autoimmune gastritis, Autoimmune hemolytic anemia (AIHA), Autoimmune hepatitis (AIH), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmunepancreatitis (AIP), Autoimmune polyglandular syndromes types I, II, & III, Autoimmune progesterone dermatitis, Balo disease, Behcet’s disease, Bullous pemphigoid, Celiac disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, Cold agglutinin disease, limited cutaneous systemic sclerosis, Crohn’s disease (CD), Dermatitis herpetiformis, Dermatomyositis, Diabetes, type 1, Discoid lupus, Eosinophilic fasciitis, Evans syndrome, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with polyangiitis (GPA, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto’s thyroiditis, Henoch- Schonlein purpura, Hurst’s disease, iga nephropathy, Immune thrombocytopenia (ITP), Juvenile idiopathic arthritis, Lambert-Eaton myasthenic syndrome (LEMS), Linear iga disease (LAD), Lupus nephritis, Lymphocytic hypophystitis / autoimmune hypophystitis, Mixed connective tissue disease (MCTD), Multiple sclerosis (MS), Myasthenia gravis (MG), Neuromyelitis Optica / Devic's disease, Ocular cicatricial pemphigoid, Palindromic rheumatism, Paraneoplastic cerebellar degeneration, Paraneoplastic pemphigus, Paroxysmal nocturnal hemoglobinuria (PNH), Parsonage-Turner syndrome, Pemphigus gestationis, Pemphigus foliaceus, Pemphigus vulgaris, POEMS syndrome, Polyarteritis nodosa, Polymyalgia rheumatica, Polymyositis, Primary biliary cirrhosis (PBC), Psoriasis, Palmoplantar Pustulosis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Raynaud’s syndrome / phenomenon, Reactive arthritis / Reiter’s syndrome, Relapsing polychondritis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleroderma, Sjogren’s syndrome, Small fiber sensory neuropathy, Systemic lupus erythematosus (SLE), Testicular autoimmunity (vasculitis, orchitis), Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), and Vitiligo.

[0062] In any one of the foregoing or related aspects, the population of engineered cells is autologous to the subject.

[0063] In any one of the foregoing or related aspects, the population of engineered cells is allogenic to the subject.

[0064] In any one of the foregoing or related aspects, the subject is human.

[0065] In any one of the foregoing or related aspects, the population of engineered cells has been engineered to express the truncated EGER via (a) a nucleic acid carrier comprising a nucleic acid that expresses the truncated EGFR or (b) gene-editing. In some cases, the gene-editing comprises utilizing a Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases, or the clustered regularly interspaced short palindromic repeats (CRISPR) system.

[0066] In any one of the foregoing or related aspects, the subject is administered with a nucleic acid carrier comprising a nucleic acid that expresses the truncated EGFR.

[0067] In any one of the foregoing or related aspects, the population of engineered cells is engineered to express the fusion protein via (a) a nucleic acid carrier comprising a nucleic acid that expresses the truncated EGFR or (b) gene-editing. In some cases, the gene-editing comprises utilizing a Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases, or the clustered regularly interspaced short palindromic repeats (CRISPR) system.

[0068] In any one of the foregoing or related aspects, the subject is administered with a nucleic acid carrier comprising the one or more polynucleotides encoding the fusion protein described herein. In somecases, the nucleic acid carrier comprises the one or more polynucleotides encoding the fusion protein and the nucleic acid that expresses the truncated EGFR. In some cases, the nucleic acid carrier is at least one of: a linear polynucleotide, a polynucleotide associated with ionic or amphiphilic compounds, a plasmid, and a virus. In some cases, the nucleic acid carrier is a nanocarrier. In some cases, the nucleic acid carrier is a viral vector, wherein the viral vector is at least one of: a Sendai viral vector, an adenoviral vector, an adeno-associated virus vectors, a retroviral vector, or a lentiviral vector. In some cases, the nucleic acid is a DNA or an RNA. In some cases, the RNA is a messenger RNA (mRNA). In some cases, the nucleic acid carrier further comprises a targeting moiety for targeting an immune cell. In some cases, the immune cell comprises a myeloid cell, a T cell or an NK cell. In some cases, the T cell comprises a T lymphocyte. In some cases, the T cell or the NK cell is induced by the vector or the nucleic acid carrier, to generate the engineered cell in vivo in the subject. In some cases, the nucleic acid carrier further comprises a promoter upstream of the nucleic acid that expresses the truncated EGFR or the fusion protein. In some cases, the promoter is a consecutively active promoter. In some cases, the promoter is an inducible promoter. In some cases, the promoter is induced by an activation signal from a chimeric antigen receptor or a chimeric autoantibody receptor expressed by the population of engineered cells.INCORPORATION BY REFERENCE

[0069] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0070] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0071] FIGs. 1A-1C show that the exemplary anti-TruEGFR-specific antibodies (xTruEGFRtab 1 and xTruEGFRtab2) selectively bind to non-signaling truncated epidermal growth factor receptor (TruEGFR) over endogenous EGFR, whereas a previously described therapeutic EGFR antibody panitumumab (xEGFR) engages both EGFR and TruEGFR. Shown is the percent binding for each antibody (y-axis) at the indicated concentrations (x-axis), as measured by an anti-human Fc detection antibody, when the antibodies were incubated with Jurkat cells that express neither EGFR nor TruEGFR (FIG. 1A); Jurkat cells that were transduced to express non-signaling TruEGFR tag (FIG. IB); or HEK293T cells that express endogenous EGFR but not the TruEGFR tag (FIG.1C). Representative xEGFR antibody binds both to TruEGFR-expressing Jurkat cells (FIG. IB) and EGFR-expressing HEK293 cells (FIG. 1C) with sub-nanomolar affinity whereas the exemplary TruEGFR-specific antibodies (xTruEGFRtab 1 and xTruEGFRtab2) only bind specifically to TruEGFR-expressing Jurkat cells (FIG. IB).

[0072] FIGs. 2A-2B show that the exemplary TruEGFR-specific antibodies (xTruEGFRtab 1 and xTruEGFRtab2) and a previously described anti-EGFR antibody (xEGFR) bind to the TruEGFR tag expressed by CAR-T cells that were lentivirally transduced to express the TruEGFR tag, but not toprimary human T cells that do not express TruEGFRtag. Shown is the percent binding for each antibody (y-axis) at the indicated concentrations (x-axis), as measured by an anti-human Fc detection antibody, when the antibodies were incubated with human non-CAR-T cells (FIG. 2A) or TruEGFR-transduced CAR-T cells (FIG. 2B).

[0073] FIG. 3 depicts the results of an assay demonstrating simultaneous binding of the exemplary anti-TruEGFR-specific antibody (xTruEGFRtab2) and the previously described anti-EGFR antibody (xEGFR) to the TruEGFRtag expressed on human CAR-T cells, suggesting that the antibodies engage TruEGFR molecule at disparate epitopes. The exogenous TruEGFRtag was expressed by lentivirus downstream of the CAR cassette on human T cells. The xEGFR antibody was conjugated to alexa fluor 594 fluorophore (y-axis) while the xTruEGFRtab2 was conjugated to alexa fluor 647 (x-axis). Single staining of individual antibodies (left and middle panels) and co-staining of the two conjugated antibodies (right panel) to TruEGFR-expressing CAR-T cells are shown.

[0074] FIGS. 4A-4D depict four different formats (formats A, B, C, and D) of fusion proteins comprising the anti-TruEGFR-specific antibodies of the present disclosure, in accordance with some embodiments. Fc fusions for these 4 formats may or may not contain knob-in-hole heterodimerization mutations. FIG. 4A shows a bivalent antibody containing one or more Fc mutations with a mutant cytokine polypeptide (e.g., IL-2, IL-21, etc.) fused to the C-terminal of one of the heavy chains. FIG. 4B shows a monovalent antibody containing one or more Fc mutations with a mutant cytokine polypeptide fused to the C-terminal of the heavy chain that lacks fragment antigen-binding (Fab) region. FIG. 4C shows a monovalent antibody containing one or more Fc mutations with a mutant cytokine polypeptide fused to the C-terminal of the heavy chain that contains Fab region. FIG. 4D shows a monovalent antibody containing one or more Fc mutations with a mutant cytokine polypeptide fused to the N-terminal of the heavy chain that lacks Fab region.

[0075] FIGS. 5A-5D show the amino acid sequences of mature IL-2 (FIG. 5A; SEQ ID NO: 1), IL- 2Ra (FIG. 5B; SEQ ID NO: 2), IL-2RJ3 ( FIG. 5C; SEQ ID NO: 3) and IL-2R / (FIG. 5D; SEQ ID NO: 4) polypeptides.

[0076] FIG. 6 shows the amino acid sequence of wild-type mature IL-2 polypeptide (SEQ ID NO: 1). “X” denotes the amino acid substituted in the sequence of wild-type IL-2 polypeptide for another amino acid to generate mutant IL-2 polypeptides of the present disclosure.

[0077] FIGS. 7A-7D show the amino acid sequences of the following polypeptides: mature IL-10 (FIG. 7A; SEQ ID NO: 95), IL-10RA (FIG. 7B; SEQ ID NO: 96), IL-10RB (FIG. 7C; SEQ ID NO: 97), and mature monomer IL-10 (FIG. 7D; SEQ ID NO: 98).

[0078] FIGS. 8A-8B show the amino acid sequences of the wild-type mature IL- 10 polypeptide dimer (FIG. 8A; SEQ ID NO: 95) and the mature monomer IL-10 (FIG. 8B; SEQ ID NO: 98). “X” denotes the amino acid substituted in the sequence of wild-type IL-10 polypeptide for another amino acid to generate the mutant IL- 10 polypeptides of the present disclosure.

[0079] FIGS. 9A-9B show the amino acid sequences of the wild-type mature IL- 10 polypeptide (FIG. 9A; SEQ ID NO: 95) and the mature monomer IL-10 (FIG. 9B; SEQ ID NO: 98). White boxes denote theresidues that were substituted to reduce IL- 10 affinity to IL- 1 ORA, grey shaded boxes denote the residues that were substituted to modify IL- 10 affinity to IL- 1 ORB. Amino acids that were substituted in place of wild-type residues for each position are shown.

[0080] FIGS. 10A-10C depict the binding results of nine exemplary TruEGFR-specific antibody formats (xTruEGFRab9, xTruEGFRablO, xTruEGFRabl 1, xTruEGFRabl2, xTruEGFRabl5, xTruEGFRabl6, xTruEGFRabl8, xTruEGFRab23, xTruEGFRab25) and a previously described anti- EGFR antibody (xEGFR) against TruEGFR tag that is expressed by CAR-T cells, but not to primary human T cells that do not express TruEGFR tag. Shown are the percent binding for each antibody (y-axis) at the indicated concentrations (x-axis), as measured by an anti-human Fc detection antibody conjugated to allophycocyanin (APC), when the antibodies were incubated with TruEGFR-expressing CAR-T cells (FIG. 10A), human non-CAR T cells (FIG. 10B), or HEK 293 cells that express endogenous full-length EGFR but not TruEGFR tag (FIG. 10C).

[0081] FIGS. 11A-11C demonstrate the ability of ten exemplary cytokine fusion proteins containing the exemplary TruEGFR-specific antibodies to selectively activate TruEGFR-expressing CAR-T cells (CAR+) over TruEGFR-non expressing T cells (CAR). Specifically, the figures show the results of two phospho-STAT5 (pSTAT5) assays performed with CAR-T cells generated from human donors cultured with the indicated fusion proteins: FIG. 11A shows the activity of an untargeted Fc fusion of a wild type recombinant IL-2 (Fc-IL2wt); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRab9 and an IL-2R[3y-binding polypeptide IL2ml (xTruEGFRab9-IL2ml); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRablO and IL2ml (xTruEGFRabl 0-IL2ml); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRab 11 and IL2m 1 (xTruEGFRabl l-IL2ml); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRabl2 and IL2ml (xTruEGFRabl2-IL2ml); FIG. 11B shows the activity of an untargeted Fc fusion of a wild type recombinant IL-2 (Fc-IL2wt); a bivalent fusion of a previously described anti-EGFR antibody (panitumumab) and IL2ml (xEGFR-IL2ml); a bivalent fusion of an exemplary anti-TruEGFR- specific antibody xTruEGFRabl3 and IL2ml (xTruEGFRabl3-IL2ml); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRabl5 and IL2ml (xTruEGFRabl5-IL2ml); FIG. 11C shows the activity of an untargeted Fc fusion of a wild type recombinant IL-2 (Fc-IL2wt); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRab 16 and IL2ml (xTruEGFRab 16- IL2ml); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRab 18 and IL2ml (xTruEGFRabl8-IL2ml); a bivalent fusion of an exemplary anti-TruEGFR-specific antibody xTruEGFRab23 and IL2ml (xTruEGFRab23-IL2ml); and a bivalent fusion of an exemplary anti- TruEGFR-specific antibody xTruEGFRab25 and IL2ml (xTruEGFRab25-IL2ml). Percent pSTAT5- expressing cells (y-axis) is depicted for either CAR-T cells that express TruEGFR tag (CAR+) or non- CAR-T cells (CAR ) at the indicated concentrations (x-axis). The exemplary targeted cytokine constructs showed selective activation of pSTAT5 in CAR-T cells (CAR+) over non-CAR-T cells (CAR), whereas untargeted Fc fusion with wild type IL-2 equally activated CAR+ and CAR- T cells.

[0082] FIGS. 12A-12F depict the results of an in vivo study demonstrating the ability of five exemplary selected anti-TruEGFR-specific cytokine fusion molecules (xTruEGFRablO-IL2ml, xTruEGFRabl l-IL2ml, xTruEGFRabl5-IL2ml, xTruEGFRabl6-IL2ml, xTruEGFRab23-IL2ml), alongside the control anti-EGFR (panitumumab) cytokine fusion molecule (xEGFR-IL2ml), to induce selective enrichment and expansion of TruEGFR-expressing CAR-T cells (CAR+) over TruEGFR-non expressing human T cells (CAR) using a flow cytometry assay on peripheral blood of treated mice. FIGS. 12A & 12D show the design of two in vivo experiments wherein engineered CAR-T cells that express an exogenous TruEGFR tag (CAR+) were generated from peripheral blood mononuclear cells from healthy human donors. A mixture of CAR+ and CAR- T cells were injected into NOD.Cg-Prkdcscid I12rgtmlWjl / SzJ (NSG) mice, wherein the experiment depicted in FIGS. 12A-12C received l.lxlO6CAR+ and 5.5xl06CAR- T cells and the experiment depicted in FIGS. 12D-12F received 2.01xl06CAR+ and 6.7xl06CAR- T cells. Control solution (PBS) or the indicated targeted cytokine constructs were injected into the mice as a single dose at 1 mg / kg one day later (FIGS. 12A-12C) or the same day (FIGS. 12D-12F). Peripheral blood was collected 14 days (FIGS. 12A-12C) or 12 days (FIGS. 12D- 12F) after targeted cytokine constructs were injected for cell content analysis by flow cytometry. FIGS. 12B & 12E depict the percent of CAR+ enrichment in the peripheral blood of mice at the indicated time points. FIGS. 12C & 12F depict the quantification and selective expansion of CAR+ cells over CAR-, as calculated by the ratio of gated flow cytometry events to counting beads in the flow cytometry analysis, shown is the number of CAR+ or CAR- T cells / pL in the peripheral blood of the mice. Overall, recipients of the exemplary xTruEGFR antibody-containing cytokine fusion proteins (FIGS. 12D-12F) as depicted in the legend (xTruEGFRablO-IL2ml, xTruEGFRabl l-IL2ml, xTruEGFRabl5-IL2ml, xTruEGFRabl6-IL2ml, xTruEGFRab23-IL2ml) show selective enrichment of CAR-T cells (CAR+) over non CAR-T cells (CAR ) similarly to recipients xEGFR-containing cytokine fusion protein (xEGFR- IL2ml) (FIGS. 12A-12C), and in contrast to recipients that received PBS treatment which show similar proportions of CAR+ and CAR- T cells.DETAILED DESCRIPTIONCertain Terminology

[0083] As used in the specification and claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a chimeric transmembrane receptor polypeptide” includes a plurality of chimeric transmembrane receptor polypeptides.

[0084] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value.

[0085] As used herein, a “cell” generally refers to a biological cell. A cell can be the basic structural, functional and / or biological unit of a living organism. A cell can originate from any organism having one or more cells. Some examples include: a prokaryotic cell, eukaryotic cell, a bacterial cell, an archaeal cell, a cell of a single-cell eukaryotic organism, a protozoa cell, a cell from a plant (e.g, cells from plant crops, fruits, vegetables, grains, soy bean, com, maize, wheat, seeds, tomatoes, rice, cassava, sugarcane, pumpkin, hay, potatoes, cotton, cannabis, tobacco, flowering plants, conifers, gymnosperms, fems, clubmosses, homworts, liverworts, mosses), an algal cell, (e.g, Botryococcus braunii, Chlamydomonas reinhardtii, Nannochloropsis gaditana, Chlorella pyrenoidosa, Sargassum patens C. Agardh, and the like), seaweeds (e.g. , kelp), a fungal cell (e.g. , a yeast cell, a cell from a mushroom), an animal cell, a cell from an invertebrate animal (e.g., fruit fly, cnidarian, echinoderm, nematode, etc.), a cell from a vertebrate animal (e.g. , fish, amphibian, reptile, bird, mammal), a cell from a mammal (e.g. , a pig, a cow, a goat, a sheep, a rodent, a rat, a mouse, a non-human primate, a human, etc.), and etcetera. Sometimes a cell is not originating from a natural organism (e.g., a cell can be a synthetically made, sometimes termed an artificial cell).

[0086] The term “antigen,” as used herein, refers to a molecule or a fragment thereof capable of being bound by a selective binding agent. As an example, an antigen can be a ligand that can be bound by a selective binding agent such as a receptor. As another example, an antigen can be an antigenic molecule that can be bound by a selective binding agent such as an immunological protein (e.g., an antibody). An antigen can also refer to a molecule or fragment thereof capable of being used in an animal to produce antibodies capable of binding to that antigen.

[0087] A “cytokine” is a form of immunomodulatory polypeptide that can mediate cross-talk between initiating / primary cells and target / effector cells. It can function as a soluble form or cell-surface associated to bind the “cytokine receptor” on target immune cells to activate signaling. “Cytokine receptor” as used here is the polypeptide on the cell surface that activates intracellular signaling upon binding the cytokine on the extracellular cell surface. Cytokines can include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by a wide range of cells, including immune cells, endothelial cells, fibroblasts, and stromal cells. A given cytokine may be produced by more than one cell type. Cytokines are pleiotropic; since the receptors are expressed on multiple immune cell subsets, one cytokine can activate the signaling pathway in multiple cells. However, depending on the cell type, the signaling events for a cytokine can result in different downstream cellular events such as activation, proliferation, survival, apoptosis, effector function and secretion of other immunomodulatory proteins. A given cytokine, in some embodiments, is a wild-type cytokine polypeptide, a fragment thereof, or a variant thereof, such as a mutated cytokine polypeptide (also referred to herein as a mutein cytokine, e.g., a mutein IL-2, a mutein IL-7).

[0088] ‘ ‘Immune cells” as described here are cells of the immune system that react to organisms or other entities that are deemed foreign to the immune system of the host. They protect the host against foreign pathogens, organisms and diseases. Immune cells, also called leukocytes, are involved in both innate and adaptive and immune responses to fight pathogens. Innate immune responses occurimmediately upon exposure to pathogens without additional priming or learning processes. Adaptive immune processes require initial priming, and subsequently create memory, which in turn leads to enhanced responsiveness during subsequent encounters with the same pathogen. Innate immune cells include monocytes, macrophages, dendritic cells, innate lymphoid cells (ILCs) including natural killer (NK) cells, neutrophils, megakaryocytes, eosinophils and basophils. Adaptive immune cells include B and T lymphocytes / cells. T cells subsets include alpha beta CD4+ T (naive CD4+, memory CD4+, effector memory CD4+, effector CD4+, regulatory CD4+), and alpha beta CD8+ T (naive CD8+, memory CD8+, effector memory CD8+, effector CD8+). B cell subsets include naive B, memory B, and plasma cells. NK T cells and T gamma delta (Tv8) cells exhibit properties of both innate and adaptive lymphocytes.

[0089] ‘ T cells” or “T lymphocytes” are immune cells that play a key role in the orchestration of immune responses in health and disease. Two major T cell subsets exist that have unique functions and properties: T cells that express the CD8 antigen (CD8+ T cells) are cytotoxic or killer T cells that can lyse target cells using the cytotoxic proteins such as granzymes and perforin; and T cells that express the CD4 antigen (CD4+ T cells) are helper T cells that are capable of regulating the function of many other immune cell types including that of CD8+ T cells, B cells, macrophages etc. Furthermore, CD4+ T cells are further subdivided into several subsets such as: T regulatory (Treg) cells that are capable of suppressing the immune response, and T helper 1 (Thl), T helper 2 (Th2), and T helper 17 (Thl7) cells that regulate different types of immune responses by secreting immunomodulatory proteins such as cytokines. T cells recognize their targets via alpha beta T cell receptors that bind to unique antigenspecific motifs and this recognition mechanism is generally required in order to trigger their cytotoxic and cytokine -secreting functions. “Innate lymphocytes” can also exhibit properties of CD8+ and CD4+ T cells, such as the cytotoxic activity or the secretion of Thl, Th2, and Th 17 cytokines. Some of these innate lymphocyte subsets include NK cells and ILC1, ILC2, and ILC3 cells; and innate-like T cells such as Ty8 cells; and NK T cells. These cells can rapidly respond to inflammatory stimuli from infected or injured tissues, such as immunomodulatory cytokines, but unlike alpha beta T cells, they can respond without the need to recognize antigen-specific patterns.

[0090] An “antigen binding domain” as described here refers to a molecule that specifically binds an antigenic determinant. A targeting moiety or an antigen binding domain may be a protein, carbohydrate, lipid, or other chemical compound. It can include antibody, antibody fragments (Chames et al, Br J Pharmacol. 2009 May; 157(2): 220-233; Chan & Carter, Nat Rev Immunol. 2010 May 10(5):301-16.; Leavy, Nat Rev Immunol. 2010 May; 10(5): 297.; Holliger & Hudson, 2005), scaffold antigen binding proteins (Gebauer and Skerra, 2009; Stumpp et al, 2008), single domain antibodies (sdAb), minibodies (Tramontane et al, 1994), the variable domain of heavy chain antibodies (nanobody, VHH), the variable domain of the new antigen receptors (VNAR), carbohydrate binding domains (CBD) (Blake et al, 2006), collagen binding domain (Knight et al, 2000), lectin binding proteins (Tetranectin), collagen binding proteins, adnectin / fibronectin (Lipovsek, 2011 Protein Eng Des Sei. 2011 Jan;24(l-2):3-9), a serum transferrin (trans-body), Evibody, Protein A-derived molecule, such as Z-domain of Protein A (Affibody)(Nygren et al, 2008), an A-domain (Avimer / Maxibody), alphabodies (WO2010066740), Avimer / Maxibody, designed ankyrin-repeat domains (DARPins) (Stumpp et al, 2008), anticalins (Skerra et al, 2008), a human gamma-crystallin or ubiquitin (Affilin molecules), a kunitz type domain of human protease inhibitors, knottins (Kolmar et al, 2008), linear or constrained peptide with or without fusion to extend half-life e.g., (Fc fusion - Peptibody) (Rentero Rebollo & Heinis, Methods. 2013 Mar 15;60(l):46-54.; EP 1144454 B2; Shimamoto et al, MAbs. 2012 Sep-Oct;4(5):586-91; US 7205275 B2), constrained bicyclic peptides (US 2018 / 0200378 Al), aptamer, engineered CH2 domains (nanoantibodies; Dimitrov, 2009) ) and engineered CH3 domain “Fcab” domains (Wozniak-Knopp et al, 2010).

[0091] The term “antibody,” as used herein, refers to a proteinaceous binding molecule with immunoglobulin-like functions. The term antibody includes antibodies (e.g., monoclonal and polyclonal antibodies), as well as derivatives, variants, and fragments thereof. Antibodies include immunoglobulins (Ig’s) of different classes (i.e. IgA, IgG, IgM, IgD and IgE) and subclasses (such as IgGl, IgG2, etc.). A derivative, variant or fragment thereof refers to a functional derivative or fragment which retains the binding specificity (e.g., complete and / or partial) of the corresponding antibody. Antigen-binding fragments include Fab, Fab', F(ab')2, variable fragment (Fv), single chain variable fragment (scFv), minibodies, diabodies, and single-domain antibodies (“sdAb” or “nanobodies” or “came lids”). The term antibody includes antibodies and antigen-binding fragments of antibodies that have been optimized, engineered or chemically conjugated. Examples of antibodies that have been optimized include affinity- matured antibodies. Examples of antibodies that have been engineered include Fc optimized antibodies (e.g., antibodies optimized in the fragment crystallizable region) and multispecific antibodies (e.g., bispecific antibodies). Wherever used herein, “human antibody” means an antibody having an amino acid sequence corresponding to that of an antibody produced by a human and / or has been made using any of the techniques for making human antibodies known in the art or of the present invention. This definition of a human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody comprising murine light chain and human heavy chain polypeptides. Human antibodies can be produced using various techniques known in the art. In some cases the human antibody is selected from a phage library, where that phage library expresses human antibodies (Vaughan et al., 1996, Nature Biotechnology, 14:309-314; Sheets et al., 1998, PNAS, (USA) 95:6157-6162; Hoogenboom and Winter, 1991, J. Mol. Biol., 227:381; Marks et al., 1991, J. Mol. Biol., 222:581 ). Human antibodies can also be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. This approach is described in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016. Alternatively, the human antibody may be prepared by immortalizing human B lymphocytes that produce an antibody directed against a target antigen (such B lymphocytes may be recovered from an individual or may have been immunized in vitro). See, e.g., Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al., 1991, J. Immunol., 147 (l):86-95; and U.S. Patent No. 5,750,373.

[0092] The terms “Fc receptor” or “FcR,” as used herein, generally refers to a receptor, or any derivative, variant or fragment thereof, that can bind to the Fc region of an antibody. In certain embodiments, the FcR is one which binds an IgG antibody (a gamma receptor, Fcgamma R) and includes receptors of the Fcgamma RI (CD64), Fcgamma RII (CD32), and Fcgamma RIII (CD 16) subclasses, including allelic variants and alternatively spliced forms of these receptors. Fcgamma RII receptors include Fcgamma RIIA (an “activating receptor”) and Fcgamma RUB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. The term “FcR” also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus.

[0093] By “effector function” as used herein is meant a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand, which vary with the antibody isotype. Effector functions include antibody -dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation. “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express FcRs (such as Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC is correlated with binding to FcyRIIIa; increased binding to FcyRIIIa leads to an increase in ADCC activity. To assess ADCC activity of a molecule of interest, an in vitro ADCC assay such as that described in U.S. Pat. No. 5,500,362 or 5,821,337 may be performed. “ADCP” or antibody dependent cell-mediated phagocytosis as used herein is meant the cell- mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0094] ‘ ‘Fc null” and “Fc null variant” are used interchangeably and used herein to describe a modifiedFc which have reduced or abolished effector functions. Such Fc null or Fc null variant have reduced or abolished to FcyRs and / or complement receptors. Preferably, such Fc null or Fc null variant has abolished effector functions. Exemplary methods for the modification include chemical alteration, amino acid residue substitution, insertion and deletions. Exemplary amino acid positions on Fc molecules where one or more modifications were introduced to decrease effector function of the resulting variant (numbering based on the EU numbering scheme) at position i) IgGl: C220, C226, C229, E233, L234, L235, G237, P238, S239 D265, S267, N297, L328, P331, K322, A327 and P329, ii) IgG2: V234, G237, D265, H268, N297, V309, A330, A331, K322 and iii) IgG4: L235, G237, D265 and E318. Exemplary Fc molecules having decreased effector function include those having one or more of the following substitutions: i) IgGl: N297A, N297Q, D265A / N297A, D265A / N297Q, C220S / C226S / C229S / P238S, S267E / L328F, C226S / C229S / E233P / L234V / L235A, L234F / L235E / P331S, L234A / L235A, L234A / L235A / G237A, L234A / L235A / G237A / K322A, L234A / L235A / G237A / A330S / A33 IS, L234A / L235A / P329G,E233P / L234V / L235A / G236del / S239K, E233P / L234V / L235A / G236del / S267K, E233P / L234V / L235A / G236del / S239K / A327G, E233P / L234V / L235A / G236del / S267K / A327G andE233P / L234V / L235A / G236del, L234A / L235A / G237deleted; ii) IgG2: A330S / A331S, V234A / G237A, V234A / G237A / D265A, D265A / A330S / A331S, V234A / G237A / D265A / A330S / A331S, and H268Q / V309L / A330S / A331S; iii) IgG4: L235A / G237A / E318A, D265A, L235A / G237A / D265A and L235A / G237A / D265A / E318A. “EU numbering” as used herein is described in Edelman, G.M. et al., “The covalent structure of an entire gammaG immunoglobulin molecule.” Proc. Natl. Acad. Sci.USA 1969, 63, 78-85; and Arikat, E.A. et al. “Sequences of Proteins of Immunological Interest, 5th ed.” DIANE Publishing: Collingdale, PA, USA, 1991.

[0095] “Epitope” as used herein refers to a determinant capable of specific binding to the variable region of an antibody molecule known as a paratope. Epitopes are groupings of molecules such as amino acids or sugar side chains and usually have specific structural characteristics, as well as specific charge characteristics. A single antigen may have more than one epitope. The epitope may comprise amino acid residues directly involved in the binding and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked by the antigen binding peptide (in other words, the amino acid residue is within the footprint of the antigen binding peptide). Epitopes may be either conformational or linear. An epitope can include at least 3, and more usually, at least 5 or 8-10 amino acids. Antibodies that recognize the same epitope can be verified in a simple immunoassay showing the ability of one antibody to block the binding of another antibody to a target antigen, for example "binning".

[0096] ‘ ‘Linker” as used herein refers to a molecule that connect two polypeptide chains. Linker can be a polypeptide linker or a synthetic chemical linker (for example, see disclosed in Protein Engineering, 9(3), 299-305, 1996). The length and sequence of the polypeptide linkers is not particularly limited and can be selected according to the purpose by those skilled in the art. Polypeptide linker comprises one or more amino acids. Preferably, polypeptide linker is a peptide with a length of at least 5 amino acids, preferably with a length of 5 to 100, more preferably of 10 to 50 amino acids. In one embodiment, said peptide linker is G, S, GS, SG, SGG, GGS, and GSG (with G=glycine and S=serine). In another embodiment, said peptide linker is (GGGS)xGn (SEQ ID NO: 5) or (GGGGS)xGn (SEQ ID NO: 6) or (GGGGGS)xGn (SEQ ID NO: 7) with x=l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 and n=0, 1, 2 or 3. Preferably, the said linker is (GGGGS)xGn with x=2,3, or 4 and n=0 (SEQ ID NO: 8); more preferably the said linker is (GGGGS)xGn with x=3 and n=0 (SEQ ID NO: 9). Synthetic chemical linkers include crosslinking agents that are routinely used to crosslink peptides, for example, N-hydroxy succinimide (NHS), disuccinimidyl suberate (DSS), bis(succinimidyl) suberate (BS3), dithiobis(succinimidyl propionate) (DSP), dithiobis(succinimidyl propionate) (DTSSP), ethylene glycol bis(succinimidyl succinate) (EGS), ethylene glycol bis(sulfosuccinimidyl succinate) (sulfo-EGS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), bis[2-(succinimidoxycarbonyloxy)ethyl] sulfone (BSOCOES), and bis[2-(succinimidoxycarbonyloxy)ethyl] sulfone (sulfo-BSOCOES).

[0097] The term “nucleotide,” as used herein, generally refers to a base-sugar-phosphate combination. A nucleotide can comprise a synthetic nucleotide. A nucleotide can comprise a synthetic nucleotide analog. Nucleotides can be monomeric units of a nucleic acid sequence (e.g, deoxyribonucleic acid(DNA) and ribonucleic acid (RNA)). The term nucleotide can include ribonucleoside triphosphates adenosine triphosphate (ATP), uridine triphosphate (UTP), cytosine triphosphate (CTP), guanosine triphosphate (GTP) and deoxyribonucleoside triphosphates such as dATP, dCTP, diTP, dUTP, dGTP, dTTP, or derivatives thereof. Such derivatives can include, for example, [aS]dATP, 7-deaza-dGTP and 7- deaza-dATP, and nucleotide derivatives that confer nuclease resistance on the nucleic acid molecule containing them. The term nucleotide as used herein, in some examples, refers to dideoxyribonucleoside triphosphates (ddNTPs) and their derivatives. Illustrative examples of dideoxyribonucleoside triphosphates can include ddATP, ddCTP, ddGTP, ddITP, and ddTTP. A nucleotide can be unlabeled or detectably labeled by well-known techniques. Labeling can also be carried out with quantum dots. Detectable labels can include, for example, radioactive isotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels and enzyme labels. Fluorescent labels of nucleotides can include fluorescein, 5 -carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5-dichloro-6-carboxyfluorescein (JOE), rhodamine, 6-carboxyrhodamine (R6G), N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6- carboxy-X -rhodamine (ROX), 4-(4'dimethylaminophenylazo) benzoic acid (DABCYL), Cascade Blue, Oregon Green, Texas Red, Cyanine and 5 -(2 '-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS). Specific examples of fluorescently labeled nucleotides can include [R6G]dUTP, [TAMRA]dUTP, [R110]dCTP, [R6G]dCTP, [TAMRA]dCTP, [JOE]ddATP, [R6G]ddATP, [FAM]ddCTP, [R110]ddCTP, [TAMRA]ddGTP, [ROX]ddTTP, [dR6G]ddATP, [dR110]ddCTP, [dTAMRA]ddGTP, and [dROX]ddTTP available from Perkin Elmer, Foster City, Calif; FluoroLink DeoxyNucleotides, FluoroLink Cy3-dCTP, FluoroLink Cy5-dCTP, FluoroLink Fluor X-dCTP, FluoroLink Cy3-dUTP, and FluoroLink Cy5-dUTP available from Amersham, Arlington Heights, Ill.; Fluorescein- 15 -dATP, Fluorescein- 12-dUTP, Tetramethyl-rodamine-6-dUTP, IR770-9-dATP, Fluorescein-12-ddUTP, Fluorescein- 12-UTP, and Fluorescein-15-2'-dATP available from Boehringer Mannheim, Indianapolis, Ind.; and Chromosome Labeled Nucleotides, BODIPY-FL-14-UTP, BODIPY-FL-4-UTP, BODIPY- TMR-14-UTP, B0DIPY-TMR-14-dUTP, B0DIPY-TR-14-UTP, BODIPY-TR-14-dUTP, Cascade Blue- 7-UTP, Cascade Blue-7-dUTP, fluorescein- 12-UTP, fluorescein- 12-dUTP, Oregon Green 488-5-dUTP, Rhodamine Green-5 -UTP, Rhodamine Green-5 -dUTP, tetramethylrhodamine-6-UTP, tetramethylrhodamine-6-dUTP, Texas Red-5-UTP, Texas Red-5-dUTP, and Texas Red-12-dUTP available from Molecular Probes, Eugene, Oreg. Nucleotides can also be labeled or marked by chemical modification. A chemically-modified single nucleotide can be biotin-dNTP. Some examples of biotinylated dNTPs can include, biotin-dATP (e.g., bio-N6-ddATP, biotin-14-dATP), biotin-dCTP (e.g., biotin-11-dCTP, biotin- 14-dCTP), and biotin-dUTP (e.g., biotin-11-dUTP, biotin- 16-dUTP, biotin-20- dUTP).

[0098] The terms “polynucleotide,” “oligonucleotide,” and “nucleic acid” are used interchangeably to refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof, either in single-, double-, or multi-stranded form. A polynucleotide can be exogenous or endogenous to a cell. A polynucleotide can exist in a cell-free environment. A polynucleotide can be a gene or fragment thereof. A polynucleotide can be DNA. A polynucleotide can be RNA. Apolynucleotide can have any three-dimensional structure, and can perform any function, known or unknown. A polynucleotide can comprise one or more analogs (e.g., altered backbone, sugar, or nucleobase). If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Some examples of analogs include: 5 -bromouracil, peptide nucleic acid, xeno nucleic acid, morpholines, locked nucleic acids, glycol nucleic acids, threose nucleic acids, dideoxynucleotides, cordycepin, 7-deaza-GTP, fluorophores (e.g., rhodamine or fluorescein linked to the sugar), thiol containing nucleotides, biotin linked nucleotides, fluorescent base analogs, CpG islands, methyl-7- guanosine, methylated nucleotides, inosine, thiouridine, pseudourdine, dihydrouridine, queuosine, and wyosine. Examples of polynucleotides include coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro- RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, cell-free polynucleotides including cell-free DNA (cfDNA) and cell-free RNA (cfRNA), nucleic acid probes, and primers. The sequence of nucleotides can be interrupted by non-nucleotide components.

[0099] The term “gene,” as used herein, refers to a nucleic acid (e.g., DNA such as genomic DNA and cDNA) and its corresponding nucleotide sequence that is involved in encoding an RNA transcript. The term as used herein with reference to genomic DNA includes intervening, non-coding regions as well as regulatory regions and can include 5’ and 3’ ends. In some uses, the term encompasses the transcribed sequences, including 5’ and 3’ untranslated regions (5’-UTR and 3’-UTR), exons and introns. In some genes, the transcribed region will contain “open reading frames” that encode polypeptides. In some uses of the term, a “gene” comprises only the coding sequences (e.g., an “open reading frame” or “coding region”) necessary for encoding a polypeptide. In some cases, genes do not encode a polypeptide, for example, ribosomal RNA genes (rRNA) and transfer RNA (tRNA) genes. In some cases, the term “gene” includes not only the transcribed sequences, but in addition, also includes non-transcribed regions including upstream and downstream regulatory regions, enhancers and promoters. A gene, in some cases, refers to an “endogenous gene” or a native gene in its natural location in the genome of an organism. A gene, in some cases, refers to an “exogenous gene” or a non-native gene. A non-native gene, in some cases, refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer. A non-native gene, in some cases, refers to a gene not in its natural location in the genome of an organism. A non-native gene, in some cases, also refers to a naturally occurring nucleic acid or polypeptide sequence that comprises mutations, insertions and / or deletions (e.g., non-native sequence).

[0100] The term “regulating” with reference to expression or activity, as used herein, refers to altering the level of expression or activity. Regulation can occur at the transcription level and / or translation level.

[0101] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein to refer to a polymer of at least two amino acid residues joined by peptide bond(s). This term does not connote a specific length of polymer, nor is it intended to imply or distinguish whether the peptide is producedusing recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring. The terms apply to naturally occurring amino acid polymers as well as amino acid polymers comprising at least one modified amino acid. In some cases, the polymer can be interrupted by non-amino acids. The terms include amino acid chains of any length, including full-length proteins, and proteins with or without secondary and / or tertiary structure (e.g., domains). The terms also encompass an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, oxidation, and any other manipulation such as conjugation with a labeling component. The terms “amino acid” and “amino acids,” as used herein, generally refer to natural and non-natural amino acids, including, modified amino acids and amino acid analogues. Modified amino acids can include natural amino acids and non-natural amino acids, which have been chemically modified to include a group or a chemical moiety not naturally present on the amino acid. Amino acid analogues can refer to amino acid derivatives. The term “amino acid” includes both D-amino acids and L-amino acids.

[0102] The terms “derivative,” “variant,” and “fragment,” when used herein with reference to a polypeptide, refers to a polypeptide related to a wild type polypeptide, for example either by amino acid sequence, structure (e.g, secondary and / or tertiary), activity (e.g., enzymatic activity) and / or function. Derivatives, variants and fragments of a polypeptide can comprise one or more amino acid variations (e.g., mutations, insertions, and deletions), truncations, modifications, or combinations thereof compared to a wild type polypeptide.

[0103] The term “residue” as used herein means a position in a protein and its associated amino acid identity. For example, Leu 234 (also referred to as Leu234 or L234) is a residue at position 234 in the human antibody IgGl.

[0104] The terms “wild-type" or “WT” as used herein refer to an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A wild-type protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.

[0105] The terms “substitution” or “mutation” refers to a change to the polypeptide backbone wherein an amino acid occurring naturally in the wild-type sequence of a polypeptide is substituted to another amino acid not naturally occurring at the same position in the said polypeptide. In some cases, a mutation or mutations is introduced to modify a polypeptide’s affinity to its receptor thereby altering its activity such that it becomes different from the affinity and activity of the wild-type cognate polypeptide. Mutations can also improve a polypeptide’s biophysical properties. Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods may include site- directed mutagenesis, PCR, gene synthesis and the like. It is contemplated that methods of altering the side chain group of an amino acid by methods other than genetic engineering, such as chemical modification, may also be useful.

[0106] The terms “affinity” or “binding affinity” refer to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1: 1 interaction between members of a binding pair (e.g., antibody and antigen). Theaffinity can generally be represented by the dissociation constant (KD), which is the ratio of dissociation and association rate constants (koffand kon, respectively). Thus, equivalent affinities may comprise different rate constants, as long as the ratio of the rate constants remains the same. Affinity can be measured by common methods known in the art, such as enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) technologies (e.g., BIAcore), BioLayer Interferometry (BLI) technologies (e.g., Octet) and other traditional binding assays (Heeley, Endocr Res 28, 217-229 (2002).

[0107] The terms “binding” or “specific binding” as used interchangeably here, can refer to the ability of a polypeptide or an antigen binding domain to selectively interact with the receptor for the polypeptide or target antigen, respectively, and this specific interaction can be distinguished from non-targeted or undesired or non-specific interactions. Examples of specific binding can include IL-2 cytokine binding to its specific receptors (e.g., IL-2Ra, IL-2RP and IL-2Ry) and an antigen binding domain binding to a specific antigen (e.g., truncated EGFR as described herein).

[0108] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, preferably a mammal such as a human. Mammals include murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.

[0109] The terms “treatment” and “treating,” as used herein, refer to an approach for obtaining beneficial or desired results including a therapeutic benefit and / or a prophylactic benefit. For example, a treatment can comprise administering a system or cell population disclosed herein. By therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. For prophylactic benefit, a composition can be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested.

[0110] The terms “effective amount,” or “therapeutically effective amount,” or “effective dose,” or “effective dosage,” refer to the quantity of a composition, for example a composition comprising immune cells such as lymphocytes (e.g., T lymphocytes and / or NK cells), which can be combined with a fusion protein of the present disclosure, that is sufficient to result in a desired activity upon administration to a subject in need thereof. Within the context of the present disclosure, the term “therapeutically effective” refers to that quantity of a composition that is sufficient to delay the manifestation, arrest the progression, relieve or alleviate at least one symptom of a disorder treated by the methods of the present disclosure.

[0111] The terms “anti-TruEGFR-specific antibody,” “xTruEGFRab,” “xTruEGFRtab,” “xtruncated EGFRab,” “truncated EGFR antibody,” “anti-truncated EGFR,” or “truncated EGFR scFv,” as used interchangeably, refer to an antibody or antigen-binding fragments thereof that targets truncated epithelial growth factor receptor (EGFR), for example, an IgG2a mouse monoclonal antibody or scFv that binds the truncated EGFR (or “TruEGFR” as used interchangeably with “truncated EGFR”). Epidermal growth factor receptor, also known as EGFR, ErbBl and HER1, is a cell-surface receptor for members of the epidermal growth factor family of extracellular ligands. EGFR is an endogenous cell-surface moleculethat can be modified or truncated to retain an extracellular epitope recognized by an antibody or functional fragment thereof (such as those described herein), and to remove any signaling or trafficking domains and / or any extracellular domains unrecognized by the antibody or functional fragment thereof. In some embodiments, the antibody or functional fragment thereof disclosed herein recognizes truncated EGFR but does not recognize (e.g., does not specifically bind to) full-length EGFR. In some cases, full- length EGFR as described herein is a wild-type EGFR. In some cases, full-length EGFR as described herein is a wild-type human EGFR. In some cases, various EGFR domains of a full-length EGFR, including the extracellular region domains I, II, III, IV, the juxtamembrane region, the tyrosine kinase domain, are described in Lemmon et al., Cold Spring Harb Perspect Biol 2014. Extracellular region domain I of a full-length EGFR spans from amino acid residue Leul to Gin 164 numbered according to SEQ ID NO: 218, extracellular region domain II of a full-length EGFR from Lys 165 to Cys 309 numbered according to SEQ ID NO: 218, extracellular region domain III of a full-length EGFR from Arg310 to Gly479 numbered according to SEQ ID NO: 218, and extracellular region domain IV of a full- length EGFR from Gln480 to Pro620 numbered according to SEQ ID NO: 218. In some cases, a truncated EGFR comprises an EGFR extracellular region domain III. In some cases, a truncated EGFR comprises a N-terminus of EGFR extracellular region domain III of the full-length EGFR. In some cases, a truncated EGFR comprises at least one or both of R310 and K311 residues of the full-length EGFR numbered according to SEQ ID NO: 218. In some cases, a truncated EGFR comprises at least the R310 residue at a N-terminus of EGFR extracellular region domain III of the full-length EGFR. In some cases, a truncated EGFR comprises the K311 residues at a N-terminus of EGFR extracellular region domain III of the full- length EGFR. In some cases, a truncated EGFR comprises the R310 and K311 residues at a N-terminus of EGFR extracellular region domain III of the full-length EGFR. In some cases, a truncated EGFR comprises a N-terminal fragment of EGFR extracellular region domain III. The N-terminal fragment of the EGFR extracellular region domain III can have the same or substantially similar secondary and / or tertiary structure as the EGFR extracellular region domain III of the full-length EGFR. In some cases, the N-terminal fragment of the EGFR extracellular region domain III do not necessarily have the same or substantially similar secondary and / or tertiary structure as the EGFR extracellular region domain III of the full-length EGFR. In some cases, the truncated EGFR comprises a N-terminal signal peptide or a portion of such N-terminal signal peptide, e.g., a C-terminus portion of such signal peptide that connects to the N-terminus of the truncated EGFR. In some cases, the N-terminal signal peptide is a GM-CSFR alpha chain signal sequences. In some cases, the portion of the N-terminal signal peptide is a C-terminal portion that comprises the 3 amino acids Leu-Ile-Pro. In some cases, the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence of the EGFR extracellular region domain III of the full-length EGFR. In some cases, the truncated EGFR comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of the EGFR extracellular region domain III of the full-length EGFR comprises amino acid mutations, substitutions, truncations, modifications, or any combinations thereof as compared to the EGFR extracellular region domain III of the full-length wild-type EGFR. In some cases,the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 222. In some cases, calling of protein domains of the truncated EGFR with mutations, substitutions, truncations, and / or modifications relative to a full-length wild-type EGFR is in accordance with the position of the corresponding wild-type amino acid in the sequence of the full-length wild-type EGFR, e.g., extracellular region domain I of a full-length EGFR spans from amino acid residue Leul to Gin 164, extracellular region domain II of a full-length EGFR from Lys 165 to Cys 309, extracellular region domain III of a full-length EGFR from Arg310 to Gly479, and extracellular region domain IV of a full-length EGFR from Gln480 to Pro620. In some cases, a truncated EGFR comprises a N-terminal fragment (e.g., at least one of R310 and K311 residues numbered according to SEQ ID NO: 218) of EGFR extracellular region Domain III of the full-length EGFR. In some cases, a truncated EGFR lacks an EGFR extracellular region Domain I, an EGFR extracellular region Domain II, an EGFR Juxtamembrane Domain, and an EGFR Tyrosine Kinase Domain as compared to the full-length EGFR. In some cases, the truncated EGFR lacks an EGFR extracellular region Domain I, an EGFR extracellular region Domain II, at least a portion of an EGFR Juxtamembrane Domain, and an EGFR Tyrosine Kinase Domain as compared to the full-length EGFR. In some cases, the truncated EGFR comprises EGFR extracellular domain III of the full-length EGFR and EGFR extracellular domain IV of the full-length EGFR. In some cases, a truncated EGFR comprises an EGFR transmembrane region, Domain III and Domain IV of the extracellular region of full- length EGFR. In some cases, the truncated EGFR comprises a N-terminal signal peptide or a portion of such N-terminal signal peptide, e.g., a C-terminus portion of such signal peptide that connects to the N- terminus of the truncated EGFR. In some cases, the N-terminal signal peptide is a GM-CSFR alpha chain signal sequences. In some cases, the portion of the N-terminal signal peptide is a C-terminal portion that comprises the 3 amino acids Leu-Ile-Pro. In some cases, the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 216, 219, 222, 239, or 415. In some cases, a truncated EGFR is encoded by the nucleic acid sequence as set forth in SEQ ID NOs: 217 or 416. Within the context of the present disclosure, “anti-TruEGFR-specific antibody,” “xTruEGFRab,” “xTruEGFRtab,” “xtruncated EGFRab,” “truncated EGFR antibody,” “anti-truncated EGFR,” or “truncated EGFR scFv,” can be unconjugated antibody or an antibody that is conjugated with an agent, such as phycoerythrin, for the purpose of flow cytometry or immunofluorescence microscopy.

[0112] The present disclosure relates to compositions of an antibody or antigen-binding fragments thereof, and relates to methods, compositions, kits, systems, regimens for treatment of a disease or condition, e.g., a proliferative disease, e.g., cancer, e.g., autoimmune disease, by a fusion protein (or an mRNA encoding such fusion protein) comprising a first moiety comprising an antibody and a second moiety comprising a polypeptide that modulates the activation of an immune cells. In some aspects, the methods, compositions, kits, systems, regimens for treatment of a disease or condition by the fusion protein comprises the use of an engineered cell (e.g., a population of engineered cells for an engineeredcell therapy). In some embodiments, the engineered cell expresses a selection marker, such as a truncated EGFR, which is targeted by the first moiety of the fusion protein.

[0113] In some aspects, provided herein is a combination approach, e.g., administration of both an engineered cell and a fusion protein (or administration of the engineered cell that expresses the fusion protein), that improves the therapeutic efficacy of the engineered cell against the disease, e.g. , proliferative disease, e.g., cancer, e.g., autoimmune disease. In some aspects, in vitro methods are provided for improving therapeutic efficacy of an engineered cell by contacting a population of the engineered cell with a fusion protein as described herein. In some aspects, in vivo methods are provided for improving therapeutic efficacy of an engineered cell by contacting a population of the engineered cell with a fusion protein as described herein. In some embodiments, the engineered cell does not express the fusion protein and the fusion protein is administered to a subject in need thereof with the engineered cell through sequential or simultaneous administration. In some cases, the engineered cells are CAR-T cells, for example, CD19-targeting CAR-T cell or B-cell maturation antigen (BCMA)-targeting CAR-T cell. In some cases, the engineered cells are CAR-Treg cells.

[0114] In some aspects, provided herein is a cell therapy approach that involves engineered cells that express the truncated EGFR and also capable of expressing the fusion protein. In some cases, the engineered cells that express the truncated EGFR further express a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof. In some cases, the engineered cells are CAR-T cells, for example, CD19-targeting CAR-T cell or B-cell maturation antigen (BCMA)-targeting CAR-T cell. In some cases, the engineered cells are CAR-Treg cells. In some embodiments, the engineered cells express comprise a polynucleotide (e.g., DNA or mRNA) encoding the fusion protein. In some cases, the polynucleotide can be introduced to the engineered cells via a nucleic acid carrier, such as a viral vector, e.g. , lentiviral or retroviral vector. In some cases, gene-editing techniques such as those utilizing a Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases, or the clustered regularly interspaced short palindromic repeats (CRISPR) system are employed to introduce the polynucleotide into the engineered cells. In some cases, the polynucleotide is expressed in the engineered cells transiently. In some cases, the polynucleotide is integrated in the genome of the engineered cells and expresses the fusion protein permanently. In some embodiments, polynucleotide comprises a promoter that allows the fusion protein to be expressed upon activation signal from CAR.

[0115] In some embodiments, the fusion protein elicits one or more of the following effects in an engineered cell: enhancing the proliferation of such engineered cell; alter cytokine secretion by the engineered cell; decrease the dependence on exogenous cytokines for survival and proliferation of the engineered cell; enhance cytotoxicity of such engineered cell; enhance the survival of such engineered cell; block apoptosis of such engineered cells; delay senescence of such engineered cells; prevent or delay exhaustion of such engineered cells; enhance the persistence of such engineered cells in vivo when administered to a subject; enhance the efficacy of engineered cells in vivo when administered to a subject;enhance the penetration of engineered cells into diseased organs or tissues (e.g., a tumor); or any combinations.

[0116] In some aspects, the antibody or antigen-binding fragments thereof that specifically binds to truncated EGFR can reduce or eliminate the number of cells expressing the truncated EGFR via antibodydependent cell-mediated cytotoxicity. In some cases, the cells are engineered cells, such as CAR-T cells. In some cases, the antibody or antigen-binding fragments thereof that specifically binds to truncated EGFR serves as a safety switch to eliminate CAR-T cells to reverse any toxicities arising from such CAR-T cells.

[0117] In some embodiments, this disclosure provides methods and compositions for improving in vivo persistence and therapeutic efficacy of engineered cells. In some embodiments, administering a therapeutic regimen comprising a population of the engineered cells and a fusion protein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, improves in vivo persistence of the population of engineered cells by at least about 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% as compared to administering the population of engineered cells alone. In some embodiments, administering a therapeutic regimen comprising a population of engineered cells and a fusion protein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, improves in vivo persistence of the population of engineered cells by at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% as compared to administering the population of engineered cells in combination with an untargeted cytokine or a functional fragment or a variant thereof. In some embodiments, administering a therapeutic regimen comprising a population of engineered cells and a fusion protein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, improves in vivo persistence of the engineered cell by at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% as compared to administering the population of engineered cells in combination with an antibody or antigen-binding fragment thereof that specifically binds to a truncated EGFR that is not fused to a cytokine protein. In some embodiments, a fusion protein of this disclosure improves the in vitro persistence of a population of engineered cells by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, when the population of engineered cells is contacted with the fusion protein.

[0118] In some embodiments, this disclosure provides methods and compositions for improving in vivo persistence and therapeutic efficacy of engineered cells. In some embodiments, administering a therapeutic regimen comprising a population of the engineered cells and a fusion protein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, improves in vivo persistence of the population of engineered cells by at least about 2-fold as compared to administering the population of engineered cells alone. In some embodiments, administering a therapeutic regimen comprising a population of engineered cells and a fusion protein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, improves in vivo persistence of the population of engineered cells by at least 2-fold as compared to administering the population of engineered cells in combination with an untargeted cytokine or a functional fragment or avariant thereof. In some embodiments, administering a therapeutic regimen comprising a population of engineered cells and a fusion protein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, improves in vivo persistence of the engineered cell by at least 2 fold as compared to administering the population of engineered cells in combination with an antibody or antigen-binding fragment thereof that specifically binds to a truncated EGFR that is not fused to a cytokine protein.

[0119] In some embodiments, the present disclosure relates to a method of reducing an effective dosage of an engineered cell in an engineered cell therapy comprising administering a population of the engineered cell and a fusion protein as described herein or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein described herein. In some embodiments, a composition comprising a population of engineered cells and a fusion protein comprises a lower amount of the engineered cell, compared to the amount in a reference composition comprising the population of the engineered cell but not the fusion protein, wherein both compositions exhibit similar efficacy.

[0120] In some embodiments, a composition comprising a population of engineered cells and a fusion protein comprises a lower amount of the engineered cell, compared to the amount in a reference composition comprising the population of engineered cells and an untargeted cytokine or a functional fragment or a variant thereof. In some embodiments, a composition comprising a population of engineered cells and a fusion protein contains a lower amount of an engineered cell, compared to the amount in a reference composition comprising the population of engineered cells and an antibody or antigen-binding fragment thereof that specifically binds to a truncated EGFR, but not the cytokine protein. In some embodiments, the effective dose or the amount, as described above, is lower in the composition by about 1.5x to about lOOOx, such as about 2x, about 4x, about 8x, about 16x, about 32x, about 50x, about 64x, about 70x, about 75x, about 80x, about 90x, about 9 lx, about 92x, about 93x, about 94x, about 95x, about 96x, about 97x, about 98x, about 99x, or about lOOOx, relative to that in the reference composition.

[0121] Studies have shown that loss of CAR-T cells is associated with either T cell-intrinsic issues preventing expansion or T cell-extrinsic immunological rejection. Patients who experience a relapse after CAR-T cell-induced remission have very early loss of CAR-T cells or loss of B-cell aplasia (absolute B cells measured by flow rising above 50 to 100 / pL)- which loss has generally been associated with relapses (e.g., CD19+ B-cell relapses). See, e.g., Nie et al. “Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR-T cell therapy and associated strategies,” Biomarker Research volume 8, Article number: 18 (2020). In patients who have relapsed after treatments with engineered cells (e.g., CAR-T cell therapy), administering a fusion protein of this disclosure can function as a salvage therapy. Thus, in some embodiments of this disclosure are provide methods of treatment by administering a fusion protein, to patients who have undergone a loss of B cell aplasia, following an engineered cell therapy.

[0122] In some aspects, provided herein is a therapeutic regimen comprising administering to a subject a population of engineered cells and a fusion protein as described herein, or administering a population of the engineered cells that express both a truncated EGFR and a fusion protein, and the method allows forat least one of: (a) avoiding a prior administering of a lymphodepleting agent to the subject, or (b) reduces the extent of prior lymphodepletion required for expansion, engraftment of the engineered cell. Examples of lymphodepleting agents include chemotherapeutic agents such as fludarabine, cyclophosphamide, and depleting antibody such as alemtuzumab.

[0123] In some embodiments, the fusion protein is administered to target engineered cells that have been generated in vivo in a subject. Various improvements to such in vivo generated engineered cells can be realized by administering the fusion protein, e.g., increased persistence, reduced rate and / or extent of exhaustion, increased expansion and / or proliferation, no increase in Treg cell count, selective potentiation and specific enrichment of the engineered cells. Example techniques for generating the engineered cells (e.g. , CAR-T or TCR-T cells) in vivo, include, administering to a subject a nucleic acid carrier that includes CAR or TCR genes. In some embodiments, the nucleic acid carrier includes CAR or TCR genes and a selection marker gene (e.g. , a truncated EGFR). In some embodiments, nucleic acid carrier is a non- viral vector, a plasmid, a linear polynucleotide, a polynucleotide associated with ionic or amphiphilic compounds, a plasmid, or a virus (such as a viral vector). In some embodiments, a viral vector is at least one of: a Sendai viral vector, an adenoviral vector, an adeno-associated virus vectors, a retroviral vector, or a lentiviral vector. The nucleic acid carriers, in some cases, comprise a targeting moiety specific for an immune cell (e.g., a T cell, an NK cell, a T lymphocyte, a myeloid cell). The immune cells targeted by the nucleic acid carriers, in some embodiments, are induced to generate the in vivo engineered cells, which express selection marker gene (e.g. , a truncated EGFR) targeted by the fusion proteins of this disclosure.Antibodies and Antigen Binding Domains

[0124] Certain aspects of the present disclosure relate to a human or humanized antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR and does not specifically bind to the full-length EGFR. Any of the anti-truncated EGFR antibodies of the present disclosure (e.g. , that specifically bind truncated EGFR) may find use in the fusion proteins, methods, and uses disclosed herein. In some cases, the truncated EGFR comprises EGFR extracellular region domain III of a full- length EGFR. In some cases, the truncated EGFR comprises a N-terminal fragment of the EGFR extracellular region domain III of a full-length EGFR. In some cases, the truncated EGFR comprises at least one or both of R310 and K311 residues numbered according to SEQ ID NO: 218. In some cases, the truncated EGFR comprises a C-terminus portion of a signal peptide that connects to the N-terminus of the truncated EGFR. In some cases, the portion of the N-terminal signal peptide is a C-terminal portion that comprises the 3 amino acids Leu-Ile-Pro.

[0125] In some embodiments, the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 216, 219, 222, 239, or 415. In some embodiments, the truncated EGFR comprises an amino acid sequence having about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 216, 219, 222, 239, or 415. In some embodiments, the truncated EGFR comprises an amino acid sequence as set forth in SEQ ID NOs: 216, 219, 222, 239, or 415. In some embodiments, the truncated EGFR comprises an amino acidsequence as set forth in SEQ ID NOs: 216. In some embodiments, the truncated EGFR comprises an amino acid sequence as set forth in SEQ ID NOs: 219. In some embodiments, the truncated EGFR comprises an amino acid sequence as set forth in SEQ ID NOs: 415. In some embodiments, the truncated EGFR comprises an amino acid sequence as set forth in SEQ ID NOs: 239. In some embodiments, the truncated EGFR consists of an amino acid sequence as set forth in SEQ ID NOs: 216. In some embodiments, the truncated EGFR consists of an amino acid sequence as set forth in SEQ ID NOs: 415.

[0126] In some embodiments, an antibody or antigen-binding fragment thereof provided herein specifically binds to amino acids at the N-terminus of the truncated EGFR. In some embodiments, the human or humanized antibody or an antigen binding fragment thereof specifically binds to the truncated EGFR at the N-terminus of the EGFR extracellular region domain III (e.g., comprising at least one or both of R310 and K311 residues according to the amino acid positions of a full-length EGFR ectodomain as set forth in SEQ ID: 218). In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to amino acid at position R310 or amino acid at position K311, the positions numbered according to SEQ ID NO: 218. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to amino acid at position R310 and amino acid at position K311, the positions numbered according to SEQ ID NO: 218. In some cases, the amino acid at position R310 is an amino acid that is not an R. In some cases, the amino acid at position K311 is an amino acid that is not a K.

[0127] In some cases, the truncated EGFR comprises a N-terminal signal peptide (or a portion of such N-terminal signal peptide, e.g., a C-terminus portion of such signal peptide that connects to the N- terminus of the truncated EGFR). In some cases, the N-terminal signal peptide has a length of from 2 to 50 amino acids, from 3 to 30 amino acids, from 3 to 20 amino acids, from 3 to 10 amino acids, from 3 to 5 amino acids. In some cases, the truncated EGFR comprises a portion of a N-terminal signal peptide that has a length of from 3 to 5 amino acids. In some cases, the truncated EGFR comprises a portion of a N- terminal signal peptide that has a length of 3 amino acids. In some cases, the N-terminal signal peptide directs surface expression of the truncated EGFR. In some cases, the N-terminal signal peptide is a GM- CSFR alpha chain signal sequences. In some cases, the truncated EGFR comprises a C-terminal portion of the signal peptide located at N-terminus of the truncated EGFR. In some cases, the portion of the N- terminal signal peptide is a C-terminal portion that comprises the 3 amino acids Leu-Ile-Pro. In some cases, the portion of the N-terminal signal peptide is a C-terminal portion that consists of the 3 amino acids Leu-Ile-Pro. In some cases, the human or humanized antibody or an antigen binding fragment thereof specifically binds to the truncated EGFR at amino acids of the N-terminal signal peptide. In some cases, the antibody or antigen-binding fragment thereof specifically binds to amino acids of the C- terminal portion of the N-terminal signal peptide. In some cases, the antibody or antigen-binding fragment thereof specifically binds to amino acids of the three amino acids Leu-Ile-Pro.

[0128] In some cases, the human or humanized antibody or an antigen binding fragment thereof specifically binds to the truncated EGFR at the three amino acids Leu-Ile-Pro located at the N-terminus of the truncated EGFR. In some cases, the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acidsequence as set forth in SEQ ID NOs: 239 or 415. In some cases, the truncated EGFR comprises an amino acid sequence having about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 239 or 415. In some embodiments, the human or humanized antibody or an antigen binding fragment thereof specifically binds to the truncated EGFR having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence as set forth in SEQ ID NOs: 239 or 415 at the N-terminus of the truncated EGFR. In some embodiments, the human or humanized antibody or an antigen binding fragment thereof specifically binds to the truncated EGFR having the amino acid sequence as set forth in SEQ ID NO: 239 at the N-terminus of the truncated EGFR.

[0129] In some cases, a truncated EGFR comprises at least one or both of R310 and K311 residues numbered according to SEQ ID NO: 218.

[0130] In some cases, a truncated EGFR comprises an ectodomain having the amino acid sequence as set forth in SEQ ID NOs: 219, 222, or 239. In some cases, a truncated EGFR comprises an ectodomain having the amino acid sequence as set forth in SEQ ID NO: 219. In some cases, atruncated EGFR comprises an ectodomain having the amino acid sequence as set forth in SEQ ID NO: 222. In some cases, atruncated EGFR comprises an ectodomain having the amino acid sequence as set forth in SEQ ID NO: 239. In some cases, a truncated EGFR comprises a transmembrane region having the amino acid sequence IATGMVGALLLLLVVALGIGLFM (SEQ ID NO: 417). In some cases, the truncated EGFR lacks an EGFR extracellular region Domain I, an EGFR extracellular region Domain II, at least a portion of an EGFR Juxtamembrane Domain, and an EGFR Tyrosine Kinase Domain as compared to the full-length EGFR.

[0131] In some cases, a truncated EGFR further comprises a modified intracellular region that is at C- terminal of the transmembrane region. The modified intracellular region lacks the function of the cytoplasmic signaling tail of the full-length EGFR. In some cases, the modified intracellular region allows for increased surface expression of the truncated EGFR. In some cases, the modified intracellular region comprises a portion of the juxtamembrane region (e.g., a N-terminal portion) of the full-length EGFR. In some cases, the modified intracellular region has from 1 to 20 amino acids, from 1 to 10 amino acids, from 2 to 10 amino acids, from 3 to 9 amino acids. In some cases, the modified intracellular region comprises three arginine residues. In some cases, the modified intracellular region consists of three arginine residues. Examples of truncated EGFR having a modified intracellular region are described in US Patent Publication No. US20210309717A1 and Tamer B. Shabaneh et al., Front. Mol. Med, 11 October 2022, each of which is hereby incorporated herein by reference in its entirety.

[0132] Truncated EGFR sequence with TruEGFR-ECD and the transmembrane region: RKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEI TGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKN LCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRG RECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPA GVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV ALGIGLFM (SEQ ID NO: 216).

[0133] In some embodiments, the truncated EGFR is encoded by the nucleic acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the nucleic sequence as set forth in: agaaaagtgtgcaacggcatcggcatcggagagttcaaggactctctgtccattaacgccaccaacatcaagcacttcaagaactgcaccagcatctcc ggcgatctgcacattctgcccgtggcctttagaggcgattccttcacccacacaccccctctcgaccctcaagagctcgacatcctcaagaccgtgaagg aaatcaccggcttcctcctcattcaagcttggcccgaaaatagaaccgatctgcacgccttcgagaatctggagatcattaggggaagaaccaaacagca cggccagttttctctggccgtggtgtctctgaatattacatctctgggactgagatctctgaaggagatttccgacggcgacgtgatcatcagcggcaacaa gaatctgtgctacgccaacaccatcaattggaagaaactcttcggcaccagcggccagaagaccaagatcatcagcaatagaggcgaaaacagctgca aggccaccggccaagtgtgtcacgctctgtgttcccccgagggctgttggggacccgagcctagagactgcgtgagctgtagaaacgtgagcagagg aagagagtgcgtggacaagtgtaatctgctggagggcgagcccagagagttcgtggagaacagcgagtgcatccagtgtcaccccgaatgtctgccc caagccatgaacatcacatgcaccggcagaggccccgacaactgcatccagtgcgcccactacattgacggccctcactgcgtgaagacatgccccg ctggcgtgatgggcgagaataacacactggtgtggaagtacgccgacgccggacatgtgtgtcacctctgccatcccaactgtacctacggctgtaccg gccccggactggagggatgccctacaaacggccccaaaatccccagcattgctaccggcatggtgggagctctgctgctgctgctggtggtggctctg ggaatcggactgtttatg (SEQ ID NO: 217).

[0134] Truncated EGFR sequence with the full signal peptide (GM-CSFR alpha chain signal sequences) at the N-terminus of the TruEGFR-ECD and the transmembrane region:MLLLVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGD SFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITS LGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPE GCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPD NCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTN GPKIPSIATGMVGALLLLLVVALGIGLFM (SEQ ID NO: 414).

[0135] Truncated EGFR sequence with Leu-Ile-Pro residues from the signal peptide (GM-CSFR alpha chain signal sequences) at the N-terminus of the ectodomain (TruEGFR-n-ECD) and the transmembrane region:LIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTV KEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGN KNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVS RGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTC PAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLL WALGIGLFM (SEQ ID NO: 415).

[0136] In some embodiments, the truncated EGFR is encoded by the nucleic acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the nucleic sequence as set forth in: atgctcctgctcgtgacatctctgctgctctgtgaactgcctcatcctgcttttctgctcatccccagaaaagtgtgcaacggcatcggcatcggagagttca aggacagcctgagcatcaatgccaccaacatcaagcacttcaagaactgcaccagcatcagcggcgacctgcacattctgcctgtggcctttagaggcg acagcttcacccacacacctccactggatccacaagagctggacatcctgaaaaccgtgaaagagatcaccggctttctgttgatccaggcttggcccga gaaccggacagatctgcacgccttcgagaacctcgagatcatcagaggccggaccaagcagcacggccagttttctctggctgtggtgtccctgaacatcaccagcctgggcctgagaagcctgaaagaaatcagcgacggcgacgtgatcatctccggcaacaagaacctgtgctacgccaacaccatcaactgg aagaagctgttcggcaccagcggccagaaaacaaagatcatctctaaccggggcgagaacagctgcaaggccaccggacaagtttgtcacgccctgt gtagccctgaaggctgttggggacctgagcctagagattgcgtgtcctgccggaatgtgtcccggggcagagaatgcgtggacaagtgcaatctgctcg agggcgagccacgcgagttcgtggaaaacagcgagtgcatccagtgtcaccccgagtgtctgccccaggccatgaacattacatgcaccggcagagg ccccgacaactgtattcagtgcgcccactacatcgacggccctcactgcgtgaaaacatgtccagcaggcgtgatgggagagaacaacaccctcgtgtg gaagtatgccgacgccggacatgtgtgccacctgtgtcaccctaattgcacctacggctgtaccggacctggcctggaaggctgtccaacaaacggccc taagatccccagcattgccaccggaatggttggagccctgctgttgctgctggtggtggcccttggaatcggcctgttcatg (SEQ ID NO: 416).

[0137] In some embodiments, the truncated EGFR lacks membrane distal EGF-binding domain of the full-length EGFR, or cytoplasmic signaling tail of the full-length EGFR, or both. In some embodiments, the truncated EGFR lacks both membrane distal EGF-binding domain of the full-length EGFR and cytoplasmic signaling tail of the full-length EGFR.

[0138] In some embodiments, the truncated EGFR lacks EGFR extracellular region domain I of the full-length EGFR and EGFR extracellular region domain II of the full-length EGFR. In some embodiments, the truncated EGFR lacks EGFR extracellular region domain I of the full-length EGFR, EGFR extracellular region domain II of the full-length EGFR, juxatmembrane domain of the full-length EGFR, and a tyrosine kinase domain of the full-length EGFR. In some embodiments, the truncated EGFR comprises EGFR extracellular region domain III of the full-length EGFR, and optionally EGFR extracellular region domain IV of the full-length EGFR. In some cases, the term “EGFR extracellular region Domain III” refers to an EGFR extracellular region Domain III of a full-length EGFR that spans from amino acid residues Arg310 to Gly479. In some cases, the truncated EGFR comprises mutations, modifications, truncations, substitutions or any combinations thereof near the C-terminus of the EGFR extracellular region domain III as compared to the EGFR extracellular region domain III of the full-length EGFR. In some cases, the truncated EGFR comprises EGFR transmembrane domain of full-length EGFR, EGFR extracellular region domain III of the full-length EGFR, and EGFR extracellular region domain IV of the full-length EGFR. In some cases, the truncated EGFR comprises one or both of R310 and K311 residues at a N-terminus of EGFR extracellular region domain III of the full-length EGFR numbered according to SEQ ID NO: 218. In some cases, the truncated EGFR comprises a N-terminal fragment of the EGFR extracellular region domain III. In some cases, the truncated EGFR comprises a N-terminal signal peptide or a portion of such N-terminal signal peptide, e.g., a C-terminus portion of such signal peptide that connects to the N-terminus of the truncated EGFR. In some cases, the N-terminal signal peptide is a GM-CSFR alpha chain signal sequences. In some cases, the portion of the N-terminal signal peptide is a C-terminal portion that comprises the 3 amino acids Leu-Ile-Pro.

[0139] In some embodiments, the truncated EGFR does not have endogenous signaling or trafficking function. In some embodiments, the truncated EGFR does not bind a natural ligand of full-length EGFR. In some embodiments, the truncated EGFR serves as a selection marker for a cell, such as an immune cell (e.g., engineered CAR+ T cell). Additional exemplary features of truncated EGFR and nucleic acid encoding the same are disclosed in U.S. Pat. Nos. 8,802,374, 10,869,889, and PCT Pub No. WO 2016 / 033570, each of which is incorporated herein by reference in its entirety.

[0140] In some cases, the antibody or antigen-binding fragment thereof binds to a region of truncated EGFR. In some cases, the antibody or antigen-binding fragment thereof specifically binds to a region of truncated EGFR. In some cases, the antibody or antigen-binding fragment thereof specifically binds to a N-terminal fragment of EGFR extracellular region domain III of the truncated EGFR. In some cases, the antibody or antigen-binding fragment thereof does not specifically bind to a full-length EGFR. In some cases, the truncated EGFR is a truncated human EGFR. In some cases, the full-length EGFR is a full- length human EGFR.

[0141] In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 1% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time. In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 30% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time. In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 20% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time. In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 20% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time. In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 10% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time. In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 5% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time. In some embodiments, binding of the antibody or antigen-binding fragment thereof to engineered immune cells that express truncated EGFR does not lead to more than 1% reduction in viability of the engineered immune cells when measured in an assay in which the engineered immune cells are treated with the antibody or antigen-binding fragment thereof for a period of time.

[0142] In some embodiments, the anti-truncated EGFR antibody of the present disclosure specifically binds truncated EGFR with at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50- fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 1,000- fold, or at least 10,000-fold higher affinity than its binding to a full-length EGFR, e.g., as expressed onimmune cells (e.g. , T cells). In some embodiments, the anti-truncated EGFR antibody of the present disclosure specifically binds truncated EGFR with at least 10,000-fold higher affinity than its binding to full-length EGFR, e.g., as expressed on engineered T cells. In some embodiments, the truncated EGFR are expressed on the surface of a human cell, e.g. , a human T cell. In some embodiments, the truncated EGFR are expressed on the surface of an engineered human cell, e.g., an engineered human T cell.

[0143] In some embodiments, the anti-truncated EGFR antibody of the present disclosure specifically binds to a cell expressing a truncated EGFR on its surface (e.g. , a human T cell) with an EC50 that is less than lOOOnM. In some embodiments, the anti-truncated EGFR antibody of the present disclosure specifically binds to truncated EGFR.

[0144] In some embodiments, the anti-truncated EGFR antibody of the present disclosure is a human antibody or antibody fragment. In some embodiments, a human antibody or antibody fragment comprises human-derived CDRs and framework sequences in the variable domain, e.g., as isolated from a human or generated using a library with human antibody sequences (e.g., CDR sequences). In some embodiments, the anti-truncated EGFR antibody of the present disclosure is a humanized antibody or antibody fragment. In some embodiments, a humanized antibody or antibody fragment comprises non-human-derived CDRs (e.g., from a mouse, rabbit, goat, etc.) and human-derived framework sequences in the variable domain. In some embodiments, a human or humanized antibody further comprises a human Fc region. In some embodiments, the human Fc region further comprises one or more Fc mutations, e.g., as disclosed herein. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant domains that correspond to the different classes of antibodies are called a, 5, a, y, and p, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0145] Multiple definitions for the CDR sequences of antibody variable domains are known in the art. Unless otherwise specified, CDR sequences are described herein according to the definition of Kabat (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3). However, other definitions are known and contemplated for use. For example, in some embodiments, CDR sequences can be described by the definition of Chothia (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987). Depending upon the specific CDR definition used, the precise framework sequences can also vary, but, as is known in the art, the first framework sequence (FW-1) refers to the sequence from the N-terminus of the VH or VL domain to the beginning of CDR-H1 / -L1, the second framework sequence (FW-2) refers to the sequence from end of CDR-H1 / -L1 to the beginning of CDR-H2 / -L2, the third framework sequence (FW-3) refers to the sequence from end of CDR-H2 / -L2 to the beginning of CDR-H3 / -L3, and the fourth framework sequence (FW-4) refers to the sequence from end of CDR-H3 / -L3 to the C-terminal boundary of the VH or VL domain.

[0146] In some embodiments, an antibody or an antigen binding fragment thereof provided herein specifically binds to a truncated epithelial growth factor receptor (EGFR) and does not specifically bindto a full-length EGFR. In some embodiments, an antibody or an antigen binding fragment thereof provided herein specifically binds to a truncated human epithelial growth factor receptor (EGFR) and does not specifically bind to a full-length human EGFR.

[0147] In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequences described in any one of Tables 1-4 and 6-27. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises six complementarity determining regions (CDRs) each having the having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the CDRs described in any one of Tables 1-4 and 6- 27, respectively. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises a variable heavy (VH) region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequences of the VH described in any one of Tables 1-4 and 6-27. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises a variable light (VL) region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of the VL described in any one of Tables 1-4 and 6-27. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises a variable heavy (VH) region and a variable light (VL) region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequences of the VH and the VL described in any one of Tables 1-4 and 6-27, respectively.

[0148] In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises any one of the amino acid sequences described in any one of Tables 1-4 and 6-27. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises six complementarity determining regions (CDRs) having the amino acid sequences of CDRs described in any one of Tables 1-4 and 6-27, respectively. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises a variable heavy (VH) region having the amino acid sequences of the VH described in any one of Tables 1-4 and 6-27. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises a variable light (VL) region having the amino acid sequence of the VL described in any one of Tables 1-4 and 6-27. In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises a variable heavy (VH) region and a variable light (VL) region having the amino acid sequences of the VH and the VL described in any one of Tables 1-4 and 6- 27, respectively.

[0149] In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 3 amino acid modifications. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 2 amino acid modifications. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 1 amino acid modification. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with 0 amino acid modifications.

[0150] In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 257, 258, 260, 262, 188, 193, 225, 230, 254-256, 259, or 261, with from 0 to 3 amino acid modifications. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 257, 258, 260, 262, 188, 193, 225, 230, 254-256, 259, or 261, with from 0 to 2 amino acid modifications. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 257, 258, 260, 262, 188, 193, 225, 230, 254-256, 259, or 261, with from 0 to 1 amino acid modification. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 257, 258, 260, 262, 188, 193, 225, 230, 254-256, 259, or 261, with 0 amino acid modifications.In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQID NOs: 246, 250, and 262, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 1 amino acid modifications.

[0151] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 amino acid modification.

[0152] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 amino acid modification.

[0153] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications. Insome embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 amino acid modification.

[0154] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 amino acid modification.

[0155] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 amino acid modification.

[0156] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 2 amino acid modifications. In some embodiments,the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 amino acid modification.

[0157] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modification; the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 2 amino acid modification; the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 1 amino acid modification; the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 1 amino acid modifications.

[0158] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise thesequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 amino acid modification.

[0159] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 amino acid modification.

[0160] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 amino acid modification.

[0161] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 amino acid modification.

[0162] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, and wherein CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 1 amino acid modification. In some embodiments, the CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 amino acid modification.

[0163] In some embodiments, an antibody or an antigen binding fragment thereof provided herein that specifically binds truncated EGFR comprises at least one light chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with from 0 to 3 amino acid modifications. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one light chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with from 0 to 2 amino acid modifications. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one light chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with from 0 to 1 amino acid modification. In some embodiments, the antibody or antigen binding fragment thereof comprises at least one light chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with 0 amino acid modifications.

[0164] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications. In some embodiments, CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 2 amino acid modifications. In some embodiments, CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 1 amino acid modifications.

[0165] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications. In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 1 amino acid modification. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 amino acid modification.

[0166] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications. In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 1 amino acid modification. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 amino acid modification.

[0167] In some embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises heavy chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications. Insome embodiments, an antibody or an antigen binding fragment provided herein that specifically binds truncated EGFR comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 1 amino acid modification. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 1 amino acid modification. In some embodiments, the CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 amino acid modification.

[0168] In some embodiments, an antibody or an antigen-binding fragment provided herein that specifically binds to truncated EGFR comprises: (a) a heavy chain that comprises a heavy chain variable (VH) domain, and (b) a light chain that comprises a heavy chain variable (VH) domain, wherein the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 3 amino acid modifications, and wherein the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with from 0 to 3 amino acid modifications. In some embodiments, the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 2 amino acid modifications. In some embodiments, the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with from 0 to 2 amino acid modifications. In some embodiments, the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 1 amino acid modification. In some embodiments, the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with from 0 to 1 amino acid modification. In some embodiments, the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240- 273, with 1 amino acid modification. In some embodiments, the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with 1 amino acid modification. In some embodiments, the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with 0 amino acid modification. In some embodiments, the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275, with 0 amino acid modification.

[0169] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs:241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications. In some cases, the heavy chain comprises a heavy chain variable (VH) domain thatcomprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241,247, and 258, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242,248, and 260, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 2 amino acid modifications; and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 2 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 2 amino acid modifications; or the sequence as set forth inSEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 2 amino acid modifications. In some cases, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 1 amino acid modifications; and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0to 1 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 1 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 1 amino acid modifications.

[0170] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 2 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 1 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 1 amino acid modifications.

[0171] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 2 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1),CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 1 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 1 amino acid modifications.

[0172] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs:243, 249, and 260, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 2 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 1 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 1 amino acid modifications.

[0173] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs:244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequenceas set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 2 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 1 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 1 amino acid modifications.

[0174] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 2 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 1 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 1 amino acid modifications.

[0175] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 2 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 2 amino acid modifications. In some embodiments, the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 1 amino acid modifications and the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 1 amino acid modifications.

[0176] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0, 1, 2, or 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0, 1, 2, or 3 amino acid modifications.

[0177] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0, 1, 2, or 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequenceas set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0, 1, 2, or 3 amino acid modifications.

[0178] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0, 1, 2, or 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0, 1, 2, or 3 amino acid modifications.

[0179] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0, 1, 2, or 3 amino acid modifications; and (b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0, 1, 2, or 3 amino acid modifications.

[0180] In some embodiments, an antibody or an antigen-binding fragment thereof described herein comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0, 1, 2, or 3 amino acid modifications; and (b) the light chain ...

Claims

CLAIMSWhat is claimed is:

1. An antibody or an antigen binding fragment thereof that specifically binds to a truncated epithelial growth factor receptor (EGFR) and does not specifically bind to a full-length EGFR.

2. An antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR, comprising at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273, with from 0 to 3 amino acid modifications.3 An antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR, comprising at least one heavy chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 257, 258, 260, 262, 188, 193, 225, 230, 254-256, 259, or 261, with from 0 to 3 amino acid modifications.4 An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications;the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications;the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 190, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 195, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 226, 227, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 231, 232, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 263, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 264, 270, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 265, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 268, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 273, and 261, respectively, each with 0 to 3 amino acid modifications; orthe sequence as set forth in SEQ ID NOs: 194, 273, and 262, respectively, each with 0 to 3 amino acid modifications.

6. An antibody or an antigen binding fragment thereof that specifically binds to a truncated EGFR, comprising at least one light chain complementarity determining region (CDR) as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275 with from 0 to 3 amino acid modifications.

7. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications.8 An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising: (a) a heavy chain that comprises a heavy chain variable (VH) domain, and (b) a light chain that comprises a light chain variable (VL) domain, wherein the VH domain comprises at least one heavy chain CDR as set forth in any of SEQ ID NOs: 186-195, 223-232, or 240-273 with from 0 to 3 amino acid modifications, and wherein the VL domain comprises at least one light chain CDR as set forth in any of SEQ ID NOs: 196-201, 233, 234, 274, or 275 with from 0 to 3 amino acid modifications.9 An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein:(a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications;the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 241, 247, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 245, 249, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 250, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications;the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 251, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications; and(b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise: the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein:(a) the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise: the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications;the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 190, and 188, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 195, and 193, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 226, 227, and 225, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 231, 232, and 230, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 263, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 254, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 255, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 256, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 189, 269, and 259, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 264, 270, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 265, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 268, 271, and 260, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 272, and 261, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 194, 273, and 261, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 194, 273, and 262, respectively, each with 0 to 3 amino acid modifications; and(b) the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise:the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications; or the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein:CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and257, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and258, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprisethe sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 186, 187, and 188, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 192, and 193, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 223, 224, and 225, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 228, 229, and 230, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 240, 247, and 254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and255, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and256, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 241, 247, and259, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprisethe sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 242, 248, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 242, 249, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 245, 249, and260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 250, and261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 251, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 253, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 251, and 261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 251, and262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprisethe sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 191, 253, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; orCDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 246, 251, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain that comprises heavy chain complementarity determining region 1 (CDRH1), CDRH2, and CDRH3, wherein the light chain comprises a light chain variable (VL) domain that comprises light chain complementarity determining region 1 (CDRL1), CDRL2, and CDRL3, and wherein:CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and257, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and258, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 190, and188, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprisethe sequence as set forth in SEQ ID NOs: 196, 197, and 198, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 195, and 193, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 226, 227, and 225, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 201, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 231, 232, and 230, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 263, 269, and 254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and254, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and255, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and256, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 259, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 264, 270, and260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprisethe sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 265, 271, and 260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 268, 271, and260, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 272, and261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications;CDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 273, and261, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications; orCDRH1, CDRH2, and CDRH3 comprise the sequence as set forth in SEQ ID NOs: 194, 273, and262, respectively, each with 0 to 3 amino acid modifications, and CDRL1, CDRL2, and CDRL3 comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively, each with 0 to 3 amino acid modifications.

13. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain that comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, 381, 383, or 384.

14. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain that comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, 381, 383, or 384, with from 0 to 5 amino acid modifications.

15. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) domain that comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205.

16. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) domain that comprises an aminoacid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205, with from 0 to 5 amino acid modifications.

17. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein:(a) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(b) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(c) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(d) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(e) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(f) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(g) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 202, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 204;(h) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 203, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205;(i) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 235, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205;(j) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 236, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(k) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 276, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(l) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 277, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(m) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 278, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(n) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 279, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(o) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 282, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(p) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 283, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(q) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 284, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(r) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 374, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(s) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 375, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(t) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 376, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(u) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 377, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(v) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 378, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(w) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 379, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(x) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 381, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(y) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 383, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; or(z) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 384, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385.

8. The antibody or antigen-binding fragment thereof of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein:(a) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 280, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(b) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 281, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(c) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 285, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(d) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 373, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(e) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 380, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(f) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 382, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(g) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 202, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 204, with from 0 to 5 amino acid modifications;(h) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 203, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 205, with from 0 to 5 amino acid modifications;(i) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 235, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 205, with from 0 to 5 amino acid modifications; or(j) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 236, with from 0 to 5 amino acid modifications, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(k) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 276, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(l) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 277, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(m) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 278, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(n) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 279, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(o) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 282, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(p) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 283, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(q) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 284, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(r) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 374, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(s) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 375, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(t) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 376, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(u) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 377, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(v) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 378, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(w) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 379, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(x) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 381, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(y) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 383, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications; or(z) the VH domain comprises an amino acid sequence as set forth in SEQ ID NO: 384, with from 0 to 5 amino acid modifications, and the VL domain comprises an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications.

19. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain that comprises a heavy chain variable (VH) domain, and wherein the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, or 381-384.

20. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) domain, and wherein the VH domain comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, 382, 202, 203, 235, 236, 276-279, 282-284, 374-379, or 381-384, with from 0 to 5 amino acid modifications.21 . An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a light chain that comprises a light chain variable (VL) domain, and wherein the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205.

22. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, wherein the antibody or antigen-binding fragment thereof comprises a light chain that comprises a light chain variable (VL) domain, and wherein the VL domain comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 237, 238, 385, 204, or 205, with from 0 to 5 amino acid modifications.

23. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain, and the light chain comprises a light chain variable (VL) domain, wherein:(a) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(b) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(c) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(d) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(e) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(f) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(g) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 202, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 204; or(h) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 203, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205;(i) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 235, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 205;(j) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 236, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(k) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 276, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(l) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 277, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(m) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 278, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(n) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 279, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(o) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 282, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(p) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 283, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(q) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 284, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(r) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 374, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(s) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 375, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(t) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 376, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(u) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 377, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(v) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 378, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(w) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 379, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(x) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 381, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(y) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 383, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385; or(z) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 384, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:

385. An antibody or an antigen-binding fragment thereof that specifically binds to a truncated EGFR, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) domain and the light chain comprises a light chain variable (VL) domain, wherein: the VH and VL domains comprise the sequence of SEQ ID NOs: 280 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 281 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 285 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 373 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 380 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 382 and 385, respectively;the VH and VL domains comprise the sequence of SEQ ID NOs: 202 and 204, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 203 and 205, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 235 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 236 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 276 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 277 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 278 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 279 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 282 and 237, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 283 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 284 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 374 and 238, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 375 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 376 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 377 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 378 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 379 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 381 and 385, respectively; the VH and VL domains comprise the sequence of SEQ ID NOs: 383 and 385, respectively; or the VH and VL domains comprise the sequence of SEQ ID NOs: 384 and 385, respectively.

25. The antibody or antigen-binding fragment thereof of any one of claims 1-12 or 19-24, wherein the antibody or antigen binding fragment thereof does not specifically bind to a full-length EGFR.

26. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises an EGFR extracellular region domain III of the full-length EGFR.

27. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises at least a N-terminus of the EGFR extracellular region domain III.

28. The antibody or antigen binding fragment thereof of claim 25, wherein the truncated EGFR comprises residue R310 or K311 numbered according to SEQ ID NO: 218.

29. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises residues R310 and K311 numbered according to SEQ ID NO: 218.

30. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises at least portion of a signal peptide at the N-terminus.31 . The antibody or antigen-binding fragment thereof of claim 30, wherein the signal peptide is a GM-CSFR alpha chain signal sequence as set forth in SEQ ID NO: 413.

32. The antibody or antigen-binding fragment thereof of claim 31, wherein the truncated EGFR comprises a C-terminal portion of the signal peptide, optionally wherein the C-terminal portion of the signal peptide consists of three amino acids Leu-Ile-Pro.

33. The antibody or antigen-binding fragment thereof of claim 32, wherein the antibody or antigen-binding fragment thereof specifically binds to amino acids of the C-terminal portion of the signal peptide, optionally wherein the antibody or antigen-binding fragment thereof specifically binds to amino acids of the three amino acids Leu-Ile-Pro.

34. The antibody or antigen-binding fragment thereof of claim 25, wherein the antibody or antigen-binding fragment thereof specifically binds to amino acids at the N-terminus of the truncated EGFR.

35. The antibody or antigen-binding fragment thereof of claim 28, wherein the antibody or antigen-binding fragment thereof specifically binds to amino acid at position R310 and / or amino acid at position K311, the positions numbered according to SEQ ID NO: 218.

36. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR lacks a membrane distal EGF -binding domain of the full-length EGFR, or a cytoplasmic signaling tail of the full- length EGFR, or both.

37. The antibody or antigen-binding fragment thereof of claim 36, wherein the truncated EGFR lacks both the membrane distal EGF-binding domain and the cytoplasmic signaling tail.

38. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR lacks EGFR extracellular domain I of the full-length EGFR, EGFR extracellular domain II of the full-length EGFR, or both.

39. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR lacks EGFR extracellular domain I of the full-length EGFR, EGFR extracellular domain II of the full-length EGFR, and the cytoplasmic signaling tail of the full-length EGFR.

40. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises EGFR extracellular domain III of the full-length EGFR and EGFR extracellular domain IV of the full- length EGFR.41 . The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises transmembrane domain of the full-length EGFR, EGFR extracellular domain III of the full-length EGFR, and EGFR extracellular domain IV of the full-length EGFR.

42. The antibody or antigen-binding fragment thereof of claim 25, wherein the full-length EGFR is a human EGFR.

43. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 216, 219, 222, 239, or 415.

44. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 239 or 415.

45. The antibody or antigen-binding fragment thereof of claim 25, wherein the truncated EGFR is encoded by a polynucleotide comprising a nucleic acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 217 or 416.

46. The antibody or antigen-binding fragment thereof of claim 25, wherein said antibody or antigen-binding fragment thereof binds to the truncated EGFR with a KD of less than lOOOnM, 800nM, 500nM, 200 nM, 150 nM, 100 nM, 80 nM, 60 nM, 50 nM, 40 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, or 1 nM, as determined by surface plasmon resonance (SPR) at 37°C.

47. The antibody or antigen-binding fragment thereof of claim 25, wherein said antibody or antigen-binding fragment thereof binds to the truncated EGFR with a KD of less than 10 nM, as determined by surface plasmon resonance (SPR) at 37°C.

48. The antibody or antigen-binding fragment thereof of claim 25, wherein said antibody or antigen-binding fragment thereof binds to the truncated EGFR with a KD of less than 2 nM, as determined by surface plasmon resonance (SPR) at 37°C.

49. The antibody or antigen-binding fragment thereof of claim 25, wherein said antibody or antigen-binding fragment thereof, at lOOnM concentration, does not specifically bind to(a) the full-length EGFR, as determined by surface plasmon resonance (SPR) at 37°C; or(b) cells that express the full-length EGFR and do not express the truncated EGFR, as determined by flow cytometry binding at 4°C.

50. The antibody or antigen-binding fragment thereof of claim 25, wherein said antibody or antigen-binding fragment thereof binds to cells expressing the truncated EGFR with a EC50 of less than lOOOnM, 800nM, 500nM, 200 nM, 150 nM, 100 nM, 80 nM, 60 nM, 50 nM, 40 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, or 1 nM, as determined by flow cytometry binding at 4°C.51 . The antibody or antigen-binding fragment thereof of claim 25, wherein the antibody or antigen-binding fragment thereof is an IgG, an IgM, an IgE, an IgA, or an IgD molecule, or is derived from one of these.

52. The antibody of claim 25, wherein the antibody is a monoclonal antibody.

53. The antibody of claim 25, wherein the antibody is a human or humanized antibody.

54. The antibody of claim 25, wherein the antibody is a chimeric antibody.

55. The antigen-binding fragment of claim 25, which is selected from the group consisting of: scFv, sc(Fv)2, dsFv, Fab, Fab', (Fab')2, a diabody, atriabody, a minibody, a sdAb, and a Variable New Antigen Receptors (VNARs).

56. The antibody or antigen-binding fragment thereof of claim 25, wherein the antibody or antigen-binding fragment thereof is bi-specific or multi-specific.

57. A fusion protein comprising:(i) a first moiety comprising the antibody or antigen binding fragment thereof of any one of claims 1-12 or 19-24; and(ii) a second moiety comprising a polypeptide that modulates activation or inhibition of a cell.

58. The fusion protein of claim 57, wherein the fusion protein selectively activates a cell that expresses the truncated EGFR with 10-fold or greater potency as compared to activation of a cell that does not express the truncated EGFR.

59. The fusion protein of claim 58, wherein the cell is an immune cell.

60. The fusion protein of claim 58, wherein the potency is measured by a pSTAT5 or a pSTAT3 activation assay.61 . The fusion protein of claim 57, wherein the second moiety comprises a cytokine, a chemokine, a growth factor, or a second antibody or antigen-binding fragment thereof.

62. The fusion protein of claim 57, wherein the second moiety comprises IL-2, IL-7, IL- 10, IL-15, and IL-21, or a functional fragment thereof, or a variant thereof, or any combinations thereof.

63. The fusion protein of any one of claims 58-62, wherein the second moiety comprises an IL-2 polypeptide, or a functional fragment thereof, or a variant thereof.

64. The fusion protein of claim 63, wherein the IL-2 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-2Ra polypeptide having an amino acid sequence of SEQ ID NO: 2, compared to the binding affinity of the wild-type IL-2 polypeptide with an amino acid sequence of SEQ ID NO: 1.

65. The fusion protein of claim 64, wherein the IL-2 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-2RP polypeptide having an amino acid sequence of SEQ ID NO: 3, and / or reduced binding affinity by at least about 50% to an IL-2Ry polypeptide having an amino acid sequence of SEQ ID NO: 4 compared to the binding affinity of the wild-type IL-2 polypeptide with an amino acid sequence of SEQ ID NO: 1.

66. The fusion protein of any claim 63, wherein the IL-2 polypeptide comprises the sequence of SEQ ID NO: 1 with one or more amino acid substitutions relative to SEQ ID NO: 1, and wherein the one or more substitution(s) comprise substitution(s) at positions of SEQ ID NO: 1 selected from the group consisting of: QI 1, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, 192, T123, Q126, S127, 1129, and S130.

67. The fusion protein of claim 66, wherein the one or more substitution(s) comprise an F42A or F42K amino acid substitution relative to SEQ ID NO: 1.

68. The fusion protein of claim 67, wherein the one or more substitution(s) further comprise an R38A, R38D, R38E, E62Q, E68A, E68Q, E68K, or E68R amino acid substitution relative to SEQ ID NO: 1.

69. The fusion protein of claim 68, wherein the one or more substitution(s) further comprise an H16E, H16D, D20N, M23A, M23R, M23K, S87K, S87A, D84L, D84N, D84V, D84H, D84Y, D84R, D84K, N88A, N88G, N88S, N88T, N88R, N88I, N88D, V91A, V91T, V91E, I92A, E95S, E95A, E95R, T123A, T123E, T123K, T123Q, Q126A, Q126S, Q126T, Q126E, S127A, S127E, S127K, or S127Q amino acid substitution relative to SEQ ID NO: 1.

70. The fusion protein of claim 69, wherein the one or more substitution(s) further comprise the amino acid mutation C125A relative to SEQ ID NO: 1.

71. The fusion protein of claim 63, wherein the IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1 with one of the following sets of amino acid substitutions (relative to the sequence of SEQ ID NO: 1): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F42A, and N88S; R38E, F42A, and N88A; R38E, F42A, and N88G; R38E, F42A, and N88D; R38E, F42A, and V91E; R38E, F42A, and D84H; R38E, F42A, and D84K; R38E, F42A, and D84R; H16D, R38E and F42A; H16E, R38E and F42A; R38E, F42A and Q126S; R38D, F42A and N88S; R38D, F42A and N88A; R38D, F42A and N88G; R38D, F42A and N88D; R38D, F42A and V91E; R38D, F42A, and D84H; R38D, F42A, and D84K; R38D, F42A, and D84R; H16D, R38D and F42A; H16E, R38D and F42A; R38D, F42A and Q126S; R38A, F42K, and N88S; R38A, F42K, and N88A; R38A, F42K, and N88G; R38A, F42K, and N88D; R38A, F42K, and V91E; R38A, F42K, and D84H; R38A, F42K, and D84K; R38A, F42K, and D84R; H16D, R38A, and F42K; H16E, R38A, and F42K; R38A, F42K, and Q126S; F42A, E62Q, and N88S; F42A, E62Q, and N88A; F42A, E62Q, and N88G; F42A, E62Q, and N88D; F42A, E62Q, and V91E; F42A, E62Q, and D84H; F42A, E62Q, and D84K; F42A, E62Q, and D84R; H16D, F42A, and E62Q; H16E, F42A, and E62Q; F42A, E62Q, and Q126S; R38E, F42A, and C125A; R38D, F42A, and C125A; F42A, E62Q, and C125A; R38A, F42K, and C125A; R38E, F42A, N88S, and C125A; R38E, F42A, N88A, and C125A; R38E, F42A, N88G, and C125A; R38E, F42A, N88D, and C125A; R38E, F42A, V91E, and C125A; R38E, F42A, D84H, and C125A; R38E, F42A, D84K, and C125A; R38E, F42A, D84R, and C125A; H16D, R38E, F42A, and C125A; H16E, R38E, F42A, and C125A; R38E, F42A, C125A and Q126S; R38D, F42A, N88S, and C125A; R38D, F42A, N88A, and Cl 25 A; R38D, F42A, N88G, and Cl 25 A; R38D, F42A, N88D, and Cl 25 A; R38D, F42A, V91E, and C125A; R38D, F42A, D84H, and C125A; R38D, F42A, D84K, and C125A; R38D, F42A, D84R, and C125A; H16D, R38D, F42A, and C125A; H16E, R38D, F42A, and C125A; R38D, F42A, C125A, and Q126S; R38A, F42K, N88S, and C125A; R38A, F42K, N88G, and C125A; R38A, F42K, N88D, and C125A; R38A, F42K, N88A, and C125A; R38A, F42K, V91E, and C125A; R38A, F42K, D84H, and C125A; R38A, F42K, D84K, and C125A; R38A, F42K, D84R, and C125A; H16D, R38A, F42K, and C125A; H16E, R38A, F42K, and C125A; R38A, F42K, C125A and Q126S; F42A, E62Q, N88S, and C125A; F42A, E62Q, N88A, and C125A; F42A, E62Q, N88G, and C125A; F42A, E62Q, N88D, and C125A; F42A, E62Q, V91E, and C125A; F42A, E62Q, and D84H, and C125A; F42A, E62Q, and D84K, and C125A; F42A, E62Q, and D84R, and C125A; H16D, F42A, and E62Q, and C125A; H16E, F42A, E62Q, and C125A; F42A, E62Q, C125A and Q126S; F42A, N88S, and C125A; F42A, N88A, and C125A; F42A, N88G, and C125A; F42A, N88D, and C125A; F42A, V91E, and C125A; F42A, D84H, and C125A; F42A, D84K, and C125A; F42A, D84R, and C125A; H16D, F42A, and C125A; H16E, F42A, and C125A; and F42A, C125A and Q126S.

72. The fusion protein of claim 63, wherein the IL-2 polypeptide comprises an amino acid sequence that is at least about 85% identical to a sequence selected from the group consisting of SEQ ID NOs: 11-90 and 137-185.

73. The fusion protein of claim 63, wherein said IL-2 polypeptide comprises a sequence that is at least about 75% identical to a sequence selected from the group consisting of SEQ ID NOs: 43, 48, 52, 49, and 156.

74. The fusion protein of any one of claims 58-62, wherein the fusion protein comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NOs: 386-412.

75. The fusion protein of any one of claims 58-62, wherein the second moiety comprises an IL-7 polypeptide, or a functional fragment thereof, or a variant thereof.

76. The fusion protein of claim 75, wherein the IL-7 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-7Ra polypeptide comprising the amino acid sequence of SEQ ID NO: 94, compared to binding affinity of a wild-type IL-7 polypeptide comprising the amino acid sequence of SEQ ID NO: 91 to the IL-7Ra polypeptide.

77. The fusion protein of claim 75, wherein the IL-7 polypeptide comprises the sequence of SEQ ID NO: 91, with one or more substitutions relative to SEQ ID NO: 91.

78. The fusion protein claim 77, wherein the one or more substitutions are at positions selected from the positions: K10, QI 1, S14, V15, V18, Q22, L35, N36, D74, L77, L80, K81, E84, 188, R133, Q136, E137, T140, and N143, and K144, numbered according to SEQ ID NO: 91.

79. The fusion protein of claim 78, wherein the substitution in position K81 is K81A and the substitution in position T140 is T140A.

80. The fusion protein of any one of claims 58-62, wherein the second moiety comprises an IL- 10 polypeptide, or a functional fragment thereof, or a variant thereof.81 . The fusion protein of claim 80, wherein the IL- 10 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-lORa polypeptide comprising the amino acid sequence of SEQ ID NO: 96, compared to binding affinity of a wild-type IL-10 polypeptide comprising the amino acid sequence of SEQ ID NO: 95 to the IL-lORa polypeptide.

82. The fusion protein of claim 81, wherein the IL- 10 polypeptide exhibits increased binding affinity by at least about 50% to an IL-10RP polypeptide comprising the amino acid sequence of SEQ ID NO: 97, compared to binding affinity of a wild-type IL- 10 polypeptide comprising the amino acid sequence of SEQ ID NO: 95 to the IL-10RP polypeptide.

83. The fusion protein of claim 80, wherein the IL-10 polypeptide comprises the sequence of SEQ ID NO:95, with one or more substitution relative to SEQ ID NO: 95.

84. The fusion protein of claim 83, wherein the IL-10 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 99-112.

85. The fusion protein of claim 80, wherein the IL- 10 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 362-372.

86. The fusion protein of any one of claims 58-62, wherein the second moiety comprises an IL-21 polypeptide, or a functional fragment thereof, or a variant thereof.

87. The fusion protein of claim 86, wherein the IL-21 polypeptide exhibits reduced binding affinity by at least about 50% to an IL-21R polypeptide comprising the amino acid sequence of SEQ ID NO: 93, comparedto binding affinity of a wild-type IL-21 polypeptide comprising the amino acid sequence of SEQ ID NO: 92 or SEQ ID NO: 115 to the IL-21R polypeptide.

88. The fusion protein of claim 86, wherein the IL-21 polypeptide comprises the sequence of SEQ ID NO: 115, with one or more substitution relative to SEQ ID NO: 115.

89. The fusion protein of claim 88, wherein the substitution in one or more positions are selected from the positions: R5, 18, R9, Rl l, Q12, 114, D15, D18, Q19, Y23, R65, S70, K72, K73, K75, R76, K77, S80, QI 16, and KI 17, wherein the position numbering is number according to the amino acid sequence of SEQ ID NO: 115.

90. The fusion protein of claim 86, wherein the IL-21 polypeptide comprises a polypeptide sequence having at least 80% sequence identity to SEQ ID NO: 115, wherein the IL-21 polypeptide has an isoelectric point that is at least about 0.6 units to about 5 units lower, compared to that of a wild-type IL-21 protein having a sequence of SEQ ID NO: 115.91 . The fusion protein of claim 90, wherein the isoelectric point of SEQ ID NO: 115 is about 9.42.

92. The fusion protein of claim 90, wherein the IL-21 polypeptide has an isoelectric point of about 7. 12 to about 8.72.

93. The fusion protein of claim 90, wherein the polypeptide provides an improved exposure compared to the wild-type IL-21 protein, as measured by at least about 1.5 times greater under the curve (AUC) for the polypeptide, relative to that of the wild-type IL-21, when administered to a subject, at equivalent concentrations.

94. The fusion protein of any one of claims 90-93, wherein the IL-21 polypeptide comprises a mutation at one or more positions selected from the group consisting of: K56, T81, N82, A83, G84, R85, R86, Q87, K88, H89, R90, L91, and T92 of SEQ ID NO: 115.

95. The fusion protein of claim 94, wherein the IL-21 polypeptide further comprises a mutation at a position selected from the group consisting of: R5, 18, R9, R11, Q12, 114, D15, D18, Q19, Y23, R65, S70, K72, K73, K75, R76, K77, S 80, QI 16, and KI 17 of SEQ ID NO: 115.

96. The fusion protein of claim 86, wherein the amino acid sequence of the IL-21 polypeptide is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to a sequence selected from the group consisting of SEQ ID NOs: 116, 118-129, and 286-303.

97. The fusion protein of claim 86, wherein the amino acid sequence of the IL-21 polypeptide is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to a sequence selected from the group consisting of SEQ ID NO: 130-135 and 304-361.

98. The fusion protein of any one of claims 58-62, wherein the first moiety and the second moiety are directly linked.

99. The fusion protein of any one of claims 58-62, wherein the first moiety and the second moiety are linked via a linker.

100. The fusion protein of claim 99, wherein the linker comprises the sequence (GGGS)xGn, (GGGGS)xGn, or (GGGGGS)xGn, S(GGGS)xGn, S(GGGGS)xGn, or S(GGGGGS)xGn, wherein x=l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and wherein n=0, 1, 2 or 3.

101. The fusion protein of claim 99, wherein the linker comprises the sequence GGGGSGGGGSGGGGS or SGGGGSGGGGSGGGGS .

102. The fusion protein of any one of claims 58-62, wherein the antibody or antigen binding fragment thereof comprises: two heavy chain polypeptides, each comprising a structure according to formula [I], from N- terminus to C-terminus:VH-CHl-hinge-CH2-CH3 [I], and two light chain polypeptides, each comprising a structure according to formula [II], from N- terminus to C-terminus:VL-CL [II], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of the CH3 domain of one of the two heavy chain polypeptides.

103. The fusion protein of any one of claims 58-62, wherein the antibody or antigen binding fragment thereof comprises: a first heavy chain polypeptide comprising a structure according to formula [I], from N-terminus to C-terminus:VH-CHl-hinge-CH2-CH3 [I], a light chain polypeptide comprising a structure according to formula [II], from N-terminus to C- terminus:VL-CL [II], and a second heavy chain polypeptide comprising a structure according to formula [III], from N- terminus to C-terminus: hinge-CH2-CH3 [III], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide.

104. The fusion protein of any one of claims 58-62, wherein the antibody or antigen binding fragment thereof comprises: a first heavy chain polypeptide comprising a structure according to formula [I], from N-terminus to C-terminus:VH-CHl-hinge-CH2-CH3 [I], a light chain polypeptide comprising a structure according to formula [II], from N-terminus to C- terminus:VL-CL [II], and a second heavy chain polypeptide comprising a structure according to formula [III], from N- terminus to C-terminus: hinge-CH2-CH3 [III], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the C-terminus of the second moiety is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide.

105. The fusion protein of any one of claims 58-62, wherein the antibody or antigen binding fragment thereof comprises: a first heavy chain polypeptide comprising a structure according to formula [I], from N-terminus to C-terminus:VH-CHl-hinge-CH2-CH3 [I], a light chain polypeptide comprising a structure according to formula [II], from N-terminus to C- terminus:VL-CL [II], and a second heavy chain polypeptide comprising a structure according to formula [III], from N- terminus to C-terminus: hinge-CH2-CH3 [III], wherein VH is the VH domain, wherein CHI is an antibody CHI domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second moiety is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide.

106. The fusion protein of any one of claims 58-62, wherein one or both of the antibody heavy chain polypeptides comprise(s) the following amino acid substitutions in the CH2 domain: L234A, L235A, and G237A, numbered according to EU numbering.

107. The fusion protein of any one of claims 58-62, wherein the first moiety comprises two antibody heavy chain polypeptides, and wherein one of the antibody heavy chain polypeptides comprises amino acid substitutions S354C and T366W in the CH3 domain, numbered according to EU numbering, and another of the antibody heavy chain polypeptides comprises amino acid substitutions Y349C, T366S, L368A and Y407V in the CH3 domain, numbered according to EU numbering.

108. The fusion protein of any one of claims 58-62, wherein the first moiety comprises one or two antibody heavy chain polypeptides and one or two antibody light chain polypeptides.

109. The fusion protein of any one of claims 58-62, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain;(b) a second polypeptide chain comprising a VH domain;(c) a third polypeptide chain comprising a VH domain; and(d) a fourth polypeptide chain comprising a VL domain; wherein the VH domains and VL domains comprise CDRs that specifically bind to the truncated EGFR and does not specifically bind to a full-length EGFR, wherein the second polypeptide chain or the third polypeptide chain is linked to the second moiety via a linker.

110. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 257, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively.

111. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 257, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively.

112. The fusion protein of claim 110 or 111, wherein:(a) the VL domain of the first polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or(ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(b) the VH domain of the second polypeptide chain comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, or(ii) an amino acid sequence as set forth in SEQ ID NO: 280, with from 0 to 5 amino acid modifications;(c) the VH domain of the third polypeptide chain comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, or(ii) an amino acid sequence as set forth in SEQ ID NO: 280, with from 0 to 5 amino acid modifications; and(d) the VL domain of the fourth polypeptide chain comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or(ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications.

13. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 241, 247, and 258, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively.

114. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 189, 269, and 258, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 274, respectively.

115. The fusion protein of claim 113 or 114, wherein:(a) the VL domain of the first polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or(ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications;(b) the VH domain of the second polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, or(ii) an amino acid sequence as set forth in SEQ ID NO: 281, with from 0 to 5 amino acid modifications;(c) the VH domain of the third polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, or(ii) an amino acid sequence as set forth in SEQ ID NO: 281, with from 0 to 5 amino acid modifications; and(d) the VL domain of the fourth polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237, or(ii) an amino acid sequence as set forth in SEQ ID NO: 237, with from 0 to 5 amino acid modifications.

116. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 243, 249, and 260, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively.

17. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 266, 271, and 260, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively.

18. The fusion protein of claim 116 or 117, wherein:(a) the VL domain of the first polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or(ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(b) the VH domain of the second polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, or(ii) an amino acid sequence as set forth in SEQ ID NO: 285, with from 0 to 5 amino acid modifications;(c) the VH domain of the third polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, or(ii) an amino acid sequence as set forth in SEQ ID NO: 285, with from 0 to 5 amino acid modifications; and(d) the VL domain of the fourth polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or(ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications.

119. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 244, 249, and 260, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively.

120. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 267, 271, and 260, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 233, 197, and 234, respectively.

121. The fusion protein of claim 119 or 120, wherein:(a) the VL domain of the first polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or(ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications;(b) the VH domain of the second polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, or(ii) an amino acid sequence as set forth in SEQ ID NO: 373, with from 0 to 5 amino acid modifications;(c) the VH domain of the third polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, or(ii) an amino acid sequence as set forth in SEQ ID NO: 373, with from 0 to 5 amino acid modifications; and(d) the VL domain of the fourth polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238, or(ii) an amino acid sequence as set forth in SEQ ID NO: 238, with from 0 to 5 amino acid modifications.

22. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 246, 250, and 262, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively.

23. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively.

124. The fusion protein of claim 122 or 123, wherein:(a) the VL domain of the first polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or(ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(b) the VH domain of the second polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, or(ii) an amino acid sequence as set forth in SEQ ID NO: 380, with from 0 to 5 amino acid modifications;(c) the VH domain of the third polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, or(ii) an amino acid sequence as set forth in SEQ ID NO: 380, with from 0 to 5 amino acid modifications; and(d) the VL domain of the fourth polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or(ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications.

25. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 191, 252, and 262, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively.

126. The fusion protein of claim 109, wherein the first moiety comprises(a) a first polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein the CDRL1, CDRL2, and CDRL3 of the first polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively;(b) a second polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively,(c) a third polypeptide chain comprising a VH domain that comprises CDRH1, CDRH2, and CDRH3, wherein the CDRH1, CDRH2, and CDRH3 of the second polypeptide comprise the sequence as set forth in SEQ ID NOs: 194, 272, and 262, respectively; and(d) a fourth polypeptide chain comprising a VL domain that comprises CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 of the fourth polypeptide comprise the sequence as set forth in SEQ ID NOs: 199, 200, and 275, respectively.

27. The fusion protein of claim 125 or 126, wherein:(a) the VL domain of the first polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or(ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications;(b) the VH domain of the second polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, or(ii) an amino acid sequence as set forth in SEQ ID NO: 382, with from 0 to 5 amino acid modifications;(c) the VH domain of the third polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, or(ii) an amino acid sequence as set forth in SEQ ID NO: 382, with from 0 to 5 amino acid modifications; and(d) the VL domain of the fourth polypeptide comprises(i) an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385, or(ii) an amino acid sequence as set forth in SEQ ID NO: 385, with from 0 to 5 amino acid modifications.

28. The fusion protein of any one of claims 58-62, wherein the first moiety comprises a single chain antibody or single chain variable fragment (scFv), wherein the scFv comprises a VH domain and a VL domain, wherein:(a) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(b) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(c) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(d) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(e) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(f) the VH domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and the VL domain comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:

385.

29. The fusion protein of any one of claims 58-62, wherein the first moiety comprises a diabody wherein the diabody comprises two VH domains and two VL domains, wherein:(a) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 280, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(b) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 281, and at least one of the VL domains comprises an amino acid sequence having at least 90%,95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 237;(c) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 285, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(d) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 373, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 238;(e) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 380, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385;(f) at least one of the VH domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 382, and at least one of the VL domains comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 385.

130. The fusion protein of any one of claims 58-62, wherein the first moiety comprises a single domain antibody or a VHH antibody comprising a VH domain that comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 280, 281, 285, 373, 380, or 382.

131. The fusion protein of any one of claims 58-62, wherein the second moiety comprises an IL-2 polypeptide having an amino acid sequence that is at least about 99% identical to the sequence of SEQ ID NOs: 52 or 156.

132. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 386;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 387 or 388; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389.

133. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 404;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 387 or 388; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389.

134. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 390;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 391 or 392; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389.

135. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 405;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 391 or 392; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 389.

136. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 393;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 394 or 395; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396.

137. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 406;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 394 or 395; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396.

138. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 397;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 398 or 399; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396.

139. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 407;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 398 or 399; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 396.

140. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 400;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 401 or 402; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403.

141. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 408;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 401 or 402; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403.

142. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 412;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 410 or 411; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403.

143. The fusion protein of any one of claims 58-62, comprising:(a) a first polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403;(b) a second polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 409;(c) a third polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 410 or 411; and(d) a fourth polypeptide comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 403.

144. One or more polynucleotides encoding polypeptides capable of forming the fusion protein of any one of claims 57-143, optionally wherein at least one of the one or more polynucleotides is a messenger RNA (mRNA).

145. One or more polynucleotides encoding polypeptides capable of forming the antibody or antigen-binding fragment thereof of any one of claims 1-56, optionally wherein at least one of the one or more polynucleotides is a messenger RNA (mRNA).

146. A vector comprising the one or more nucleotide sequences encoding polypeptides capable of forming the fusion protein of any one of claims 57-143, or the antibody or antigen-binding fragment thereof of any one of claims 1-56.

147. A host cell comprising the one or more polynucleotides of claim 144 or 145 or the vector of claim 146.

148. A method comprising culturing the host cell of claim 147 under conditions for production of the fusion protein, or the antibody or antigen-binding fragment thereof.

149. A pharmaceutical composition comprising the fusion protein of any one of claims 57-143, and / or the one or more polynucleotides of claim 144 or 145, or the antibody or antigen binding fragment thereof of any one of claims 1-56, and at least one of: a pharmaceutically acceptable excipient, carrier, or diluent, or any combination thereof.

150. The pharmaceutical composition of claim 149, further comprising a population of engineered cells.

151. The pharmaceutical composition of claim 150, wherein the population of engineered cells comprises engineered cells that express the truncated EGFR.

152. The pharmaceutical composition of claim 151, wherein the engineered cells that express the truncated EGFR further express a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

153. The pharmaceutical composition of claim 151 or 152, wherein the engineered cells that express the truncated EGFR comprise the fusion protein of any one of claims 57-143 and / or the one or more polynucleotides of claim 144.

154. A cell therapy kit comprising the pharmaceutical composition of claim 149, and instructions specified for administering the pharmaceutical composition to a subject.

155. The cell therapy kit of claim 154, further comprising a pharmaceutical composition that comprises a population of engineered cells and instructions specified for administering the population of engineered cells to the subject.

156. The cell therapy kit of claim 155, wherein the pharmaceutical composition that comprises the fusion protein and the pharmaceutical composition that comprises the population of engineered cells are for sequential or simultaneous administration.

157. The cell therapy kit of claim 155, wherein the pharmaceutical composition that comprises the antibody or antigen binding fragment thereof is administered after the pharmaceutical composition that comprises the population of engineered cells.

158. A cell therapy kit comprising a pharmaceutical composition that comprises a population of engineered cells and instructions specified for administering the population of engineered cells to the subject, wherein the population of engineered cells comprises engineered cells comprising the fusion protein of any one of claims 57-136 and / or the one or more polynucleotides of claim 144.

159. The cell therapy kit of any one of claims 155-158, wherein the population of engineered cells comprises engineered cells that express the truncated EGFR, optionally wherein the population of engineered cellsthat expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

160. A method of treating a disease or condition in a subject, the method comprising administering to the subject (a) (i) the fusion protein of any one of claims 57-136 or (ii) the one or more polynucleotides of claim 144; or (b)(i) the antibody or antigen-binding fragment thereof of any one of claims 1-56 or (ii) the one or more polynucleotides of claim 145.

161. A method of treating a disease or condition in a subject, the method comprising administering to the subject a population of engineered cells that expresses the truncated EGFR, and wherein the population of engineered cells that expresses the truncated EGFR (i) expresses the fusion protein of any one of claims 57-143 and / or (ii) comprises the one or more polynucleotides of claim 144.

162. The method of claim 161, wherein the population of engineered cells that expresses the truncated EGFR expresses the fusion protein of any one of claims 110-143, optionally wherein the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

163. The method of claim 161 or 162, wherein the population of engineered cells that expresses the truncated EGFR comprises the one or more polynucleotides of claim 144.

164. The method of any one of claims 161-163, wherein the population of engineered cells comprises tumor infdtrating lymphocytes (TILs) autologous to the subject, wherein the TILs have been engineered to express the truncated EGFR.

165. A method of treating a disease or condition in a subject, the method comprising administering to the subject a therapeutic regimen comprising: (a) an engineered cell therapy that comprises a population of engineered cells that expresses the truncated EGFR and (b)(i) the fusion protein of any one of claims 57- 136 or (ii) the one or more polynucleotides of claim 144.

166. The method of claim 165, wherein the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

167. The method of claim 165 or 166, wherein the subject has received administration of the engineered cell therapy that comprises a population of engineered cells prior to the administration of the fusion protein or the one or more polynucleotides, or is scheduled to receive administration of the engineered cell therapy within a period of time after the administration of the fusion protein or the one or more polynucleotides.

168. The method of any one of claims 161-167, wherein the fusion protein results in an increase in expansion and / or proliferation of the population of the engineered cells, as compared to the expansion and / or proliferation of a population of otherwise same cells that do not express the truncated EGFR.

169. The method of any one of claims 161-168, wherein the fusion protein results in an increased in vivo persistence of the population of engineered cells, as compared to the in vivo persistence of a population of otherwise same cells that do not express the truncated EGFR.

170. The method of any one of claims 161-169, wherein the fusion protein results in an increase in activation, effector function, expansion and / or proliferation of the population of engineered cells, as compared to the activation, effector function, expansion and / or proliferation of the population of engineered cells, when administered without the fusion protein.

171. The method of claim 170, wherein the activation, effector function, expansion and / or proliferation takes place in vivo or in vitro.

172. The method of any one of claims 161-171, wherein the fusion protein results in an increased in vivo persistence of the population of the engineered cells, as compared to the in vivo persistence of the population of engineered cells, when administered without the fusion protein.

173. The method of claim 172, wherein the in vivo persistence of the population of engineered cells comprises a period of about 15 days, about 30 days to about a year.

174. The method of any one of claims 161-173, wherein the fusion protein reduces a rate and / or extent of exhaustion of the population of the engineered cells, as compared to the rate and / or extent of exhaustion of the population of engineered cells, when administered without the fusion protein.

175. The method of any one of claims 161-174, wherein the fusion protein results in selective potentiation of the engineered cells, allowing enhanced specific enrichment of the population of the engineered cells, as compared to specific enrichment of a population of engineered cells when administered with the second moiety alone.

176. The method of any one of claims 161-175, wherein the fusion protein does not increase count of Treg cells in a biological sample isolated from the subject, as compared to the count of Treg cells in a biological sample isolated from a subject who has been administered the second moiety alone.

177. The method of claim 176, wherein the biological sample is at least one of: a tumor biopsy or peripheral blood.

178. The method of any one of claims 161-177, wherein the subject is previously administered a preconditioning regimen.

179. The method of claim 178, wherein administering the fusion protein or the one or more polynucleotides allows for reduction in at least one of: severity or duration of the pre-conditioning regimen.

180. The method of claim 178 or 179, wherein pre-conditioning regimen is used to decrease the endogenous lymphocyte population so as to allow a population of the engineered cell to expand.

181. The method of any one of claims 160-177, wherein the method eliminates the need for administering, or minimizes the severity of, a pre-conditioning regimen prior to administering an engineered cell therapy.

182. The method of claim 181, wherein the subject has not been administered the pre-conditioning regimen.

183. The method of any one of claims 165-182, wherein the fusion protein is administered within or within about 2 days, 3 days, 6 days, 12 days, 15 days, 30 days, 60 days or 90 days following administration of the engineered cell therapy.

184. The method of any one of claims 165-182, wherein the fusion protein is administered about 2 days, 3 days, 6 days, 12 days, 15 days, 30 days, 60 days or 90 days or more prior to administration of the engineered cell therapy.

185. The method of any one of claims 165-182, wherein the fusion protein is administered simultaneously with administering the engineered cell therapy.

186. The method of any one of claims 165-185, wherein an effective dose of the engineered cells in the therapeutic regimen is lower than that of a reference therapeutic regimen that comprises administering the engineered cells but does not comprise administering the fusion protein.

187. The method of claim 186, wherein the effective dose of the engineered cells in the therapeutic regimen is at least about 1.5x to about lOOOx lower than the effective dosage of the engineered cell in the reference therapeutic regimen.

188. A method of treating a disease or condition in a subject, the method comprising administering to the subject a therapeutic regimen comprising: (a) an engineered cell therapy that comprises a population of engineered cells that expresses the truncated EGFR and (b)(i) the antibody or antigen-binding fragment thereof of any one of claims 1-56 or (ii) the one or more polynucleotides of claim 145.

189. The method of claim 188, wherein the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

190. The method of claim 188 or 189, wherein the subject is scheduled to receive administration of the engineered cell therapy within a period of time after the administration of antibody or antigen-binding fragment thereof or the one or more polynucleotides.

191. The method of any one of claims 188-190, wherein the antibody or antigen-binding fragment thereof results in(a) a decrease in expansion and / or proliferation of the population of the engineered cells, as compared to the expansion and / or proliferation of a population of otherwise same cells that do not express the truncated EGFR; and / or(b) a decrease in vivo persistence of the population of engineered cells, as compared to the in vivo persistence of a population of otherwise same cells that do not express the truncated EGFR.

192. The fusion protein of any one of claims 57-143, the one or more polynucleotides of claim 144, the antibody or antigen-binding fragment thereof of any one of claims 1-56 or the one or more polynucleotides of claim 145, for use in treating a disease or condition a subject in need thereof.

193. The fusion protein or the one or more polynucleotides for use according to claim 192, wherein the fusion protein or the one or more polynucleotides is administered to the subject simultaneously or sequentially with an engineered cell therapy that comprises a population of engineered cells that expresses the truncated EGFR.

194. The fusion protein or the one or more polynucleotides for use according to claim 192, wherein the fusion protein or the one or more polynucleotides is administered to the subject via an engineered celltherapy that comprises a population of engineered cells that (a) expresses the truncated EGFR and (b)(i) expresses the fusion protein and / or (ii) comprises the one or more polynucleotides.

195. The fusion protein or the one or more polynucleotides for use according to claim 193 or 194, wherein the population of engineered cells that expresses the truncated EGFR further expresses a chimeric antigen receptor (CAR), an engineered T cell receptor, an engineered B cell receptor, a chimeric autoantibody receptor, or any combination thereof.

196. Use of the fusion protein of any one of claims 57-143 or one or more polynucleotides of claim 144 in the manufacture of a medicament for treating a disease or a condition, optionally wherein the disease or condition comprises cancer, chronic infection, autoimmune disease or immune-mediated disorder.

197. A method of enriching or expanding a population of engineered cells that expresses the truncated EGFR, the method comprising: contacting the population of engineered cells with the fusion protein of any one of claims 57-143 or the one or more polynucleotides of claim 144.

198. A method of reducing or eliminating a population of engineered cells that expresses the truncated EGFR, the method comprising: contacting the population of engineered cells with the antibody or antigen-binding fragment thereof of any one of claims 1-56.

199. The method of claim 197 or 198, wherein the population of engineered cells is present in vitro.

200. The method of claim 197 or 198, wherein the population of engineered cells is present in vivo in a subject, and the method comprises administering the fusion protein or the one or more polynucleotides, or the antibody or antigen-binding fragment thereof to the subject.

201. The method of claim 200, wherein the administration of the fusion protein or the one or more polynucleotides results in an increase in activation, effector function, expansion and / or proliferation of the population of engineered cells generated in vivo, as compared to the activation, effector function, expansion and / or proliferation of the population of the engineered cells generated in vivo, when the subject is not administered the fusion protein or the one or more polynucleotides.

202. The method of claim 200 or 201, wherein the administration of the fusion protein or the one or more polynucleotides results in an increase in persistence of the population of engineered cells generated in vivo, as compared to the persistence of the population of the engineered cells generated in vivo, when the subject is not administered the fusion protein or the one or more polynucleotides.

203. The method of any one of claims 200-202, wherein the administration of the fusion protein or the one or more polynucleotides reduces a rate and / or extent of exhaustion of the population of engineered cells generated in vivo, as compared to the rate and / or extent of exhaustion of the population of the engineered cell generated in vivo, when administered without the fusion protein or the one or more polynucleotides.

204. The method of any one of claims 200-203, wherein the administration of the fusion protein or the one or more polynucleotides results in selective potentiation of the engineered cells generated in vivo, allowing enhanced specific enrichment of a population of the engineered cells generated in vivo, as compared to specific enrichment of a population of engineered cells when administered with the second moiety alone.

205. The method of any one of claims 200-204, wherein the administration of the fusion protein or the one or more polynucleotides does not increase count of Treg cells in a biological sample isolated from the subject, as compared to the count of Treg cells in a biological sample isolated from a subject who has been administered the second moiety alone, wherein the subject has cancer, and optionally wherein the biological sample is at least one of: a tumor biopsy or peripheral blood.

206. The method of any one of claims 200-205, wherein the persistence of the population of engineered cells comprises a period of at least about 30 days to about a year.

207. The method of any one of claims 161-191 or 197-206 or the fusion protein or the one or more polynucleotides for use according to any one of claims 193-195, wherein the population of engineered cells comprises at least one of: a T cell expressing a T cell receptor (a TCR-T cell), a gamma delta T cell, a pluripotent stem cell derived T cell, or an induced pluripotent stem cell derived T cell, a natural killer cell (NK cell), a pluripotent stem cell derived NK cell, or an induced pluripotent stem cell (iPSC) derived NK cell, a T cell engineered to express a chimeric antigen receptor (a CAR-T cell), a T cell engineered to express a chimeric autoantibody receptor (a CAAR-T cell), a macrophage engineered to express a chimeric antigen receptor (a CAR-M cell), a B cell engineered to express a chimeric antigen receptor (a CAR-B cell), a CD8-positive T cell, a CD4-positive T cell, a cytotoxic T cell, a tumor infdtrating lymphocyte, a CAR-NK cell, a gamma delta T cell, a myeloid cell, a hematopoietic lineage cell, a hematopoietic stem and progenitor cell (HSC), a hematopoietic multipotent progenitor cell (MPP), a pre-T cell progenitor cell, a T cell progenitor cell, a NK cell progenitor cell.

208. The method of or the fusion protein or the one or more polynucleotides for use according to claim 207, wherein the population of engineered cells comprises T cells engineered to express a chimeric antigen receptor, an engineered T cell receptor, or both.

209. The method of or the fusion protein or the one or more polynucleotides for use according to claim 208, wherein the T cells comprises CD8-positive T cells, CD4-positive T cells, cytotoxic T cells, tumor infiltrating lymphocytes.

210. The method of or the fusion protein or the one or more polynucleotides for use according to any one of claims 207-209, wherein the population of engineered cells comprises a T cell engineered to express a chimeric antigen receptor (a CAR-T cell), wherein the chimeric antigen receptor targets an antigen expressed by a cancer cell, optionally wherein the chimeric antigen receptor targets CD 19 or B-cell maturation antigen (BCMA).

211. The method of any one of claims 160-191 or 197-210 or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-195, wherein the subject has a cancer.

212. The method of claim 205 or 211 or the use of claim 196, wherein the cancer is acute lymphoblastic leukemia (ALL) (including non T cell ALL), acute myeloid leukemia, B cell prolymphocytic leukemia, B cell acute lymphoid leukemia (“BALL”), blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloid leukemia, chronic or acute leukemia, diffuse large B cell lymphoma (DLBCL), follicularlymphoma (FL), hairy cell leukemia, Hodgkin's Disease, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma (NHL), plasma cell proliferative disorder (including asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, plasmacytomas (including plasma cell dyscrasia; solitary myeloma; solitary plasmacytoma; extramedullary plasmacytoma; and multiple plasmacytoma), POEMS syndrome (also known as Crow-Fukase syndrome; Takatsuki disease; and PEP syndrome), primary mediastinal large B cell lymphoma (PMBC), small cell- or a large cell-follicular lymphoma, splenic marginal zone lymphoma (SMZL), systemic amyloid light chain amyloidosis, T cell acute lymphoid leukemia (“TALL”), T cell lymphoma, transformed follicular lymphoma, or Waldenstrom macroglobulinemia, Mantlecell lymphoma (MCL), Transformed follicular lymphoma (TFL), Primary mediastinal B cell lymphoma (PMBCL), Multiple myeloma, Hairy cell lymphoma / leukemia, lung cancer, small-cell lung cancer, non-small cell lung (NS CL) cancer, bronchioloalveolar cell lung cancer, squamous cell cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, head and neck cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, thyroid cancer, uterine cancer, gastrointestinal cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, endometrial carcinoma, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the cervix, carcinoma of the vagina, vulval cancer, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, bladder cancer, liver cancer, hepatoma, hepatocellular cancer, cervical cancer, salivary gland carcinoma, biliary cancer, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenoma and Ewings sarcoma, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers.

213. The method of any one of claims 160-191 or 197-211 or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-195, wherein the subject has undergone B cell aplasia.

214. The method of any one of claims 160-191 or 197-213 or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-195, further comprising administering to the subject a T cell therapy, cancer vaccine, chemotherapeutic agent, or immune checkpoint inhibitor (ICI).

215. The method of or the fusion protein or the one or more polynucleotides for use according to claim 214, wherein the ICI is an inhibitor of PD-1, PD-L1, or CTLA-4.

216. The method of or the fusion protein or the one or more polynucleotides for use according to claim 214, wherein the T cell therapy comprises a chimeric antigen receptor (CAR)-based T cell therapy, a tumorinfiltrating lymphocyte (TIL)-based therapy, or a therapy with T cells bearing a transduced TCR.

217. The method of any one of claims 160-191 or 197-209 or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-194, wherein the subject has an autoimmune disease or an immune-mediated disorder, optionally a B-cell mediated autoimmune disease.

218. The method of or the fusion protein or the one or more polynucleotides for use according to claim 207- 209 or 217, wherein the population of engineered cells comprises a T cell engineered to express a chimeric antigen receptor (a CAR-T cell), wherein the chimeric antigen receptor targets an antigen expressed by an autoreactive immune cell, optionally wherein the chimeric antigen receptor targets CD 19, CD20, CD22, CD7, or B-cell maturation antigen (BCMA).

219. The method of or the fusion protein or the one or more polynucleotides for use according to claim 207, wherein the population of engineered cells comprises T cells engineered to express a chimeric autoantibody receptor.

220. The method of or the fusion protein or the one or more polynucleotides for use according to claim 219, wherein the chimeric autoantibody receptor targets a B cell membrane -bound autoantibody, optionally wherein the B cell membrane-bound autoantibody is anti-DSG3 B cell receptor (BCR).

221. The method of any one of claims 161-175, 179-191, 197-207, or 217 orthe fusion protein or the one or more polynucleotides for use according to any one of claims 193-195, wherein the population of engineered cells comprises regulatory T (Treg) cells, optionally wherein the Treg cells are autologous to the subject and are engineered ex vivo to express the truncated EGFR.

222. The method of or the fusion protein or the one or more polynucleotides for use according to claim 221, wherein the Treg cells are engineered to express a chimeric antigen receptor (CAR-Treg).

223. The method of or the fusion protein or the one or more polynucleotides for use according to claim 221 or 222, wherein the Treg cells are obtained via engineering CD4+ and / or CD3+ T cells to express FoxP3, a chimeric antigen receptor, and the truncated EGFR, optionally wherein the CD4+ and / or CD3+ T cells are contacted with a nucleic acid carrier comprising a nucleic acid that expresses FoxP3 and a nucleic acid that expresses the chimeric antigen receptor and the truncated EGFR ex vivo.

224. The method of or the fusion protein or the one or more polynucleotides for use according to any one of claims 221-223, wherein the chimeric antigen receptor of the Treg cells targets an HLA-A2 MHC complex (optionally HLAA2*02), CD83, CD19, insulin, glucose-dependent insulinotropic polypeptide receptor (GIPR), HiP2, a citrullinated protein (optionally citrullinated vimentin), myelin oligodendrocyte glycoprotein, myelin basic protein (MBP), Ganglioside D3, 2,4,6-trinitrophenol (TNP), carcinoembryonic antigen (CEA), IL-23 R, Factor VIII (FVIII), or AAV Capsid.

225. The method of or the fusion protein or the one or more polynucleotides for use according to any one of claims 221-224, wherein the Treg cells comprise CD4+CD25+ Treg cells, natural Treg cells (nTreg), induced Treg cells (iTreg), CD8 CD45RC1™ Treg cells, CD4+ FoxP3+ Treg cells, or CD3+Treg cells.

226. The method of or the fusion protein or the one or more polynucleotides for use according to any one of claims 217-225 or the use of claim 196, wherein the autoimmune disease or immune-mediated disorder comprises systemic lupus erythematosus (SLE), refractory antisynthetase syndrome, myasthenia gravis, neuromyelitis optica spectrum disorder (NMOSD), Sjogren’s syndrome (SS), Scleroderma, immune nephritis, pemphigus vulgaris (PV), idiopathic inflammatory myopathies, and systemic sclerosis.

227. The method of or the fusion protein or the one or more polynucleotides for use according to any one of claims 217-225 or the use of claim 196, wherein the autoimmune disease or immune-mediated disorder comprises graft-versus-host disease (GvHD), Type 1 Diabetes, Rheumatoid Arthitis, Multiple Sclerosis, Vitiligo, Inflammatory Bowel Disease, asthma, hemophilia, and Immune Response to Gene Therapies.

228. The method of or the fusion protein or the one or more polynucleotides for use according to any one of claims 217-225 or the use of claim 196, wherein the autoimmune disease or immune-mediated disorder comprises Acquired aplastic anemia, Agammaglobulinemia, primary, Alopecia areata, Ankylosing spondylitis (AS), Antiphospholipid syndrome (APS), Autoimmune Addison’s disease (AAD), Autoimmune autonomic ganglionopathy (AAG), Autoimmune encephalitis | acute disseminated encephalomyelitis (ADEM), Autoimmune gastritis, Autoimmune hemolytic anemia (AIHA), Autoimmune hepatitis (AIH), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis (AIP), Autoimmune polyglandular syndromes types I, II, & III, Autoimmune progesterone dermatitis, Balo disease, Behcet’s disease, Bullous pemphigoid, Celiac disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, Cold agglutinin disease, limited cutaneous systemic sclerosis, Crohn’s disease (CD), Dermatitis herpetiformis, Dermatomyositis, Diabetes, type 1, Discoid lupus, Eosinophilic fasciitis, Evans syndrome, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with polyangiitis (GPA, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto’s thyroiditis, Henoch- Schonlein purpura, Hurst’s disease, iga nephropathy, Immune thrombocytopenia (ITP), Juvenile idiopathic arthritis, Lambert-Eaton myasthenic syndrome (LEMS), Linear iga disease (LAD), Lupus nephritis, Lymphocytic hypophystitis / autoimmune hypophystitis, Mixed connective tissue disease (MCTD), Multiple sclerosis (MS), Myasthenia gravis (MG), Neuromyelitis Optica / Devic's disease, Ocular cicatricial pemphigoid, Palindromic rheumatism, Paraneoplastic cerebellar degeneration, Paraneoplastic pemphigus, Paroxysmal nocturnal hemoglobinuria (PNH), Parsonage-Turner syndrome, Pemphigus gestationis, Pemphigus foliaceus, Pemphigus vulgaris, POEMS syndrome, Polyarteritis nodosa, Polymyalgia rheumatica, Polymyositis, Primary biliary cirrhosis (PBC), Psoriasis, Palmoplantar Pustulosis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Raynaud’s syndrome / phenomenon, Reactive arthritis / Reiter’s syndrome, Relapsing polychondritis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleroderma, Sjogren’s syndrome, Small fiber sensory neuropathy, Systemic lupus erythematosus (SLE), Testicular autoimmunity (vasculitis, orchitis), Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), and Vitiligo.

229. The method of any one of claims 161-191 or 197-228 or the fusion protein or the one or more polynucleotides for use according to any one of claims 193-195, wherein the population of engineered cells is autologous to the subject.

230. The method of any one of claims 161-191 or 197-228, or the fusion protein or the one or more polynucleotides for use according to any one of claims 193-195, wherein the population of engineered cells is allogenic to the subject.

231. The method of any one of claims 160-191 or 197-230, or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-194, wherein the subject is human.

232. The pharmaceutical composition of claim 151, the cell therapy of claim 159, or the method of any one of claims 161-191 or 197-231, the fusion protein or the one or more polynucleotides for use according to any one of claims 193-195, wherein the population of engineered cells has been engineered to express the truncated EGFR via (a) a nucleic acid carrier comprising a nucleic acid that expresses the truncated EGFR or (b) gene-editing, optionally wherein the gene-editing comprises utilizing a Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases, or the clustered regularly interspaced short palindromic repeats (CRISPR) system.

233. The method of any one of claims 160-191 or 197-231, or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-194, wherein the subject is administered with a nucleic acid carrier comprising a nucleic acid that expresses the truncated EGFR.

234. The pharmaceutical composition of claim 153, the cell therapy of claim 158, or the method of any one of claims 161-191, 197, or 206-233, or the fusion protein or the one or more polynucleotides for use according to any one of claims 193-195, wherein the population of engineered cells is engineered to express the fusion protein via (a) a nucleic acid carrier comprising a nucleic acid that expresses the truncated EGFR or (b) gene-editing, optionally wherein the gene-editing comprises utilizing a Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases, or the clustered regularly interspaced short palindromic repeats (CRISPR) system.

235. The method of any one of claims 160-191 or 197-231, or the fusion protein or the one or more polynucleotides for use according to any one of claims 192-194, wherein the subject is administered with a nucleic acid carrier comprising the one or more polynucleotides of claim 144.

236. The method of any one of claims 232-235, wherein the nucleic acid carrier comprises the one or more polynucleotides of claim 144 and the nucleic acid that expresses the truncated EGFR.

237. The method of any one of claims 232-236, wherein the nucleic acid carrier is at least one of: a linear polynucleotide, a polynucleotide associated with ionic or amphiphilic compounds, a plasmid, and a virus.

238. The method of claim 236, wherein the nucleic acid carrier is a nanocarrier.

239. The method of claim 236, wherein the nucleic acid carrier is a viral vector, wherein the viral vector is at least one of: a Sendai viral vector, an adenoviral vector, an adeno-associated virus vectors, a retroviral vector, or a lentiviral vector.

240. The method of any one of claims 232-239, wherein the nucleic acid is a DNA or an RNA.

241. The method of claim 240, wherein the RNA is a messenger RNA (mRNA).

242. The method of any one of claims 232-241, wherein the nucleic acid carrier further comprises a targeting moiety for targeting an immune cell.

243. The method of claim 242, wherein the immune cell comprises a myeloid cell, a T cell or an NK cell.

244. The method of claim 243, wherein the T cell comprises a T lymphocyte.

245. The method of claim 243 or 244, wherein the T cell or the NK cell is induced by the vector or the nucleic acid carrier, to generate the engineered cell in vivo in the subject.

246. The method of any one of claims 232-245, wherein the nucleic acid carrier further comprises a promoter upstream of the nucleic acid that expresses the truncated EGFR or the fusion protein.

247. The method of claim 246, wherein the promoter is a consecutively active promoter.

248. The method of claim 246, wherein the promoter is an inducible promoter, optionally wherein the promoter is induced by an activation signal from a chimeric antigen receptor or a chimeric autoantibody receptor expressed by the population of engineered cells.

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