TROP2 binding proteins and uses thereof

Abstract

Provided herein are antigen binding protein constructs (ABPC) that bind to TROP2 and uses thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 596,306, filed November 5, 2023, and 63 / 455,278, filed March 29, 2023, the entire contents of which are hereby incorporated by reference.

[0003] sequence list

[0004] This application contains a sequence list that has been submitted electronically as an XML file named “45395-0063WO_SL_ST26”. The XML file, created on November 4, 2023, is 683,397 bytes in size, and the material contained therein is hereby incorporated by full reference. Technical Field

[0005] This disclosure relates to the field of antigen-binding molecules. Summary of the Invention

[0006] This invention is based on the concept that antigen-binding protein (ABP) constructs can be generated that exhibit enhanced efficacy in increasing toxin release, lysosomal delivery, and cell killing in target mammalian cells.

[0007] Trophoblastic cell surface antigen 2 (TROP2), also known as tumor-associated calcium signaling transducer 2 (TACSTD2), is a cellular target of increasing interest in oncology. TROP2 is overexpressed in many large cancers, such as NSCLC and breast cancer, and the anti-TROP2 ADC sacituzumab govitecan (Trodelvy®) has been approved for metastatic TNBC. Another anti-TROP2 ADC, datopotamab deruxtecan, has shown encouraging efficacy in both the HR+ / HER2- and TNBC cohorts in a phase 3 trial. Notably, Trodelvy's efficacy in patients with low TROP2 levels is lower than in those with high TROP2 levels, indicating an unmet need in patients with tumors exhibiting low TROP2 expression. Furthermore, the significant expression of TROP2 in normal tissues leads to target-mediated clearance of anti-TROP2 ADCs and presents a challenge in selectively increasing delivery to tumor cells rather than normal cells.

[0008] Because pH engineering of TROP2 antibodies may reduce the uptake of the corresponding ADC in normal tissues, the applicant sought to develop an anti-TROP2 binding protein as disclosed herein. Compared to existing pH-independent anti-TROP2 ADCs, this type of anti-TROP2 pH-ADC has the potential to reduce "on-target" toxicity and broaden the therapeutic window. The pH-ADC disclosed herein can also improve efficacy by increasing tumor uptake and improving the PK curve, which is particularly beneficial for patients with tumors characterized by low TROP2 expression.

[0009] As disclosed herein, the applicant designed, generated, and extensively evaluated approximately 700 antigen-binding protein construct (ABPC) candidates to generate ABPC scores exhibiting superior pH-dependent internalization and cytotoxicity (e.g., ADC) compared to their corresponding non-enhanced control ABPCs (or control ADCs). Of these initial candidates, nearly ten percent exhibited 1.4-fold cellular internalization compared to their corresponding control ABPCs, and many of these superior internalizers demonstrated associated superior cytotoxicity against TROP2-positive cells. In summary, the results disclosed herein demonstrate that the use of pH-engineered anti-TROP2 antibodies (and conjugates derived therefrom) can effectively target cellular TROP2, which exhibit strong binding at physiological pH but not at the acidic pH found in the lysosome / lysosomal compartment. Ongoing and future studies will evaluate the capabilities of these enhanced anti-TROP2 ABPCs, particularly their ability to carry any desired cargo into TROP2-positive cells in vitro and in vivo.

[0010] Therefore, this article provides antigen-binding protein constructs (ABPCs) and pharmaceutical compositions comprising an effective amount of ABPC, said ABPC comprising: a first antigen-binding domain (ABD) capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of target mammalian cells, wherein: (a) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a faster rate than at a pH of about 7.0 to about 8.0; and / or (b) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a greater rate than at a pH of about 7.0 to about 8.0.

[0011] In some embodiments, the first ABD comprises an HCVD of a heavy chain variable domain (HCVD) of goxatozumab, dedabrotuzumab, hu7E6SVG, or A1,2X4, each HCVD having at least one (1) histidine substitution (or alanine, wherein histidine is already present).

[0012] As used herein, when listing histidine or alanine substitutions, the histidine or alanine substitution may be present in one or more of the heavy chain CDR and / or the light chain CDR, wherein each such CDR is determined by the Kabat method, IMGT or the additive “Kabat-IMGT” method described in Example 1 (i.e., a given CDR is defined by including amino acid residues present in either or both of the Kabat and IMGT CDR definitions).

[0013] In some embodiments, the first ABD comprises an LCVD of a light chain variable domain (LCVD) of goxatozumab, dedabrotuzumab, hu7E6SVG, or A1,2X4, each LCVD having at least one (1) histidine substitution (or alanine, wherein histidine is already present).

[0014] In some embodiments, the first ABD includes one of (a) to (d): (a) an HCVD of goxatozumab and / or an LCVD of goxatozumab; (b) an HCVD of dabrabutamol and / or an LCVD of dabrabutamol; (c) an HCVD of hu7E6SVG and / or an LCVD of hu7E6SVG; and (d) an HCVD of A1,2X4 and / or an LCVD of A1,2X4, each HCVD or LCVD having one or more amino acids substituted with histidine (or alanine, wherein histidine is already present).

[0015] In some embodiments, the HCVD comprises one of (a) to (d): (a) an HCVD of goxatozumab comprising SEQ ID NO: 4; (b) an HCVD of dapoxetine comprising SEQ ID NO: 80; (c) an HCVD of hu7E6SVG comprising SEQ ID NO: 156; and (d) an HCVD of A1,2X4 comprising SEQ ID NO: 234, each HCVD having one or more amino acids substituted with histidine (or alanine, wherein histidine is already present).

[0016] In some embodiments, the LCVD comprises one of (a) to (d): (a) an LCVD of goxatozumab comprising SEQ ID NO: 5; (b) an LCVD of dapoxetine comprising SEQ ID NO: 81; (c) an LCVD of hu7E6SVG comprising SEQ ID NO: 157; and (d) an LCVD of A1,2X4 comprising SEQ ID NO: 235, each LCVD having one or more amino acids substituted with histidine (or alanine, wherein histidine is already present).

[0017] In some embodiments, the first TROP2 binding domain includes an HCVD that is itself one of (a) to (d): (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; (c) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 158, 159, and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159, and 160 are collectively substituted with histidine; and (d) an HCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 236, 237, and 238, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0018] In some embodiments, the first ABD comprises one of (a) to (d): (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 are collectively substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 161, 162, and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162, and 163 are collectively substituted with histidine; and (d) an LCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0019] In some embodiments, the first ABD comprises one of (a) to (d): (a) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 ... (c) HCVD, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 158, 159 and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 161, 162 and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162 and 163 are collectively substituted with histidine; and (d) HCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 236, 237 and 238, wherein the SEQ ID NO: One or more amino acid positions in 236, 237, and 238 are collectively substituted with histidine; and / or LCVD, said LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in SEQ ID NO: 239, 240, and 241 are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0020] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (d) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (e ...e SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD of SEQ ID NO: 234, wherein the HCVD comprises histidine at one or more positions of SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0021] In some embodiments, the first ABD comprises one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5. SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0022] In some embodiments, the first ABD comprises an HCVD that is itself one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein the HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is identical to SEQ ID NO: 4: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 234, wherein the HCVD comprises histidine at two or more positions in SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0023] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is identical to SEQ ID NO: 5: SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at two or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0024] In some embodiments, the first ABD comprises one of (a) to (d): (a) at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; and / or at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) identical to SEQ ID NO: 80 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; and / or is at least 90%, 95%, or 98% identical to LCVD in SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: The LCVD in SEQ ID NO: 156 comprises histidine at one or more of the following positions: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 157, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 234, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 235 comprises histidine at one or more of the NO: 235 contains histidine at one or more positions.In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0025] In some embodiments, the first ABD includes one of (a) to (d): (a) is an HCVD of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350; (b) is an HCVD of one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; (c) is an HCVD of one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: 427-457; and (d) is an HCVD of SEQ ID NO: 234 or SEQ ID NO: The first ABD comprises one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396; (b) one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: 407-426; (c) one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492; and (d) one of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0026] In some embodiments, the first ABD includes one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350, and / or an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 4 and the LCVD of SEQ ID NO: 5; (ii) an HCVD that is itself SEQ ID NO: 4 and is not SEQ ID NO: LCVD of one of 57, 58, 59, 61, 62, 64, 65, 66, 67, 71, 74, 75, 76, 77, 78, 79, 351, 352, 353, 354, 355, 359, 360, 361, 362, 365, 366, 367, 368, 370, 371, 372, 373, 376, 377, 383, 386, 387, 388, 389, 392, 393, 394, 395, and 396; or (iii) an LCVD that is itself SEQ ID NO: 5 and not SEQ ID NO: HCVD of one of SEQ ID NO: 80, SEQ ID NO: 88-128 or SEQ ID NO: 397-406; and / or LCVD of one of SEQ ID NO: 81, SEQ ID NO: 129-155 or SEQ ID NO: 407-426, wherein the first ABD does not include (i) SEQ ID NO: 80, SEQ ID NO: 129-155. (i) HCVD of SEQ ID NO: 80 and LCVD of SEQ ID NO: 81; (ii) HCVD that is itself SEQ ID NO: 80 and LCVD that is not one of SEQ ID NO: 131, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 147, 151, 152, 153, 411, 412, 417, 418 and 423;Or (iii) an LCVD that is itself SEQ ID NO: 81 and not one of SEQ ID NO: 91, 101, 103, 112, 113, 116, 119, 122, 123, 125, and 126; (c) an LCVD that is itself one of the sequences shown in SEQ ID NO: 156 or SEQ ID NO: 164-202; and / or an LCVD that is itself one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 156 and the LCVD of SEQ ID NO: 157; (ii) an HCVD that is itself SEQ ID NO: 156 and not one of SEQ ID NO: 91, 101, 103, 112, 113, 116, 119, 122, 123, 125, and 126. The LCVD of one of the sequences shown in 204, 211, 213, 215, 218, 220, 221, 222, 223, 224, 225, 228, 229, 231, 232, 233, 459, 460, 462, 464, 465, 466, 467, 468, 469, 470, 473, 474, 485, 488, 489, and 491; or (iii) the LCVD of itself being SEQ ID NO: 157 and not being SEQ ID NO: HCVD of one sequence of the sequences shown in SEQ ID NO: 164, 167, 168, 171, 172, 175, 178, 180, 181, 183, 196, 197, 200, 201, 427, 428, 429, 430, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 447, 449, 451, 454, 456, and 457; and (d) HCVD of one sequence of the sequences shown in SEQ ID NO: 234 or SEQ ID NO: 242-280; and / or LCVD of one sequence of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312, wherein the first ABD does not include SEQ ID NO: HCVD of SEQ ID NO: 234 and LCVD of SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0027] In some embodiments, the ABPC is degraded in the target mammalian cells after being internalized. In some embodiments, the ABPC comprises a conjugated toxin, a radioisotope, a drug, or a small molecule.

[0028] In some embodiments, the composition provides an increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 20% increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 50% increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 2-fold increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 5-fold increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0029] In some embodiments, the composition provides an increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 20% or 50% in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 2-fold or 5-fold in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0030] In some embodiments, the composition provides an increase in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 20% or 50% in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 2-fold or 5-fold in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0031] In some embodiments, the composition causes a less reduction in the level of TROP2 presented on the surface of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition does not cause a detectable reduction in the level of TROP2 presented on the surface of the target mammalian cells.

[0032] This document also provides a pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC), said ABPC comprising: a first ABD capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of a target mammalian cell; and a conjugated toxin, radioisotope, drug, or small molecule, wherein: (a) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a rate greater than at a pH of about 7.0 to about 8.0; or the first ABD has a dissociation constant (KD) at a pH of about 4.0 to about 6.5 greater than at a pH of about 7.0 to about 8.0; and (b) the composition provides one or more of the following: increased toxin release in the target mammalian cell compared to a composition comprising the same amount of a control ABPC; increased killing of the target mammalian cell compared to a composition comprising the same amount of a control ABPC; and increased lysosomal delivery in the target mammalian cell compared to a composition comprising the same amount of a control ABPC.

[0033] In some embodiments, the first ABD comprises an HCVD, which is one of (a) to (d): (a) an HCVD of goxatozumab; (b) an HCVD of dabrabutazine; (c) an HCVD of hu7E6SVG; and (d) an HCVD of A1,2X4, each HCVD having one or more histidine substitutions. In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD of goxatozumab; (b) an LCVD of dabrabutazine; (c) an LCVD of hu7E6SVG; and (d) an LCVD of A1,2X4, each LCVD having one or more histidine substitutions. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0034] In some embodiments, the first ABD comprises one of (a) to (d): (a) an HCVD of goxatuzumab and / or an LCVD of goxatuzumab; (b) an HCVD of dabrabutazine and / or an LCVD of dabrabutazine; (c) an HCVD of hu7E6SVG and / or an LCVD of hu7E6SVG; and (d) an HCVD of A1,2X4 and / or an LCVD of A1,2X4, each HCVD and / or LCVD having one or more histidine substitutions. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0035] In some embodiments, the HCVD includes one of (a) to (d): (a) an HCVD of goxatozumab, the HCVD including SEQ ID NO: 4; (b) an HCVD of dapoxetine, the HCVD including SEQ ID NO: 80; (c) an HCVD of hu7E6SVG, the HCVD including SEQ ID NO: 156; and (d) an HCVD of A1,2X4, the HCVD including SEQ ID NO: 234. In some embodiments, the LCVD comprises one of (a) to (d): (a) an LCVD of goxatozumab comprising SEQ ID NO: 5; (b) an LCVD of dabrechtinger comprising SEQ ID NO: 81; (c) an LCVD of hu7E6SVG comprising SEQ ID NO: 157; and (d) an LCVD of A1,2X4 comprising SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0036] In some embodiments, the first ABD comprises HCVD, the HCVD comprising one of (a) to (d): (a) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; (b) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; (c) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 158, 159, and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159, and 160 are collectively substituted with histidine; and (d) HCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 236, 237, and 238, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0037] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 are collectively substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 161, 162, and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162, and 163 are collectively substituted with histidine; and (d) an LCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0038] In some embodiments, the first ABD comprises one of (a) to (d): (a) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 ... (c) HCVD, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 158, 159 and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 161, 162 and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162 and 163 are collectively substituted with histidine; and (d) HCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 236, 237 and 238, wherein the SEQ ID NO: One or more amino acid positions in 236, 237, and 238 are collectively substituted with histidine; and / or LCVD, said LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in SEQ ID NO: 239, 240, and 241 are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0039] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (d) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (e ...e SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD of SEQ ID NO: 234, wherein the HCVD comprises histidine at one or more positions of SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0040] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is identical to SEQ ID NO: 5: SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0041] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 234, wherein the HCVD comprises histidine at two or more positions in SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0042] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is identical to SEQ ID NO: 5: SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at two or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0043] In some embodiments, the first ABD comprises one of (a) to (d): (a) at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; and / or at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) identical to SEQ ID NO: 80 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; and / or is at least 90%, 95%, or 98% identical to LCVD in SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: The LCVD in SEQ ID NO: 156 comprises histidine at one or more of the following positions: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 157, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 234, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 235 comprises histidine at one or more of the NO: 235 contains histidine at one or more positions.In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0044] In some embodiments, the first ABD includes an HCVD, which is one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350; (b) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; (c) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: 427-457; and (d) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 234 or SEQ ID NO: 242-280. In some embodiments, the first ABD includes an LCVD that is itself one of (a) to (d): (a) an LCVD that is itself one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79 or one of the sequences shown in SEQ ID NO: 351-396; (b) an LCVD that is itself one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155 or one of the sequences shown in SEQ ID NO: 407-426; (c) an LCVD that is itself one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233 or one of the sequences shown in SEQ ID NO: 458-492; and (d) an LCVD that is itself one of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312.

[0045] In some embodiments, the first ABD includes one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350, and / or an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 4 and the LCVD of SEQ ID NO: 5; (ii) an HCVD that is itself SEQ ID NO: 4 and is not SEQ ID NO: LCVD of one of 57, 58, 59, 61, 62, 64, 65, 66, 67, 71, 74, 75, 76, 77, 78, 79, 351, 352, 353, 354, 355, 359, 360, 361, 362, 365, 366, 367, 368, 370, 371, 372, 373, 376, 377, 383, 386, 387, 388, 389, 392, 393, 394, 395, and 396; or (iii) is itself not SEQ ID NO: The HCVD of 15, 18, 19, 22, 24, 25, 32, 33, 34, 35, 36, 37, 38, 41, 43, 46, 47, 50, 318, 320, 322, 323, 324, 325, 328, 332, 333, 334, 336, 337, 343, 344, 345, 347, and 348 and the LCVD of SEQ ID NO: 5; (b) the HCVD of a sequence that is itself one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; and / or the HCVD of a sequence that is itself one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: The LCVD of one of the sequences shown in 407-426, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 80 and the LCVD of SEQ ID NO: 81;(ii) An HCVD that is itself SEQ ID NO: 80 and an LCVD that is not one of SEQ ID NO: 131, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 147, 151, 152, 153, 411, 412, 417, 418, and 423; or (iii) An HCVD that is not one of SEQ ID NO: 91, 101, 103, 112, 113, 116, 119, 122, 123, 125, and 126 and an LCVD that is SEQ ID NO: 81; (c) A sequence that is itself one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: The first ABD includes (i) the HCVD of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 156 and the LCVD of SEQ ID NO: 157; (ii) the HCVD that is itself SEQ ID NO: 156 and is not SEQ ID NO: LCVD of one of the sequences shown in 204, 211, 213, 215, 218, 220, 221, 222, 223, 224, 225, 228, 229, 231, 232, 233, 459, 460, 462, 464, 465, 466, 467, 468, 469, 470, 473, 474, 485, 488, 489, and 491; or (iii) is itself not SEQ ID NO: HCVD of one of the sequences shown in SEQ ID NO: 164, 167, 168, 171, 172, 175, 178, 180, 181, 183, 196, 197, 200, 201, 427, 428, 429, 430, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 447, 449, 451, 454, 456 and 457 and LCVD of SEQ ID NO: 157; and (d) HCVD of one of the sequences shown in SEQ ID NO: 234 or SEQ ID NO: 242-280;And / or is itself an LCVD of one of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312, wherein the first ABD does not include the HCVD of SEQ ID NO: 234 and the LCVD of SEQ ID NO: 235.

[0046] In some embodiments, the composition provides an increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 20% or 50% in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 2-fold or 5-fold in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0047] In some embodiments, the composition provides an increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 20% or 50% in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 2-fold or 5-fold in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0048] In some embodiments, the composition provides an increase in lysosomal delivery, including an increase of at least 20% or 50%, compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides an increase of at least 2-fold or 5-fold in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0049] In some embodiments, the composition causes a less reduction in the level of TROP2 presented on the surface of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition does not cause a detectable reduction in the level of TROP2 presented on the surface of the target mammalian cells. In some embodiments, the target mammalian cells are cancer cells.

[0050] In some embodiments, the dissociation rate of the ABD at a pH of about 4.0 to about 6.5 is at least 10% faster than the dissociation rate of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the dissociation rate of the ABD at a pH of about 4.0 to about 6.5 is at least 3 times faster than the dissociation rate of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the dissociation rate of the ABD at a pH of about 4.0 to about 6.5 is at least 10 times faster than the dissociation rate of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the K of the ABD at a pH of about 4.0 to about 6.5 is... D Compared to the ABD at a pH of about 7.0 to about 8.0, K D At least 10%. In some embodiments, the K of the ABD at a pH of about 4.0 to about 6.5 is... D The K of the ABD at a pH of about 7.0 to about 8.0 D At least 3 times. In some embodiments, the ABD is K at a pH of about 4.0 to about 6.5. D The K of the ABD at a pH of about 7.0 to about 8.0 D At least 10 times.

[0051] In some embodiments, the ABPC has cytotoxicity or cytoinhibitory effects on the target mammalian cells.

[0052] In some embodiments, the ABPC exhibits cross-reactivity with non-human primate TROP2 and human TROP2. In some embodiments, the ABPC exhibits cross-reactivity with one or both of non-human primate TROP2, human TROP2, rat TROP2, and mouse TROP2. In some embodiments, the ABPC exhibits cross-reactivity with non-human primate TROP2, human TROP2, rat TROP2, and mouse TROP2. In some embodiments, the ABD binds to an epitope of TROP2 present on the surface of cells from Old World monkeys.

[0053] In some embodiments, the ABPC comprises a single polypeptide. In some embodiments, the ABD is selected from the VH domain, VHH domain, VNAR domain, and scFv. In some embodiments, the ABPC is BiTe, (scFv)2, nanobody, nanobody-HSA, DART, TandAb, sc bifunctional antibody, sc bifunctional antibody-CH3, scFv-CH-CL-scFv, HSAbody, sc bifunctional antibody-HSA, or tandem scFv.

[0054] In some embodiments, the ABPC comprises two or more polypeptides. In some embodiments, the ABPC is selected from the group consisting of: antibody, VHH-scAb, VHH-Fab, dual scFab, F(ab')2, bifunctional antibody, crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, common light chain of mortar and pestle, mortar and pestle assembly, charge pair, Fab arm exchange, SEEDbody, LUZ-Y, Fcab, κλ body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Bifunctional Antibody-CH3, Trifunctional Antibody, Microbody, Microbody, TriBi Microbody, scFv-CH3 KIH, Fab-scFv, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, Quadrivalent HCAb, sc Bifunctional Antibody-Fc, Bifunctional Antibody-Fc, Tandem scFv-Fc, VHH-Fc, Tandem VHH-Fc, VHH-Fc KiH, Fab-VHH-Fc, Intracellular Antibody, Docking Locking Antibody, ImmTAC, IgG-IgG Conjugate, Cov-X-Body, scFv1-PEG-scFv2, Adnectin, DARPin, Fibronectin, DEP Conjugate, PROTAB and PROTAC.

[0055] In some embodiments, the ABPC or ABD comprises a proteolysis-targeting antibody (PROTAB) (as described, for example, in Marei et al., “Antibody targeting of E3ubiquitin ligases for receptor degradation”, Nature, October 6, 2022). In some embodiments, a PROTAB or PROTAC can link a cell surface E3 ubiquitin ligase to a transmembrane protein, causing targeted degradation both in vitro and in vivo.

[0056] In some embodiments, at least one polypeptide of the ABPC is conjugated to the toxin, the radioisotope, the drug, or the small molecule via a cleavable linker. In some embodiments, at least one polypeptide of the ABPC is conjugated to the toxin, the radioisotope, the drug, or the small molecule via an uncleavable linker.

[0057] In some embodiments, the in vivo half-life of the ABPC is increased compared to the in vivo half-life of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is increased by about 5% to about 95% compared to the in vivo half-life of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is increased by about 10% to about 95% compared to the in vivo half-life of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is increased by about 30% to about 95% compared to the in vivo half-life of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is increased by about 50% to about 95% compared to the in vivo half-life of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is increased by about 70% to about 95% compared to the in vivo half-life of a control ABPC. In other embodiments, the in vivo half-life may be reduced.

[0058] In some embodiments, the control ABPC is capable of specifically binding to TROP2 or a TROP2 epitope presented on the surface of target mammalian cells, wherein: (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5 is no more than 3 times the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K0) of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5. D () is K at a pH of approximately 7.0 to approximately 8.0 D No more than 3 times.

[0059] In some embodiments, the control ABPC is capable of specifically binding to TROP2 or a TROP2 epitope presented on the surface of target mammalian cells, wherein: (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5 is no more than twice the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K0) of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5. D () is K at a pH of approximately 7.0 to approximately 8.0 D The amount shall not exceed twice the standard rate.

[0060] In some embodiments, the control ABPC is capable of specifically binding to TROP2 or a TROP2 epitope presented on the surface of target mammalian cells, wherein: (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5 is no more than 1 times the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K0) of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5. D () is K at a pH of approximately 7.0 to approximately 8.0 D The amount shall not exceed 1 time.

[0061] In some embodiments, the control ABPC is selected from one of the following: (a) goxatozumab; (b) dapoxetine; (c) hu7E6SVG; and (d) A1,2X4.

[0062] In some embodiments, the ABPC includes a second ABD.

[0063] This document also provides a kit comprising at least one dose of any of the pharmaceutical compositions described herein.

[0064] This article also provides antigen-binding protein constructs (ABPCs) comprising: a first ABD capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of target mammalian cells, wherein: (a) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a faster rate than at a pH of about 7.0 to about 8.0; or (b) the first ABD has a dissociation constant (Ki) at a pH of about 4.0 to about 6.5. D The K+ at a pH of approximately 7.0 to approximately 8.0 D big.

[0065] In some embodiments, the first ABD comprises one of (a) to (d): (a) an HCVD of goxatozumab, wherein one or more amino acids are substituted with histidine; (b) an HCVD of descapotuzumab, wherein one or more amino acids are substituted with histidine; (c) an HCVD of hu7E6SVG, wherein one or more amino acids are substituted with histidine; and (d) an HCVD of A1,2X4, wherein one or more amino acids are substituted with histidine. In some embodiments, the first ABD comprises one of (a) to (d): (a) an LCVD of goxatozumab, wherein one or more amino acids are substituted with histidine; (b) an LCVD of descapotuzumab, wherein one or more amino acids are substituted with histidine; (c) an LCVD of hu7E6SVG, wherein one or more amino acids are substituted with histidine; and (d) an LCVD of A1,2X4, wherein one or more amino acids are substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0066] In some embodiments, the first ABD comprises one of (a) to (d): (a) HCVD of goxatozumab and / or LCVD of goxatozumab, wherein one or more amino acids of either or both are substituted with histidine; (b) HCVD of descapotuzumab and / or LCVD of descapotuzumab, wherein one or more amino acids of either or both are substituted with histidine; (c) HCVD of hu7E6SVG and / or LCVD of hu7E6SVG, wherein one or more amino acids of either or both are substituted with histidine; and (d) HCVD of A1,2X4 and / or LCVD of A1,2X4, wherein one or more amino acids of either or both are substituted with histidine. In some embodiments, the HCVD includes one of (a) to (d): (a) an HCVD of goxatozumab, the HCVD including SEQ ID NO: 4; (b) an HCVD of dapoxetine, the HCVD including SEQ ID NO: 80; (c) an HCVD of hu7E6SVG, the HCVD including SEQ ID NO: 156; and (d) an HCVD of A1,2X4, the HCVD including SEQ ID NO: 234. In some embodiments, the LCVD comprises one of (a) to (d): (a) an LCVD of goxatozumab comprising SEQ ID NO: 5; (b) an LCVD of dapoxetine comprising SEQ ID NO: 81; (c) an LCVD of hu7E6SVG comprising SEQ ID NO: 157; and (d) an LCVD of A1,2X4 comprising SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0067] In some embodiments, the first ABD comprises HCVD, the HCVD being one of (a) to (d): (a) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; (b) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; (c) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 158, 159, and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159, and 160 are collectively substituted with histidine; and (d) HCVD comprising SEQ ID NO: CDR1, CDR2 and CDR3 of SEQ ID NO: 236, 237 and 238, wherein one or more amino acid positions in total are collectively substituted with histidine. In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 are collectively substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 161, 162, and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162, and 163 are collectively substituted with histidine; and (d) an LCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0068] In some embodiments, the first ABD comprises one of (a) to (d): (a) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 ... (c) HCVD, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 158, 159 and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 161, 162 and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162 and 163 are collectively substituted with histidine; and (d) HCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 236, 237 and 238, wherein the SEQ ID NO: One or more amino acid positions in 236, 237, and 238 are collectively substituted with histidine; and / or LCVD, said LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in SEQ ID NO: 239, 240, and 241 are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0069] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (d) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (e ...e SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD of SEQ ID NO: 234, wherein the HCVD comprises histidine at one or more positions of SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0070] In some embodiments, the first ABD comprises an LCVD, the LCVD being one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5; (c) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5. 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 157: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more positions in SEQ ID NO: 235.

[0071] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 234, wherein the HCVD comprises histidine at two or more positions in SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0072] In some embodiments, the first ABD comprises an LCVD, the LCVD being one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at two or more positions selected from the group consisting of: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97 in SEQ ID NO: 5; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at two or more positions selected from the group consisting of: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95 in SEQ ID NO: 5; (c) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at two or more positions selected from the group consisting of: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95 in SEQ ID NO: 5; SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at two or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0073] In some embodiments, the first ABD comprises one of (a) to (d): (a) at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; and / or at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) identical to SEQ ID NO: 80 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; and / or is at least 90%, 95%, or 98% identical to LCVD in SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: The LCVD in SEQ ID NO: 156 comprises histidine at one or more of the following positions: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 157, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 234, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 235 comprises histidine at one or more of the NO: 235 contains histidine at one or more positions.In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0074] In some embodiments, the first ABD includes an HCVD, the HCVD being one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350; (b) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; (c) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: 427-457; and (d) an HCVD that is itself SEQ ID NO: 234 or SEQ ID NO: The first ABD includes an HCVD of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79 or an LCVD of one of the sequences shown in SEQ ID NO: 351-396; (b) an LCVD of one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155 or an LCVD of one of the sequences shown in SEQ ID NO: 407-426; (c) an LCVD of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233 or an LCVD of one of the sequences shown in SEQ ID NO: 458-492; and (d) an LCVD of one of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0075] In some embodiments, the first ABD includes one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350, and / or an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 4 and the LCVD of SEQ ID NO: 5; (ii) an HCVD that is itself SEQ ID NO: 4 and is not SEQ ID NO: LCVD of one of 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 71, 74, 75, 76, 77, 78, 79, 351, 352, 353, 354, 355, 359, 360, 361, 362, 365, 366, 367, 368, 370, 371, 372, 373, 376, 377, 383, 386, 387, 388, 389, 392, 393, 394, 395, and 396; or (iii) is itself not SEQ ID NO: The HCVD of 15, 18, 19, 22, 24, 25, 32, 33, 34, 35, 36, 37, 38, 41, 43, 46, 47, 50, 318, 320, 322, 323, 324, 325, 328, 332, 333, 334, 336, 337, 343, 344, 345, 347, and 348 and the LCVD of SEQ ID NO: 5; (b) the HCVD of a sequence that is itself one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; and / or the HCVD of a sequence that is itself one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: The LCVD of one of the sequences shown in 407-426, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 80 and the LCVD of SEQ ID NO: 81;(ii) An HCVD that is itself SEQ ID NO: 80 and an LCVD that is not one of SEQ ID NO: 131, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 147, 151, 152, 153, 411, 412, 417, 418, and 423; or (iii) An HCVD that is not one of SEQ ID NO: 91, 101, 103, 112, 113, 116, 119, 122, 123, 125, and 126 and an LCVD that is SEQ ID NO: 81; (c) A sequence that is itself one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: The first ABD includes (i) the HCVD of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 156 and the LCVD of SEQ ID NO: 157; (ii) the HCVD that is itself SEQ ID NO: 156 and is not SEQ ID NO: LCVD of one of the sequences shown in 204, 211, 213, 215, 218, 220, 221, 222, 223, 224, 225, 228, 229, 231, 232, 233, 459, 460, 462, 464, 465, 466, 467, 468, 469, 470, 473, 474, 485, 488, 489, and 491; or (iii) is itself not SEQ ID NO: HCVD of one of the sequences shown in SEQ ID NO: 164, 167, 168, 171, 172, 175, 178, 180, 181, 183, 196, 197, 200, 201, 427, 428, 429, 430, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 447, 449, 451, 454, 456 and 457 and LCVD of SEQ ID NO: 157; and (d) HCVD of one of the sequences shown in SEQ ID NO: 234 or SEQ ID NO: 242-280;And / or is itself an LCVD of one of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312, wherein the first ABD does not include the HCVD of SEQ ID NO: 234 and the LCVD of SEQ ID NO: 235.

[0076] In some embodiments, the ABPC is degraded in the target mammalian cells after being internalized. In some embodiments, the ABPC comprises a conjugated toxin, a radioisotope, a drug, or a small molecule.

[0077] In some embodiments, the composition comprising the ABPC provides an increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 20% or 50% increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 2-fold or 5-fold increase in toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0078] In some embodiments, the composition comprising the ABPC provides an increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 20% or 50% increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 2-fold or 5-fold increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0079] In some embodiments, the composition including the ABPC provides an increase in lysosomal delivery in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the ABPC provides at least a 20% increase in lysosomal delivery in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 50% increase in lysosomal delivery in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 2-fold increase in lysosomal delivery in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 5-fold increase in lysosomal delivery in the target mammalian cells compared to a composition including the same amount of control ABPC.

[0080] In some embodiments, compositions comprising the ABPC result in a smaller reduction in the level of TROP2 presented on the surface of the target mammalian cells compared to compositions comprising the same amount of control ABPC. In some embodiments, compositions comprising the ABPC do not cause a detectable reduction in the level of TROP2 presented on the surface of the target mammalian cells.

[0081] This article also provides antigen-binding protein constructs (ABPCs) comprising: a first ABD capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of target mammalian cells; and a conjugated toxin, radioisotope, drug, or small molecule, wherein: (a) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a faster rate than at a pH of about 7.0 to about 8.0; or the first ABD has a dissociation constant (K0) at a pH of about 4.0 to about 6.5. D () is greater than K at a pH of about 7.0 to about 8.0 D (b) The composition provides one or more of the following: increased toxin release in the target mammalian cells compared to a composition comprising the same amount of control ABPC; increased killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC; and increased lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0082] In some embodiments, the first ABD comprises one of (a) to (d): (a) HCVD of goxatozumab; (b) HCVD of dabrabutazine; (c) HCVD of hu7E6SVG; and (d) HCVD of A1,2X4, wherein each or any one of them has one or more amino acids substituted with histidine. In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) LCVD of goxatozumab; (b) LCVD of dabrabutazine; (c) LCVD of hu7E6SVG; and (d) LCVD of A1,2X4, wherein each or any one of them has one or more amino acids substituted with histidine. In some embodiments, the first ABD includes one of (a) to (d): (a) HCVD and LCVD of goxatuzumab; (b) HCVD and LCVD of dabrechtinger; (c) HCVD and LCVD of hu7E6SVG; and (d) HCVD and LCVD of A1,2X4, wherein each or any of the domains has one or more amino acids substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0083] In some embodiments, the HCVD includes one of (a) to (d): (a) an HCVD of goxatozumab, the HCVD including SEQ ID NO: 4; (b) an HCVD of dapoxetine, the HCVD including SEQ ID NO: 80; (c) an HCVD of hu7E6SVG, the HCVD including SEQ ID NO: 156; and (d) an HCVD of A1,2X4, the HCVD including SEQ ID NO: 234. In some embodiments, the LCVD comprises one of (a) to (d): (a) an LCVD of goxatozumab comprising SEQ ID NO: 5; (b) an LCVD of dabrechtinger comprising SEQ ID NO: 81; (c) an LCVD of hu7E6SVG comprising SEQ ID NO: 157; and (d) an LCVD of A1,2X4 comprising SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0084] In some embodiments, the first ABD comprises HCVD, the HCVD being one of (a) to (d): (a) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; (b) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; (c) HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 158, 159, and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159, and 160 are collectively substituted with histidine; and (d) HCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 236, 237, and 238, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0085] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 are collectively substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 161, 162, and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162, and 163 are collectively substituted with histidine; and (d) an LCVD comprising SEQ ID NO: CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in total are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0086] In some embodiments, the first ABD comprises one of (a) to (d): (a) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine; (b) HCVD, wherein the HCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 ... (c) HCVD, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 158, 159 and 160, wherein one or more amino acid positions in SEQ ID NO: 158, 159 and 160 are collectively substituted with histidine; and / or LCVD, wherein the LCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 161, 162 and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162 and 163 are collectively substituted with histidine; and (d) HCVD, wherein the HCVD comprises CDR1, CDR2 and CDR3 of SEQ ID NO: 236, 237 and 238, wherein the SEQ ID NO: One or more amino acid positions in 236, 237, and 238 are collectively substituted with histidine; and / or LCVD, said LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in SEQ ID NO: 239, 240, and 241 are collectively substituted with histidine. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0087] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (d) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; (e ...e SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD of SEQ ID NO: 234, wherein the HCVD comprises histidine at one or more positions of SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0088] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is identical to SEQ ID NO: 5: SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0089] In some embodiments, the first ABD comprises HCVD, said HCVD being one of (a) to (d): (a) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; (b) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein said HCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 4; (c) an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4; SEQ ID NO: 156 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD in SEQ ID NO: 156 comprises histidine at two or more positions selected from the following: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and (d) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 234, wherein the HCVD comprises histidine at two or more positions in SEQ ID NO: 234. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0090] In some embodiments, the first ABD comprises an LCVD that is itself one of (a) to (d): (a) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) an LCVD that is identical to SEQ ID NO: 5: SEQ ID NO: 157 is at least 90%, 95%, or 98% identical to the LCVD, wherein the LCVD comprises histidine at two or more positions selected from the following in SEQ ID NO: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to the LCVD of SEQ ID NO: 235, wherein the LCVD comprises histidine at two or more positions in SEQ ID NO: 235. In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0091] In some embodiments, the first ABD comprises one of (a) to (d): (a) at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; and / or at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97; (b) identical to SEQ ID NO: 80 is at least 90%, 95%, or 98% identical to HCVD, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; and / or is at least 90%, 95%, or 98% identical to LCVD in SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95; (c) is at least 90%, 95%, or 98% identical to HCVD in SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: The LCVD in SEQ ID NO: 156 comprises histidine at one or more of the following positions: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 157, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 234, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more of the following positions: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the HCVD in SEQ ID NO: 234 comprises histidine at one or more of the following positions; and / or is at least 90%, 95%, or 98% identical to SEQ ID NO: 235, wherein the LCVD in SEQ ID NO: 235 comprises histidine at one or more of the NO: 235 contains histidine at one or more positions.In each of the foregoing embodiments, alanine may be substituted where histidine is already present.

[0092] In some embodiments, the first ABD includes one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350; (b) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; (c) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: 427-457; and (d) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 234 or SEQ ID NO: 242-280. In some embodiments, the first ABD includes one of (a) to (d): (a) an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79 or SEQ ID NO: 351-396; (b) an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155 or SEQ ID NO: 407-426; (c) an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233 or SEQ ID NO: 458-492; and (d) an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 235 or SEQ ID NO: 281-312.

[0093] In some embodiments, the first ABD includes one of (a) to (d): (a) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350, and / or an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 4 and the LCVD of SEQ ID NO: 5; (ii) an HCVD that is itself SEQ ID NO: 4 and is not SEQ ID NO: LCVD of one of 57, 58, 59, 61, 62, 64, 65, 66, 67, 71, 74, 75, 76, 77, 78, 79, 351, 352, 353, 354, 355, 359, 360, 361, 362, 365, 366, 367, 368, 370, 371, 372, 373, 376, 377, 383, 386, 387, 388, 389, 392, 393, 394, 395, and 396; or (iii) is itself not SEQ ID NO: The HCVD of 15, 18, 19, 22, 24, 25, 32, 33, 34, 35, 36, 37, 38, 41, 43, 46, 47, 50, 318, 320, 322, 323, 324, 325, 328, 332, 333, 334, 336, 337, 343, 344, 345, 347, and 348 and the LCVD of SEQ ID NO: 5; (b) the HCVD of a sequence that is itself one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406; and / or the HCVD of a sequence that is itself one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: The LCVD of one of the sequences shown in 407-426, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 80 and the LCVD of SEQ ID NO: 81;(ii) An HCVD that is itself SEQ ID NO: 80 and an LCVD that is not one of SEQ ID NO: 131, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 147, 151, 152, 153, 411, 412, 417, 418, and 423; or (iii) An HCVD that is not one of SEQ ID NO: 91, 101, 103, 112, 113, 116, 119, 122, 123, 125, and 126 and an LCVD that is SEQ ID NO: 81; (c) A sequence that is itself one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: The first ABD includes (i) the HCVD of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492, wherein the first ABD does not include (i) the HCVD of SEQ ID NO: 156 and the LCVD of SEQ ID NO: 157; (ii) the HCVD that is itself SEQ ID NO: 156 and is not SEQ ID NO: LCVD of one of the sequences shown in 204, 211, 213, 215, 218, 220, 221, 222, 223, 224, 225, 228, 229, 231, 232, 233, 459, 460, 462, 464, 465, 466, 467, 468, 469, 470, 473, 474, 485, 488, 489, and 491; or (iii) is itself not SEQ ID NO: The HCVD of one sequence and the LCVD of SEQ ID NO: 157 of the sequences shown in SEQ ID NO: 164, 167, 168, 171, 172, 175, 178, 180, 181, 183, 196, 197, 200, 201, 427, 428, 429, 430, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 447, 449, 451, 454, 456, and 457; and (d) the HCVD of one sequence which is itself SEQ ID NO: 234 or SEQ ID NO: 242-280; and / or the HCVD of one sequence which is itself SEQ ID NO: 235 or SEQ ID NO: 242-280. The LCVD of one sequence shown in sequences 281-312, wherein the first ABD does not include the HCVD of SEQ ID NO: 234.

[0094] In some embodiments, the composition including the ABPC provides an increase in toxin release in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 20% increase in toxin release in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 50% increase in toxin release in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 2-fold increase in toxin release in the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, the composition including the ABPC provides at least a 5-fold increase in toxin release in the target mammalian cells compared to a composition including the same amount of control ABPC.

[0095] In some embodiments, the composition comprising the ABPC provides an increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 20% or 50% increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 2-fold or 5-fold increase in the killing of the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0096] In some embodiments, the composition comprising the ABPC provides an increase in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 20% or 50% increase in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising the ABPC provides at least a 2-fold or 5-fold increase in lysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0097] In some embodiments, a composition including the ABPC results in a less reduction in the level of TROP2 presented on the surface of the target mammalian cells compared to a composition including the same amount of control ABPC. In some embodiments, a composition including the ABPC does not cause a detectable reduction in the level of TROP2 presented on the surface of the target mammalian cells. In some embodiments, the target mammalian cells are cancer cells.

[0098] In some embodiments, the dissociation rate of the ABD at a pH of about 4.0 to about 6.5 is at least 10% faster than the dissociation rate of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the dissociation rate of the ABD at a pH of about 4.0 to about 6.5 is at least 3 times faster than the dissociation rate of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the dissociation rate of the ABD at a pH of about 4.0 to about 6.5 is at least 10 times faster than the dissociation rate of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the K of the ABD at a pH of about 4.0 to about 6.5 is... D Compared to the ABD at a pH of about 7.0 to about 8.0, K D At least 10%. In some embodiments, the K of the ABD at a pH of about 4.0 to about 6.5 is... D The K of the ABD at a pH of about 7.0 to about 8.0 D At least 3 times. In some embodiments, the ABD is K at a pH of about 4.0 to about 6.5. D The K of the ABD at a pH of about 7.0 to about 8.0 D At least 10 times.

[0099] In some embodiments, the ABPC has cytotoxicity or cytoinhibitory effects on the target mammalian cells.

[0100] In some embodiments, the ABPC exhibits cross-reactivity with non-human primate TROP2 and human TROP2. In some embodiments, the ABPC exhibits cross-reactivity with one or both of non-human primate TROP2, human TROP2, rat TROP2, and mouse TROP2. In some embodiments, the ABPC exhibits cross-reactivity with non-human primate TROP2, human TROP2, rat TROP2, and mouse TROP2. In some embodiments, the ABD binds to an epitope of TROP2 present on the surface of cells from Old World monkeys.

[0101] In some embodiments, the ABPC comprises a single polypeptide. In some embodiments, the ABD is selected from the VH domain, VHH domain, VNAR domain, and scFv. In some embodiments, the ABPC is BiTe, (scFv)2, nanobody, nanobody-HSA, DART, TandAb, sc bifunctional antibody, sc bifunctional antibody-CH3, scFv-CH-CL-scFv, HSAbody, sc bifunctional antibody-HSA, or tandem scFv.

[0102] In some embodiments, the ABPC comprises two or more polypeptides. In some embodiments, the ABPC is selected from the group consisting of: antibody, VHH-scAb, VHH-Fab, dual scFab, F(ab')2, bifunctional antibody, crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, common light chain of mortar and pestle, mortar and pestle assembly, charge pair, Fab arm exchange, SEEDbody, LUZ-Y, Fcab, κλ body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Bifunctional Antibody-CH3, Trifunctional Antibody, Microbody, Microbody, TriBi Microbody, scFv-CH3 KIH, Fab-scFv, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, Quadrivalent HCAb, sc Bifunctional Antibody-Fc, Bifunctional Antibody-Fc, Tandem scFv-Fc, VHH-Fc, Tandem VHH-Fc, VHH-Fc KiH, Fab-VHH-Fc, Intracellular Antibody, Docking Locking Antibody, ImmTAC, IgG-IgG Conjugate, Cov-X-Body, scFv1-PEG-scFv2, Adnectin, DARPin, Fibronectin, DEP Conjugate, PROTAB and PROTAC.

[0103] In some embodiments, at least one polypeptide of the ABPC is conjugated to the toxin, the radioisotope, the drug, or the small molecule via a cleavable linker. In some embodiments, at least one polypeptide of the ABPC is conjugated to the toxin, the radioisotope, the drug, or the small molecule via an uncleavable linker.

[0104] In some embodiments, the in vivo half-life of the ABPC is reduced compared to that of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is reduced by about 5% to 95% compared to that of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is reduced by about 10% to 95% compared to that of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is reduced by about 30% to 95% compared to that of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is reduced by about 50% to 95% compared to that of a control ABPC. In some embodiments, the in vivo half-life of the ABPC is reduced by about 70% to 95% compared to that of a control ABPC.

[0105] In some embodiments, the control ABPC is capable of specifically binding to TROP2 or a TROP2 epitope presented on the surface of target mammalian cells, wherein: (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5 is no more than 3 times the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K0) of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5. D () is K at a pH of approximately 7.0 to approximately 8.0 D No more than 3 times.

[0106] In some embodiments, the control ABPC is capable of specifically binding to TROP2 or a TROP2 epitope presented on the surface of target mammalian cells, wherein: (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5 is no more than twice the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K0) of the first ABD of the ABPC at a pH of about 4.0 to about 6.5. D () is K at a pH of approximately 7.0 to approximately 8.0 D The amount shall not exceed twice the standard rate.

[0107] In some embodiments, the control ABPC is capable of specifically binding to TROP2 or a TROP2 epitope presented on the surface of target mammalian cells, wherein: (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5 is no more than 1 times the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K0) of the first ABD of the control ABPC at a pH of about 4.0 to about 6.5.D () is K at a pH of approximately 7.0 to approximately 8.0 D The amount shall not exceed 1 time.

[0108] In some embodiments, the control ABPC is goxatozumab, dabbittumab, hu7E6SVG, or A1,2X4.

[0109] In some embodiments, the ABPC includes a second ABD.

[0110] This document also provides a kit comprising at least one dose of any ABPC described herein.

[0111] This article also provides a method for treating cancer characterized by having a population of cancer cells having TROP2 or an epitope of TROP2 presented on the surface of the cancer cells, the method comprising: administering to a subject identified as having cancer a therapeutically effective amount of any of the pharmaceutical compositions described herein or any of the ABPCs described herein, the cancer characterized by having a population of said cancer cells.

[0112] This article also provides a method for reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells having TROP2 or an epitope of TROP2 presented on the surface of the cancer cells, the method comprising: administering to a subject identified as having cancer a therapeutically effective amount of any of the pharmaceutical compositions described herein or any of the ABPCs described herein, wherein the cancer is characterized by having a population of said cancer cells.

[0113] This article also provides a method for inducing cell death in cancer cells of a subject, wherein the cancer cells have TROP2 or TROP2 epitopes presented on the surface of the cancer cells, wherein the method comprises: administering to a subject identified as having cancer a therapeutically effective amount of any of the pharmaceutical compositions described herein, any of the ABPCs described herein, wherein the cancer is characterized by having a population of said cancer cells.

[0114] In some embodiments, the cancer is a primary tumor. In some embodiments, the cancer is metastatic.

[0115] In some embodiments, the cancer is a non-T-cell invasive tumor. In some embodiments, the cancer is a T-cell invasive tumor.

[0116] This article also provides methods for reducing the risk of metastasis or further metastasis in subjects with cancer, wherein the cancer is characterized by a population of cancer cells having TROP2 or an epitope of TROP2 presented on the surface of the cancer cells, the methods comprising administering to a subject identified as having cancer a therapeutically effective amount of any of the pharmaceutical compositions described herein or any of the ABPCs described herein, wherein the cancer is characterized by a population of said cancer cells.

[0117] In some embodiments, the cancer is a non-T-cell invasive tumor. In some embodiments, the cancer is a T-cell invasive tumor.

[0118] As used herein, the term "antigen-binding protein construct" means: (i) a single polypeptide comprising at least one ABD; or (ii) a complex of two or more polypeptides (e.g., the same polypeptide or different polypeptides) together forming at least one ABD. Non-limiting examples and aspects of antigen-binding protein constructs are described herein. Further examples and aspects of antigen-binding protein constructs are known in the art.

[0119] A “multispecific ABPC” is an ABPC comprising two or more different ABDs that specifically bind to two or more different epitopes. The two or more different epitopes can be epitopes on the same antigen (e.g., a single polypeptide present on a cell surface) or on different antigens (e.g., different proteins present on the same cell surface or on different cell surfaces). In some aspects, the antigen is present on a cell surface. In some aspects, a multispecific ABPC binds to two different epitopes (i.e., a “bispecific ABPC”). In some aspects, a multispecific ABPC binds to three different epitopes (i.e., a “trispecific ABPC”). In some aspects, a multispecific ABPC binds to four different epitopes (i.e., a “tetraspecific ABPC”). In some aspects, a multispecific ABPC binds to five different epitopes (i.e., a “pentaspecific ABPC”). Each binding specificity can exist at any suitable valence. Non-limiting examples of multispecific ABPCs are described herein.

[0120] An "antigen-binding protein" or "ABD" is one or more protein domains (e.g., formed from amino acids from a single polypeptide or from amino acids from two or more polypeptides, e.g., the same or different polypeptides) capable of specifically binding to one or more different antigens. In some instances, an ABD may bind to an antigen or epitope with similar specificity and affinity to naturally occurring antibodies. In some embodiments, an ABD may be an antibody or a fragment thereof. In some embodiments, an ABD may include an alternative scaffold. Non-limiting examples of ABDs are described herein. Further examples of ABDs are known in the art. In some instances, an ABD may bind to a single antigen.

[0121] The term "antibody" is used herein in the broadest sense and includes certain types of immunoglobulin molecules, including one or more ABDs that specifically bind to an antigen or epitope. Antibodies specifically include, for example, intact antibodies (e.g., intact immunoglobulins, such as human IgG (e.g., human IgG1, human IgG2, human IgG3, human IgG4)), antibody fragments, and multispecific antibodies. One example of an ABD is an ABD formed from a VH-VL dimer. Further examples of antibodies are described herein. Further examples of antibodies are known in the art.

[0122] The phrase “endosome / lysosome pathway” refers to the network of endosomes (early endosomes, multivesicular bodies, late endosomes and lysosomes) in the cytoplasm of mammalian cells, in which molecules are sorted through cell-mediated internalization processes (e.g., pinocytosis, micropinocytosis, receptor-mediated endocytosis and / or phagocytosis).

[0123] Once purified or isolated, endosomes in the endosome / lysosome pathway can be used to determine the target protein (e.g., the antigen-binding protein construct described herein) using methods known in the art (ELISA, Western blot, immunofluorescence, and immunoprecipitation followed by protein concentration determination), and can be used to determine the concentration or relative level of the target protein in the endosome. Alternatively, immunofluorescence microscopy can be used with detectable labeled antibodies (e.g., fluorophore-labeled antibodies, dye-labeled antibodies, or GFP-labeled antibodies, such as CellLight) that specifically bind to characteristic proteins present in the endosome (e.g., EEA1 of early nucleosomal endosomes). TM Endosomes in the endosome / lysosome pathway can be imaged using early endosome-GFP and antibodies labeled with fluorophores that specifically bind to target proteins (e.g., ABPC), and the level of target proteins in endosomes can be determined by quantifying the overlap in the fluorescence emission of two different antibodies.

[0124] The phrase “endolysosomal delivery” refers to the cumulative rate of ABPCs (e.g., any ABPCs described herein) in the endosome / lysosomal pathway of mammalian cells (e.g., any exemplary target mammalian cells described herein) over time or the total cumulative rate at a specific time point.

[0125] An exemplary method for calculating the increase in lysosomal delivery of a pH-engineered ABPC variant compared to its corresponding starting ABPC from cellular fluorescence data is to measure the average fluorescence intensity of the variant minus the average fluorescence intensity of the non-binding IgG control, and then divide the result by the ratio of the average fluorescence intensity of the variant's corresponding starting ABPC minus the average fluorescence intensity of the IgG control.

[0126] Exemplary assays for measuring the endolysosomal delivery of any ABPC described herein include those involving labeling the ABPC with a fluorescent dye, then incubating the labeled ABPC with cells and measuring cellular fluorescence as an indicator of ABPC endolysosomal delivery (e.g., broadly described in Wustner, *Traffic* 7(6):699-715, 2006). Alternatively, pH-sensitive dyes that preferentially fluoresce at acidic pH rather than neutral pH may be used to label any ABPC described herein, and the ABPC may then be incubated with cells and cellular fluorescence measured as an indicator of ABPC delivery into acidic endolysosomal compartments.

[0127] When the term "cluster" is used before a noun, it refers to two or more specific nouns. For example, the phrase "cluster of cancer cells" means "two or more cancer cells." Non-limiting examples of cancer cells are described in this article.

[0128] The phrase "cell-inhibiting" refers to a direct or indirect reduction of the proliferation (cell division) of cells (e.g., cancer cells) in vivo or in vitro. When an agent is cell-inhibiting, it can, for example, directly or indirectly cause cell cycle arrest in cells (e.g., cancer cells). In some instances, a cell-inhibiting agent can reduce the number of cells in the S phase in a cell population (compared to the number of cells in the S phase in the cell population before contact with the agent). In some instances, a cell-inhibiting agent can reduce the percentage of cells in the S phase by at least 20%, at least 40%, at least 60%, or at least 80% (e.g., compared to the percentage of cells in the S phase in the cell population before contact with the agent).

[0129] The phrase “cytotoxic to cells” refers to the direct or indirect induction of cell death (e.g., necrosis or apoptosis) in cells (e.g., mammalian cells, such as cancer cells).

[0130] “Affinity” refers to the strength of the sum of non-covalent interactions between an antigen-binding site and its binding partner (e.g., an antigen or epitope). Unless otherwise stated, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between an ABD and a member of an antigen or epitope. The affinity of molecule X for its partner Y can be expressed using the dissociation equilibrium constant (K0). D Affinity can be measured by common methods known in the art, including those described herein. Affinity can be measured, for example, using surface plasmon resonance (SPR) techniques (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO). ® To determine affinity for ABD and its corresponding antigens or epitopes, other methods are known in the art.

[0131] The term "epitope" refers to a portion of an antigen specifically bound by an ABD through a set of physical interactions between: (i) all monomers (e.g., individual amino acid residues, sugar side chains, and post-translational modified amino acid residues) on the portion of the antigen specifically bound by the ABD, and (ii) all monomers (e.g., individual amino acid residues, sugar side chains, and post-translational modified amino acid residues) on the portion of the antigen specifically bound by the ABD. An epitope may consist, for example, of surface-accessible amino acid residues, sugar side chains, phosphorylated amino acid residues, methylated amino acid residues, and / or acetylated amino acid residues, and may have specific three-dimensional structural features and specific charge features. The distinction between conformational and non-conformational epitopes lies in their binding to the former, not the latter, and they may be lost in the presence of denaturing solvents. In some embodiments, an epitope is defined by a linear amino acid sequence of at least about 3 to 6 amino acids or about 10 to 15 amino acids. In some embodiments, an epitope refers to a portion or a part of a full-length protein defined by a three-dimensional structure (e.g., protein folding). In some embodiments, an epitope is defined by a discontinuous amino acid sequence aggregated via protein folding. In some embodiments, epitopes are defined by discontinuous amino acid sequences aggregated by quaternary structures (e.g., gaps formed by the interaction of two distinct polypeptide chains). The amino acid sequence between the residues defining the epitope may not be critical to the three-dimensional structure of the epitope. Conformational epitopes can be identified and screened using assays that compare the binding of antigen-binding protein constructs to denatured forms of antigens in order to generate linear epitopes. Epitopes may include binding to directly involved amino acid residues and binding to other amino acid residues not directly involved.

[0132] Methods for identifying epitopes that specifically bind to ABD are known in the art, such as structure-based analyses (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g., based on antigens and / or antigen-ABD complexes) and / or mutagenesis-based analyses (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis), wherein the binding assay measures mutants using binding couplers, many of which are known in the art.

[0133] The term "complementary site" refers to a portion of an ABD that specifically binds to an antigen through a set of physical interactions between: (i) all monomers (e.g., individual amino acid residues, sugar side chains, post-translational modified amino acid residues) on the portion of the ABD that specifically binds to the antigen, and (ii) all monomers (e.g., individual amino acid residues, sugar side chains, post-translational modified amino acid residues) on the portion of the antigen that is specifically bound by the ABD. A complementary site may consist, for example, of surface-accessible amino acid residues and may have specific three-dimensional structural features and specific charge features. In some embodiments, a complementary site refers to a portion or a part of a full-length ABD defined by a three-dimensional structure (e.g., protein folding). In some embodiments, a complementary site is defined by a discontinuous amino acid sequence aggregated together via protein folding. In some embodiments, an epitope is defined by a discontinuous amino acid sequence aggregated together by a quaternary structure (e.g., a gap formed by the interaction of two different polypeptide chains). The amino acid sequence between the residues defining the complementary site may not be critical to the three-dimensional structure of the complementary site. A complementary site may comprise both directly involved amino acid residues and other directly uninvolved amino acid residues.

[0134] Methods for identifying complementary sites that specifically bind to ABD are known in the art, such as structure-based analyses (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g., based on ABD and / or ABD-antigen complexes) and / or mutagenesis-based analyses (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis), wherein the binding assay measures the mutant with the binding partner, many of which are known in the art.

[0135] The phrase “present on the surface of mammalian cells” means (1) an antigen that is physically attached to or at least partially embedded in the plasma membrane of a mammalian cell (e.g., a transmembrane protein, a peripheral membrane protein, a lipid-anchored protein (e.g., a GPI-anchor), an N-myristate-modified protein, or an S-palmitoylated protein) or (2) an antigen that is stably bound to its homologous receptor, wherein the homologous receptor is physically attached to the plasma membrane of the cell (e.g., a ligand that binds to its homologous receptor, wherein the homologous receptor is physically attached to the plasma membrane). Non-limiting methods for determining the presence of antigens on the surface of mammalian cells include fluorescence activated cell sorting (FACS), immunohistochemistry, cell grading assays, and Western blotting.

[0136] The phrase “control ABPC” or “control antigen-binding protein construct” means (i) an ABPC capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of mammalian cells (e.g., target mammalian cells), wherein one or both of the following are true: (a) the dissociation rate of the first ABD at a pH of about 4.0 to about 6.5 (e.g., any subrange of this range described herein) is no more than 3 times (e.g., no more than) the dissociation rate at a pH of about 7.0 to about 8.0 (e.g., any subrange of this range described herein). (a) More than 2.8 times, not more than 2.6 times, not more than 2.5 times, not more than 2.4 times, not more than 2.2 times, not more than 2.0 times, not more than 1.8 times, not more than 1.6 times, not more than 1.5 times, not more than 1.4 times, not more than 1.2 times, not more than 1.0 times, not more than 0.8 times, not more than 0.6 times, not more than 0.5 times, not more than 0.4 times, not more than 0.3 times, not more than 0.2 times, or not more than 0.1 times; or (b) the dissociation constant (Ki) of the first ABD at pH from about 4.0 to about 6.5 (e.g., any subrange of this range described herein). D K is the pH at a range of about 7.0 to about 8.0 (e.g., any subrange within this range described herein). D (i) not exceeding 3 times (e.g., not exceeding 2.8 times, not exceeding 2.6 times, not exceeding 2.5 times, not exceeding 2.4 times, not exceeding 2.2 times, not exceeding 2.0 times, not exceeding 1.8 times, not exceeding 1.6 times, not exceeding 1.5 times, not exceeding 1.4 times, not exceeding 1.2 times, not exceeding 1.0 times, not exceeding 0.8 times, not exceeding 0.6 times, not exceeding 0.5 times, not exceeding 0.4 times, not exceeding 0.3 times, not exceeding 0.2 times or not exceeding 0.1 times); (ii) goxatozumab; (iii) dedabrotuzumab; (iv) hu7E6SVG; and / or (v) A1,2X4.

[0137] The term "extracellular space" refers to the fluid outside the plasma membrane of mammalian cells. When mammalian cells are in vitro, the extracellular space can be a liquid culture medium. When mammalian cells are in vivo, the extracellular space can be, for example, plasma, serum, blood, interstitial fluid, or lymph.

[0138] The term "endolysosomal space" refers to the fluid encapsulated by vesicles and organelles that constitute the endosome / lysosomal pathway in mammalian cells.

[0139] The phrase “a reduced level” or “a decreased level” can mean a reduction or decrease of at least 1% compared to a reference level or value (e.g., at least 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 99%).

[0140] The term "cytotoxic efficacy" refers to the ability of an agent (e.g., any ABPC described herein) to directly or indirectly induce apoptosis and / or necrosis in mammalian cells (e.g., cancer cells) at a rate measured over time or at relevant time points. Methods for determining cytotoxic efficacy of cells are known in the art (e.g., trypan blue staining, microscopy, fluorescence-assisted cell sorting, and assays for detecting apoptotic markers (e.g., annexin V)). In non-limiting examples, cytotoxic efficacy can be measured, for example, by cell killing at a single concentration of the agent, by the IC50 of the agent (i.e., the concentration at which half of the maximum cytotoxic efficacy is achieved), or by the ratio of the agent's dissociation constant KD on mammalian cells to its IC50. In some non-limiting examples, the IC50 and / or KD ratios described herein are compared to the ratios of control ABPCs (as defined herein), and optionally, it is demonstrated that the ABPCs described herein possess higher cytotoxic efficacy compared to control ABPCs.

[0141] The term "toxin release" refers to the ability of mammalian cells (e.g., non-cancer mammalian cells or cancer cells) (measured over time or at a specific time point) to internalize (e.g., via pinocytosis and / or receptor-mediated endocytosis) any ABPC conjugated herein (e.g., any ABPC described herein or a control ABPC) and subsequently release the ABPC-conjugated toxin. Toxin release can be assessed using a variety of different exemplary assays, such as ELISA, immunofluorescence, cell killing assays, cell cycle arrest assays, DNA damage assays, mass spectrometry, HPLC, and / or isotope-labeled toxins.

[0142] The phrase "target cell" or "target mammalian cell" or "mammalian target cell" means a mammalian cell having at least one TROP2 present on its surface. In some instances, mammalian target cells can be cancer cells. In some embodiments of target mammalian cells, the total number of TROP2 present on the plasma membrane of the target mammal may be approximately the following (each ± ​​about 10%): 1-10E6, 1-9E6, 1-8E6, 1-7E6, 1-6E6, 1-5E6, 1-4E6, 1-3E6, 1-2E6, 1-1E6, 1-800,000, 1-600,000, 1-400,000, 1-200,000, 1-100,000, 1-80,000, 1-80,000, 1-75,000 1-70,000, 1-65,000, 1-60,000, 1-55,000, 1-50,000, 1-45,000, 1-40,000, 1-35,000, 1-30,000, 1-25,000, 1-20,000, 1-15,000, 1-10,000, 1-7,500, 1-5,000, 1-4,000, 1-3,000, 1-2,000, 1-1,000, 1-50, 1-10, or any of the ranges of numbers listed in paragraph

[0065] of US 2022 / 0281984.

[0143] The phrase “antigen density” refers to the amount of TROP2 present on the surface of target mammalian cells or the average amount of TROP2 on the surface of a population of a specific type of target mammalian cells. “Antigen density” can be measured using, for example, the Quantibright Bead Kit or radiolabeled (e.g., the BD Biosciences PE Phycoerythrin Quantitative Releasing Kit, catalog number 340495).

[0144] The phrase "amino acid replaced by histidine" means that an amino acid residue in the reference polypeptide sequence that is not histidine is replaced by histidine. This article describes a non-limiting method for replacing amino acid residues in a reference polypeptide with histidine. Other methods for replacing amino acid residues in a reference polypeptide with histidine are known in the art.

[0145] The phrase "amino acid replaced by alanine" means that an amino acid residue that is histidine in the reference polypeptide sequence is replaced by alanine. This document describes a non-limiting method for replacing histidine in a reference polypeptide with alanine. Other methods for replacing histidine in a reference polypeptide with alanine are known in the art.

[0146] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. This document describes the methods and materials used in this invention; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification (including definitions) shall prevail.

[0147] Other features and advantages of the invention will become apparent from the following detailed description, the accompanying drawings, and the claims. Attached Figure Description

[0148] Many aspects of this disclosure can be better understood with reference to the following figures. The components in the figures are not necessarily drawn to scale, but the emphasis is on clearly illustrating the principles of this disclosure.

[0149] Figure 1A-1B Octet plots of goxatozumab and its heavy chain (HC) and light chain (LC) variants (MYT11566-MYT11621) are presented. 1A: Y-axis is fixed; 1B: Y-axis is automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0150] Figure 2A-2B This plot presents octet graphs of goxatozumab and several variants of its LC variants (MYT11566, MYT11622-MYT11635), and dabotezumab and its HC variants (MYT11622-MYT11676). 2A: Y-axis is fixed; 2B: Y-axis is automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0151] Figures 3A-3B present octet plots of the additional HC and LC variants (MYT11635-MYT11755). 3A: X and Y axes are fixed; 3B: X and Y axes are automatically applied to maximize vertical spacing. The gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0152] Figures 4A-4B Octet plots are presented for the additional HC and LC variants (MYT12389-MYT12425). 4A: X and Y axes are fixed; 4B: X and Y axes are automatically applied to maximize vertical spacing. The gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0153] Figures 5A-5B Octet plots are presented for the additional HC and LC variants (MYT12405-MYT12473). 5A: X and Y axes are fixed; 5B: X and Y axes are automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0154] Figures 6A-6B Octet plots are presented for the additional HC and LC variants (MYT12385-MYT12409). 6A: X and Y axes are fixed; 6B: X and Y axes are automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0155] Figures 7A-7B present octet plots of the additional HC and LC variants (MYT12296-MYT12465). 7A: X and Y axes are fixed; 7B: X and Y axes are automatically applied to maximize vertical spacing. The gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0156] Figures 8A-8B Octet plots are presented for the additional HC and LC variants (MYT12294-MYT12456). 8A: X and Y axes are fixed; 8B: X and Y axes are automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0157] Figure 9 This is a graph showing the results of the internalization assay. The median fluorescence intensity (MFI) of the indicated IgG construct is shown.

[0158] Figure 10 This is a diagram showing the MFI of the indicated IgG construct.

[0159] Figure 11This is a graph showing the cytotoxicity of the indicated antibody against NCI-H1975 cells as a function of the fold (FoD) relative to dapoxetine.

[0160] Figure 12 This is a graph showing the depth of killing of NCI-H1975 cells by the indicated antibody as a function of FoD.

[0161] Figures 13A-13B Presents octet plots for variants MYT13160-MYT13203. 13A: X and Y axes are fixed; 13B: X and Y axes are automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0162] Figures 14A-14B present octet plots of variants MYT13204-MYT13257. 14A: X and Y axes are fixed; 14B: X and Y axes are automatically applied to maximize vertical spacing. The gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0163] Figures 15A-15B Presents octet plots for variants MYT13258-MYT13309. 15A: X and Y axes are fixed; 15B: X and Y axes are automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0164] Figures 16A-16B present octet plots of variants MYT13366-MYT13447. 16A: X and Y axes are fixed; 16B: X and Y axes are automatically applied to maximize vertical spacing. The gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0165] Figures 17A-17B Octet plots are presented for the connector-toxin conjugate variants 112-DXd, 165-DXd, 166-DXd, 167-DXd, 168-DXd, 169-DXd, 170-DXd, 171-DXd, and 172-DXd. 17A: X and Y axes are fixed; 17B: X and Y axes are automatically applied to maximize vertical spacing. Gray and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0166] Further advantages of this disclosure will be set forth in part in the description which follows, and will be apparent in part from the description, or may be learned by practice of this disclosure. The advantages of this disclosure will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only, and do not limit the claimed disclosure. Detailed Implementation

[0167] This document provides antigen-binding protein constructs (ABPCs) comprising: a first ABD capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of target mammalian cells, wherein: (a) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a faster rate than at a pH of about 7.0 to about 8.0; and / or (b) the first ABD has a greater dissociation constant (KD) at a pH of about 4.0 to about 6.5 than at a pH of about 7.0 to about 8.0. In some instances of these ABPCs, the ABPC is degraded in the target mammalian cells after internalization. Some instances of any ABPCs described herein may further include conjugated toxins, radioisotopes, drugs, or small molecules (e.g., fluorophores or dyes).

[0168] Also provided are antigen-binding protein constructs (ABPCs) comprising: a first ABD capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of target mammalian cells; and a conjugated toxin, radioisotope, drug, or small molecule, wherein: (a) the first ABD dissociates at a pH of about 4.0 to about 6.5 at a faster rate than at a pH of about 7.0 to about 8.0; and / or the first ABD has a dissociation constant (KD) at a pH of about 4.0 to about 6.5 that is faster than at a pH of about 7.0 to about 8.0. (b) The composition comprising the ABPC provides one or more (e.g., two or three) of the following: increased toxin release in the target mammalian cells (e.g., a detectable increase) compared to a composition containing the same amount of control ABPC; increased killing of target mammalian cells (e.g., a detectable increase) compared to a composition containing the same amount of control ABPC; and increased lysosomal delivery in the target mammalian cells (e.g., a detectable increase) compared to a composition containing the same amount of control ABPC.

[0169] In some instances, the first ABD includes the HCVD domain of goxatuzumab, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD includes the LCVD domain of goxatuzumab, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD includes the HCVD domain of goxatuzumab, wherein one or more amino acids are substituted with histidine; and the LCVD domain of goxatuzumab, wherein one or more amino acids are substituted with histidine. In some instances, the HCVD of goxatuzumab comprises SEQ ID NO: 4. In some instances, the LCVD of goxatuzumab comprises SEQ ID NO: 5. In each of the foregoing instances, alanine may be substituted where histidine is already present.

[0170] In some instances, the first ABD comprises HCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, respectively, wherein one or more amino acid positions in SEQ ID NO: 6, 7, and 8 are collectively substituted with histidine. In some instances, the first ABD comprises LCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, respectively, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine. In some instances, the first ABD includes: an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 6, 7, and 8, wherein one or more amino acid positions in NO: 6, 7, and 8 are collectively substituted with histidine; and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 9, 10, and 11, wherein one or more amino acid positions in SEQ ID NO: 9, 10, and 11 are collectively substituted with histidine. In each of the foregoing examples, alanine may be substituted at a location where histidine is already present.

[0171] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD in SEQ ID NO: 4 comprises histidine at one or more amino acid positions selected from the following: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD in SEQ ID NO: 5 comprises histidine at one or more amino acid positions selected from the following: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the HCVD identical to SEQ ID NO: 4, wherein the HCVD in SEQ ID NO: 4 comprises histidine at one or more amino acid positions selected from the following: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108; and at least 90%, 95%, or 98% of the LCVD identical to SEQ ID NO: 5, wherein the LCVD in SEQ ID NO: 5 comprises histidine at one or more amino acid positions selected from the following: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97.

[0172] In some instances, the first HCVD comprises at least 90%, 95%, or 98% the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0173] Table 1. Exemplary combinations of amino acid positions that can be substituted in SEQ ID NO: 4

[0174]

[0175] In some instances, the first ABD comprises at least 90%, 95%, or 98% the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 5 listed in Table 2, and / or wherein the LCVD comprises alanine at position 91 of SEQ ID NO: 5.

[0176] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5.

[0177] In some instances, the first ABD comprises: an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5; and an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108.

[0178] In some instances, the first ABD comprises at least 90%, 95%, or 98% the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5. In some instances, the first ABD comprises: an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5; and an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 4: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108.

[0179] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the LCVD identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more amino acid positions selected from the group consisting of: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96, and 97 in SEQ ID NO: 5, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the HCVD identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at position 91 in SEQ ID NO: 5. The HCVD in 4 comprises histidine at one or more of the following amino acid positions: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105 and 108, and / or wherein the HCVD comprises alanine at position 91.

[0180] Table 2. Exemplary combinations of amino acid positions in SEQ ID NO: 5 that can be substituted by histidine (or alanine (A) in the case of position 91).

[0181]

[0182] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 5 listed in Table 2.

[0183] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 5 listed in Table 2, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0184] In some instances, the first ABD comprises LCVD and HCVD, wherein the LCVD comprises SEQ ID NO: 5, and the HCVD is at least 90%, 95%, or 98% identical to SEQ ID NO: 4, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0185] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 28 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0186] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 29 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0187] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 30 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0188] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0189] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 31 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0190] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 32 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0191] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 33 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0192] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 50 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0193] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 51 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0194] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 52 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0195] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 53 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0196] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 89 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0197] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 92 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0198] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 93 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0199] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 94 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0200] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 95 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0201] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 96 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0202] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at position 97 in SEQ ID NO: 5; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 4 listed in Table 1.

[0203] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 4, wherein the HCVD comprises histidine at any of positions 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105, and 108 in SEQ ID NO: 4; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 5, wherein the LCVD comprises histidine at any specific combination of two or more amino acid positions listed in Table 2 in SEQ ID NO: 5.

[0204] In some instances, the first ABD comprises an HCVD of one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350; and / or the first ABD comprises an LCVD of one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396.

[0205] In some instances of ABPC, the first ABD includes LCVD and HCVD, wherein the LCVD comprises a sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396, and the HCVD comprises a sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0206] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 4, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0207] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 12, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0208] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 13, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0209] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 14, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0210] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 15, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0211] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 16, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0212] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 17, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0213] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 18, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0214] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 19, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0215] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 20, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0216] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 21, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0217] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 22, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0218] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 23, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0219] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 24, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0220] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 25, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0221] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 26, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0222] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 27, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0223] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 28, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0224] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 29, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0225] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 30, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0226] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 31, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0227] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 32, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0228] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 33, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0229] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 34, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0230] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 35, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0231] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 36, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0232] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 37, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0233] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 38, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0234] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 39, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0235] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 40, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0236] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 41, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0237] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 42, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0238] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 43, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0239] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 44, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0240] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 45, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0241] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 46, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0242] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 47, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0243] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 48, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0244] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 49, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0245] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 50, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0246] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 51, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0247] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 52, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0248] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 313, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0249] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 314, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0250] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 315, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0251] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 316, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0252] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 317, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0253] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 318, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0254] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 319, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0255] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 320, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0256] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 321, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0257] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 322, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0258] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 323, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0259] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 324, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0260] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 325, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0261] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 326, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0262] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 327, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0263] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 328, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0264] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 329, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0265] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 330, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0266] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 331, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0267] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 332, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0268] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 333, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0269] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 334, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0270] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 335, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0271] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 336, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0272] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 337, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0273] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 338, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0274] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 339, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0275] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 340, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0276] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 341, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0277] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 342, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0278] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 343, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0279] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 344, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0280] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 345, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0281] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 346, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0282] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 347, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0283] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 348, and the LCVD contains the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0284] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 349, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0285] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 350, and the LCVD comprises the sequence of SEQ ID NO: 5, one of the sequences shown in SEQ ID NO: 53-79, or one of the sequences shown in SEQ ID NO: 351-396.

[0286] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 5, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0287] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 53, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0288] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 54, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0289] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 55, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0290] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 56, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0291] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 57, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0292] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 58, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0293] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 59, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0294] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 60, and the LCVD comprises the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0295] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 61, and the LCVD comprises the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0296] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 62, and the LCVD comprises the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0297] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 63, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0298] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 64, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0299] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 65, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0300] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 66, and the LCVD comprises the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0301] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 67, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0302] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 68, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0303] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 69, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0304] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 70, and the LCVD comprises the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0305] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 71, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0306] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 72, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0307] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 73, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0308] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 74, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0309] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 75, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0310] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 76, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0311] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 77, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0312] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 78, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0313] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 79, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0314] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 351, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0315] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 352, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0316] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 353, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0317] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 354, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0318] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 355, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0319] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 356, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0320] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 357, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0321] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 358, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0322] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 359, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0323] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 360, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0324] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 361, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0325] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 362, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0326] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 363, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0327] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 364, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0328] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 365, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0329] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 366, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0330] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 367, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0331] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 368, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0332] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 369, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0333] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 370, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0334] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 371, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0335] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 372, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0336] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 373, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0337] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 374, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0338] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 375, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0339] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 376, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0340] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 377, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0341] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 378, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0342] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 379, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0343] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 380, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0344] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 381, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0345] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 382, ​​and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0346] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 383, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0347] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 384, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0348] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 385, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0349] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 386, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0350] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 387, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0351] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 388, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0352] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 389, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0353] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 390, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0354] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 391, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0355] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 392, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0356] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 393, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0357] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 394, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0358] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 395, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0359] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 396, and the LCVD contains the sequence of SEQ ID NO: 4, one of the sequences shown in SEQ ID NO: 12-52, or one of the sequences shown in SEQ ID NO: 313-350.

[0360] In some instances, the first ABD comprises the HCVD domain of dedabrotumab, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD comprises the LCVD domain of dedabrotumab, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD comprises the HCVD domain of dedabrotumab, wherein one or more amino acids are substituted with histidine; and the LCVD domain of dedabrotumab, wherein one or more amino acids are substituted with histidine. In some instances, the HCVD of dedabrotumab comprises SEQ ID NO: 80. In some instances, the LCVD of dedabrotumab comprises SEQ ID NO: 81. In each of the foregoing instances, alanine may be substituted where histidine is already present.

[0361] In some instances, the first ABD comprises HCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 82, 83, and 84, wherein one or more amino acid positions in SEQ ID NO: 82, 83, and 84 are collectively substituted with histidine. In some instances, the first ABD comprises LCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NO: 85, 86, and 87 are collectively substituted with histidine. In some instances, the first ABD includes: an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 82, 83, and 84, wherein one or more amino acid positions in NOs: 82, 83, and 84 are collectively substituted with histidine; and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 85, 86, and 87, wherein one or more amino acid positions in SEQ ID NOs: 85, 86, and 87 are collectively substituted with histidine. In each of the foregoing examples, alanine may be substituted at locations where histidine is already present.

[0362] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95.

[0363] In some instances, the first HCVD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in a particular combination of two or more amino acid positions listed in Table 3.

[0364] In some instances, the first ABD comprises at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises alanine at position 54 in SEQ ID NO: 80.

[0365] In some instances, the first ABD comprises: an HCVD that is at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) identical to SEQ ID NO: 80, wherein the HCVD comprises alanine at position 54 in SEQ ID NO: 80; and an LCVD that is at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95.

[0366] Table 3. Exemplary combinations of amino acid positions in SEQ ID NO: 80 that can be substituted by histidine (or alanine (A) in the case of position 54).

[0367]

[0368] In some instances, the first ABD comprises at least 90%, 95%, or 98% the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 81 listed in Table 4, and / or wherein the LCVD comprises alanine at position 91 of SEQ ID NO: 81.

[0369] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81.

[0370] In some instances, the first ABD comprises: at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108.

[0371] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81. In some instances, the first ABD comprises: an LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 81: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81; and an HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108.

[0372] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at one or more amino acid positions selected from the group consisting of: 26, 28, 29, 30, 31, 33, 34, 50, 51, 52, 53, 54, 89, 93, 94, and 95 in SEQ ID NO: 81, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at one or more amino acid positions selected from the group consisting of: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108 in SEQ ID NO: 80, and / or wherein the HCVD comprises alanine at position 54 in SEQ ID NO: 80.

[0373] Table 4. Exemplary combinations of amino acid positions that can be substituted in SEQ ID NO: 81

[0374]

[0375] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 81 listed in Table 4.

[0376] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 81 listed in Table 4, and / or wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0377] In some instances, the first ABD comprises LCVD and HCVD, wherein the LCVD comprises SEQ ID NO: 81, and the HCVD is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0378] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 26 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0379] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 28 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0380] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 29 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0381] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises alanine at position 91 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0382] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 30 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0383] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 31 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0384] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 33 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0385] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 34 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0386] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 50 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0387] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 51 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0388] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 52 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0389] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 53 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0390] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 54 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0391] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 89 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0392] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 93 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0393] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 94 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0394] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at position 95 in SEQ ID NO: 81; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 80 listed in Table 3.

[0395] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 80, wherein the HCVD comprises histidine at any of positions 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108 in SEQ ID NO: 80; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 81, wherein the LCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 81 listed in Table 4.

[0396] In some instances, the first ABD comprises an HCVD of one sequence of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, or SEQ ID NO: 397-406; and / or the first ABD comprises an LCVD of one sequence of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: 407-426.

[0397] In some instances of ABPC, the first ABD includes LCVD and HCVD, wherein the LCVD comprises one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: 407-426, and the HCVD comprises one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, or SEQ ID NO: 397-406.

[0398] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 80, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0399] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 88, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0400] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 89, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0401] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 90, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0402] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 91, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0403] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 92, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0404] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 93, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0405] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 94, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0406] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 95, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0407] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 96, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0408] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 97, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0409] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 98, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0410] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 99, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0411] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 100, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0412] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 101, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0413] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 102, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0414] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 103, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0415] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 104, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0416] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 105, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0417] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 106, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0418] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 107, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0419] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 108, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0420] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 109, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0421] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 110, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0422] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 111, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0423] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 112, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0424] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 113, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0425] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 114, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0426] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 115, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0427] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 116, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0428] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 117, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0429] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 118, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0430] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 119, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0431] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 120, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0432] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 121, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0433] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 122, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0434] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 123, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0435] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 124, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0436] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 125, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0437] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 126, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0438] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 127, and the LCVD contains the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0439] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 128, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0440] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 397, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0441] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 398, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0442] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 399, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0443] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 400, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0444] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 401, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0445] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 402, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0446] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 403, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0447] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 404, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0448] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 405, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0449] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 406, and the LCVD comprises the sequence of SEQ ID NO: 81, one of the sequences shown in SEQ ID NO: 129-155, or one of the sequences shown in SEQ ID NO: 407-426.

[0450] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 81, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0451] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 129, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0452] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 130, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0453] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 131, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0454] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 132, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0455] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 133, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0456] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 134, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0457] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 135, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0458] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 136, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0459] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 137, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0460] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 138, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0461] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 139, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0462] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 140, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0463] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 141, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0464] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 142, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0465] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 143, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0466] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 144, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0467] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 145, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0468] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 146, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0469] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 147, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0470] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 148, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0471] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 149, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0472] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 150, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0473] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 151, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0474] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 152, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0475] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 153, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0476] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 154, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0477] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 155, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0478] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 407, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0479] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 408, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0480] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 409, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0481] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 410, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0482] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 411, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0483] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 412, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0484] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 413, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0485] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 414, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0486] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 415, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0487] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 416, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0488] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 417, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0489] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 418, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0490] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 419, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0491] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 420, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0492] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 421, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0493] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 422, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0494] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 423, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0495] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 424, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0496] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 425, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0497] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 426, and the LCVD contains the sequence of SEQ ID NO: 80, one of the sequences shown in SEQ ID NO: 88-128, or one of the sequences shown in SEQ ID NO: 397-406.

[0498] In some instances, the first ABD includes the HCVD domain of hu7E6SVG, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD includes the LCVD domain of hu7E6SVG, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD includes the HCVD domain of hu7E6SVG, wherein one or more amino acids are substituted with histidine; and the LCVD domain of hu7E6SVG, wherein one or more amino acids are substituted with histidine. In some instances, the HCVD of hu7E6SVG comprises SEQ ID NO: 156. In some instances, the LCVD of hu7E6SVG comprises SEQ ID NO: 157. In each of the foregoing examples, alanine may be substituted where histidine is already present.

[0499] In some instances, the first ABD comprises HCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 158, 159, and 160, respectively, wherein one or more amino acid positions in SEQ ID NO: 158, 159, and 160 are collectively substituted with histidine. In some instances, the first ABD comprises LCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 161, 162, and 163, respectively, wherein one or more amino acid positions in SEQ ID NO: 161, 162, and 163 are collectively substituted with histidine. In some instances, the first ABD includes: an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 158, 159, and 160, wherein one or more amino acid positions in NO: 158, 159, and 160 are collectively substituted with histidine; and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 161, 162, and 163, wherein one or more amino acid positions in SEQ ID NO: 161, 162, and 163 are collectively substituted with histidine. In each of the foregoing examples, alanine may be substituted at locations where histidine is already present.

[0500] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD in SEQ ID NO: 156 comprises histidine at one or more amino acid positions selected from the following: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more amino acid positions selected from the following: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD in SEQ ID NO: 156 comprises histidine at one or more amino acid positions selected from the following: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD in SEQ ID NO: 157 comprises histidine at one or more amino acid positions selected from the following: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101.

[0501] Table 5. Exemplary combinations of amino acid positions that can be substituted in SEQ ID NO: 156

[0502]

[0503] In some instances, the first HCVD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0504] In some instances, the first LCVD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 157 listed in Table 6.

[0505] In some instances, the first ABD comprises at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises alanine at position 35 in SEQ ID NO: 156.

[0506] In some instances, the first ABD comprises: an HCVD that is at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) identical to SEQ ID NO: 156, wherein the HCVD comprises alanine at position 35 in SEQ ID NO: 156; and an LCVD that is at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) identical to SEQ ID NO: 157, wherein the LCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 157: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101.

[0507] In some instances, the first ABD comprises at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises alanine at position 38 in SEQ ID NO: 157.

[0508] In some instances, the first ABD comprises: at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) of the same LCVD as SEQ ID NO: 157, wherein the HCVD comprises alanine at position 38 in SEQ ID NO: 157; and at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 156: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106.

[0509] In some instances, the first ABD comprises at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises alanine at position 94 in SEQ ID NO: 157.

[0510] In some instances, the first ABD comprises: at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises alanine at position 94 in SEQ ID NO: 157; and at least 90% (e.g., at least 92%, 94%, 96%, 98%, at least 99%, or 100%) of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more amino acid positions selected from the following in SEQ ID NO: 156: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106.

[0511] Table 6. Exemplary combinations of amino acid positions that can be substituted in SEQ ID NO: 157

[0512]

[0513] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 157 listed in Table 6.

[0514] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 157 listed in Table 6, and / or wherein the LCVD comprises alanine at position 38 or 94 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any combination of specific combinations of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0515] In some instances, the first ABD comprises LCVD and HCVD, wherein the LCVD comprises SEQ ID NO: 157, and the HCVD is at least 90%, 95%, or 98% identical to SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0516] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 25 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0517] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 32 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0518] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 34 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0519] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises alanine at position 38 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0520] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises alanine at position 94 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0521] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 36 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0522] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 54 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0523] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 56 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0524] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 57 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0525] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 58 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0526] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 59 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0527] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 60 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0528] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 93 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0529] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 94 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0530] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 96 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0531] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 97 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0532] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 99 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0533] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 100 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any particular combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0534] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at position 101 in SEQ ID NO: 157; and at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 156 listed in Table 5.

[0535] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the same HCVD as SEQ ID NO: 156, wherein the HCVD comprises histidine at any of positions 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103, and 106 in SEQ ID NO: 156; and at least 90%, 95%, or 98% of the same LCVD as SEQ ID NO: 157, wherein the LCVD comprises histidine at any specific combination of two or more amino acid positions in SEQ ID NO: 157 listed in Table 6.

[0536] In some instances, the first ABD comprises an HCVD of one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: 427-457; and / or the first ABD comprises an LCVD of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492.

[0537] In some instances of ABPC, the first ABD includes LCVD and HCVD, wherein the LCVD comprises a sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492, and the HCVD comprises a sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0538] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 156, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0539] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 164, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0540] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 165, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0541] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 166, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0542] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 167, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0543] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 168, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0544] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 169, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0545] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 170, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0546] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 171, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0547] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 172, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0548] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 173, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0549] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 174, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0550] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 175, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0551] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 176, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0552] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 177, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0553] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 178, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0554] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 179, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0555] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 180, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0556] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 181, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0557] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 182, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0558] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 183, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0559] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 184, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0560] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 185, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0561] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 186, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0562] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 187, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0563] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 188, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0564] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 189, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0565] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 190, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0566] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 191, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0567] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 192, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0568] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 193, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0569] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 194, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0570] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 195, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0571] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 196, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0572] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 197, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0573] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 198, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0574] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 199, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0575] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 200, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0576] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 201, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0577] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 202, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0578] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 427, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0579] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 428, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0580] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 429, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0581] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 430, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0582] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 431, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0583] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 432, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0584] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 433, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0585] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 434, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0586] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 435, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0587] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 436, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0588] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 437, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0589] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 438, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0590] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 439, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0591] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 440, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0592] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 441, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0593] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 442, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0594] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 443, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0595] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 444, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0596] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 445, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0597] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 446, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0598] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 447, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0599] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 448, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0600] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 449, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0601] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD comprises the sequence of SEQ ID NO: 450, and the LCVD comprises the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0602] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 451, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0603] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 452, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0604] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 453, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0605] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 454, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0606] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 455, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0607] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 456, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0608] In some instances, the first ABD includes HCVD and LCVD, wherein the HCVD contains the sequence of SEQ ID NO: 457, and the LCVD contains the sequence of SEQ ID NO: 157, one of the sequences shown in SEQ ID NO: 203-233, or one of the sequences shown in SEQ ID NO: 458-492.

[0609] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 157, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0610] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 203, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0611] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 204, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0612] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 205, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0613] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 206, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0614] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 207, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0615] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 208, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0616] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 209, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0617] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 210, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0618] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 211, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0619] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 212, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0620] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 213, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0621] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 214, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0622] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 215, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0623] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 216, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0624] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 217, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0625] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 218, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0626] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 219, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0627] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 220, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0628] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 221, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0629] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 222, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0630] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 223, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0631] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 224, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0632] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 225, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0633] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 226, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0634] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 227, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0635] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 228, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0636] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 229, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0637] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 230, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0638] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 231, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0639] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 232, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0640] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 233, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0641] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 458, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0642] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 459, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0643] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 460, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0644] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 461, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0645] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 462, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0646] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 463, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0647] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 464, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0648] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 465, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0649] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 466, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0650] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 467, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0651] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 468, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0652] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 469, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0653] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 470, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0654] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 471, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0655] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 472, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0656] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 473, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0657] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 474, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0658] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 475, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0659] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 476, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0660] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 477, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0661] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 478, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0662] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 479, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0663] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 480, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0664] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 481, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0665] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 482, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0666] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 483, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0667] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 484, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0668] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 485, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0669] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 486, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0670] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 487, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0671] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 488, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0672] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 489, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0673] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 490, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0674] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 491, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0675] In some instances, the first ABD includes LCVD and HCVD, wherein the HCVD contains the sequence of SEQ ID NO: 492, and the LCVD contains the sequence of SEQ ID NO: 156, one of the sequences shown in SEQ ID NO: 164-202, or one of the sequences shown in SEQ ID NO: 427-457.

[0676] In some instances, the first ABD includes an A1,2X4 HCVD domain, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD includes an A1,2X4 LCVD domain, wherein one or more amino acids are substituted with histidine. In some instances, the first ABD includes an A1,2X4 HCVD domain, wherein one or more amino acids are substituted with histidine; and an A1,2X4 LCVD domain, wherein one or more amino acids are substituted with histidine. In some instances, the A1,2X4 HCVD comprises SEQ ID NO: 234. In some instances, the A1,2X4 LCVD comprises SEQ ID NO: 235. In each of the foregoing examples, alanine may be substituted where histidine is already present.

[0677] In some instances, the first ABD comprises HCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 236, 237, and 238, wherein one or more amino acid positions in SEQ ID NO: 236, 237, and 238 are collectively substituted with histidine. In some instances, the first ABD comprises LCVD, which comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in SEQ ID NO: 239, 240, and 241 are collectively substituted with histidine. In some instances, the first ABD includes: an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 236, 237, and 238, wherein one or more amino acid positions in NO: 236, 237, and 238 are collectively substituted with histidine; and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO: 239, 240, and 241, wherein one or more amino acid positions in SEQ ID NO: 239, 240, and 241 are collectively substituted with histidine. In each of the foregoing examples, alanine may be substituted at locations where histidine is already present.

[0678] In some instances, the first ABD comprises at least 90%, 95%, or 98% of the HCVD identical to SEQ ID NO: 234, wherein the HCVD comprises histidine at one or more amino acid positions in SEQ ID NO: 234. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the LCVD identical to SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more amino acid positions in SEQ ID NO: 235. In some instances, the first ABD comprises at least 90%, 95%, or 98% of the HCVD identical to SEQ ID NO: 234, wherein the HCVD comprises histidine at one or more amino acid positions in SEQ ID NO: 234; and at least 90%, 95%, or 98% of the LCVD identical to SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more amino acid positions in SEQ ID NO: 235. In each of the foregoing examples, alanine may be substituted where histidine is already present.

[0679] This document also provides pharmaceutical compositions comprising any of the ABPCs described herein. This document also provides a method for treating a subject in need, the method comprising administering to the subject a therapeutically effective amount of any of the ABPCs described herein.

[0680] In some instances, compositions comprising ABPC (e.g., any of the ABPCs described herein) may provide an increase (e.g., a detectable increase) in toxin release from target mammalian cells (e.g., any of the target mammalian cells described herein) compared to compositions comprising the same amount of control ABPC (e.g., any of the exemplary control ABPCs described herein). This increase may be any of the percentage increase or range of percentage increase listed on pages 389-404 of WO 2021 / 022039 (or the corresponding publication US 2022 / 0281984, which is incorporated herein by reference in its entirety).

[0681] In some instances, compositions comprising ABPCs (e.g., any of the ABPCs described herein) may provide an increase (e.g., a detectable increase) in toxin release from target mammalian cells (e.g., any of the fold increases or ranges of fold increases listed on pages 404-420 of WO 2021 / 022039 (or the corresponding publication US 2022 / 0281984, which is incorporated herein by reference in its entirety) compared to compositions comprising the same amount of control ABPCs (e.g., any of the exemplary control ABPCs described herein).

[0682] In some instances, compositions comprising ABPCs (e.g., any of the ABPCs described herein) can provide an increase (e.g., a detectable increase) in the killing of target mammalian cells (e.g., at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%) compared to compositions comprising the same amount of control ABPCs. 95%, 100%, 120%, 140%, 160%, 180%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 1,000%, 2,000%, 3,000%, 4,000%, 5,000%, 6,000%, 7,000%, 8,000%, 9,000%, or 10,000%, or increase by about 1% to 10,000% (e.g., or any of the sub-ranges described herein).

[0683] In some instances, compositions comprising ABPCs (e.g., any of the ABPCs described herein) can provide an increase (e.g., a detectable increase) in the killing of target mammalian cells (e.g., at least 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1.0-fold, 1.2-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.8-fold, 2.0-fold, 2.2-fold, or 2.4-fold) compared to compositions comprising the same amount of control ABPCs. Increase by 2.5 times, 2.6 times, 2.8 times, 3.0 times, 3.5 times, 4.0 times, 4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5 times, 7.0 times, 7.5 times, 8.0 times, 8.5 times, 9.0 times, 9.5 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 40 times, 45 times, 50 times, 55 times, 60 times, 65 times, 70 times, 80 times, 85 times, 90 times, 95 times, or at least 100 times, or 0.1-100 times).

[0684] In some instances, IC50 compositions comprising the same amount of control ABPC were used. 50 In contrast, compositions comprising any of the ABPCs described herein (e.g., upon contact with target mammalian cells presenting TROP2 on their surface) have IC 50(For killing target mammalian cells) reduction (e.g., reduction ≥ 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 99%, about 1% to 99%, or any subrange of this range described herein).

[0685] In some instances, for example, compositions comprising any of the ABPCs described herein (e.g., upon contact with target mammalian cells presenting TROP2 on their surface) can provide K+ on target mammalian cells presenting TROP2 on their surface at neutral pH, compared to control ABPCs. D IC50 on the same target cells at neutral pH 50 The increase in the ratio (e.g., at least 0.1x, 0.2x, 0.4x, 0.6x, 0.8x, 1x, 2x, 5x, 10x, 15x, 20x, 25x, 30x, 35x, 40x, 45x, 50x, 55x, 60x, 65x, 70x, 75x, 80x, 85x, 90x, 95x, or at least 100x, or about 0.1-500x (or any subrange of this range described herein)).

[0686] In some instances, compositions comprising ABPCs (e.g., any of the ABPCs described herein) can provide an increase (e.g., a detectable increase) in lysosomal delivery in target mammalian cells (e.g., at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90%) compared to compositions comprising the same amount of control ABPCs. 5%, 100%, 120%, 140%, 160%, 180%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 1,000%, 2,000%, 3,000%, 4,000%, 5,000%, 6,000%, 7,000%, 8,000%, 9,000%, or at least 10,000%, or an increase of about 1% to 10,000% (e.g., or any subrange of this range described herein).

[0687] In some instances, compositions comprising ABPC have provided an increase in lysosomal delivery in target mammalian cells (e.g., ≥ 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5, 2.6, 2.8, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6) compared to compositions comprising the same amount of control ABPC. Increases of 0.0 times, 6.5 times, 7.0 times, 7.5 times, 8.0 times, 8.5 times, 9.0 times, 9.5 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 55 times, 60 times, 65 times, 70 times, 75 times, 80 times, 85 times, 90 times, 95 times, or at least 100 times, or approximately 0.1-100 times.

[0688] In any instance of the ABPC described herein, the target mammalian cells do not express the FcRn receptor, or express a low (e.g., detectably low) level of the FcRn receptor compared to control cells expressing FcRn (e.g., HUVEC – Thermo Fisher Scientific, No. C0035C). In some instances, the target mammalian cells are cancer cells. In some instances, the ABPC is cytotoxic or inhibitory to the said target mammalian cells.

[0689] In some instances, compositions comprising any of the ABPCs described herein (e.g., when administered to a subject) cause a lesser reduction (e.g., from a 1% decrease to about 99% or any subrange of this range described herein) in the presentation of TROP2 on the surface of target cells compared to compositions comprising the same amount of a control ABPC (e.g., any of the control ABPCs described herein). In some instances, the compositions do not cause a detectable reduction in the presentation of TROP2 on the surface of target mammalian cells.

[0690] In some instances, ABPC exhibits cross-reactivity with non-human primate TROP2 and human TROP2. In some instances, ABPC exhibits cross-reactivity with one or both of non-human primate TROP2, human TROP2, and rat TROP2 and mouse TROP2. In some instances, ABPC exhibits cross-reactivity with non-human primate TROP2, human TROP2, rat TROP2, and mouse TROP2. In some instances, ABPC exhibits cross-reactivity with mouse TROP2 and rat TROP2. In some instances, ABD binds to the TROP2 epitope present on the surface of cells from Old World monkeys.

[0691] Some instances of any ABPC described herein may further include a second ABD (e.g., any of the exemplary ABDs described herein). Non-limiting aspects of these methods are described below and can be used without limitation in any combination. Further aspects of these methods are known in the art.

[0692] TROP2 or TROP2 epitope

[0693] Several TROP2-binding monoclonal antibodies have been described in the literature, which can be used as templates for engineered pH-dependent binding. The amino acid sequence of mature human TROP2 can be found in SEQ ID NO: 2. The amino acid sequence of the extracellular domain of TROP2 can be found in SEQ ID NO: 3.

[0694] Antigen-binding protein construct

[0695] Any of the antigen-binding protein constructs (ABPCs) described herein may be a single polypeptide, or may include 2, 3, 4, 5, 6, 7, 8, 9, or 10 (identical or different) polypeptides. In some embodiments where the ABPC is a single polypeptide, the ABPC may include a single ABD or two ABDs. In some embodiments where the ABPC is a single polypeptide and includes two ABDs, the first ABD and the second ABD may be identical or different from each other (and may bind specifically to the same or different antigens or epitopes).

[0696] In some embodiments where the ABPC is a single polypeptide, the first ABD and the second ABD (if present) can each be independently selected from the group consisting of: VH domain, VHH domain, VNAR domain, and scFv. In some embodiments where the ABPC is a single polypeptide, the antigen-binding protein construct can be BiTe, (scFv)2, nanobody, nanobody-I, DART, TandAb, sc bifunctional antibody, sc bifunctional antibody-CH3, scFv-CH-CL-scFv, HSAbody, sc bifunctional antibody-HAS, tandem-scFv, Adnectin, DARPin, fibronectin, DEP conjugate, PROTAB, or PROTAC. Further examples of ABDs that can be used when the ABPC is a single polypeptide are known in the art.

[0697] V H The H domain is a single, monomeric, variable antibody domain that can exist within a camel's body. V NAR A domain is a single, monomeric, variable antibody domain that can exist within cartilaginous fish. V H H domain and V NARThe non-restrictive aspects of the domains are described in, for example, the following literature: Cromie et al., Current Issues in Medicinal Chemistry (Curr. Top. Med. Chem.) 15:2543-2557, 2016; De Genst et al., Developmental and Comparative Immunology (Dev. Comp. Immunol.) 30:187-198, 2006; De Meyer et al., Trends in Biotechnology (Trends Biotechnol.) 32:263-270, 2014; Kijanka et al., Nanomedicine 10:161-174, 2015; Kovaleva et al., Expert Opinion on Biotherapy (Expert. Opin. Biol. Ther.) 14:1527-1539, 2014; Krah et al., Immunopharmacol. Immunotoxicol. 38:21-28, 2016; Mujic-Delic et al., *Trends in Pharmacology* 35:247-255, 2014; Muyldermans, *Journal of Biotechnol* 74:277-302, 2001; Muyldermans et al., *Trends in Biochemistry* 26:230-235, 2001; Muyldermans, *Annals of Biochemistry* 82:775-797, 2013; Rahbarizadeh et al., *Immunol. Invest* 40:299-338, 2011; Van Audenhove et al., *EbioMedicine* 8:40-48, 2016; Van Bockstaele et al., Current Views on Drugs (Curr. Opin. Investig. Drugs) 10:1212-1224, 2009; Vincke et al., Methods in Molecular Biology (Methods Mol. Biol.) 911:15-26, 2012; and Wesolowski et al., Med. Microbiol. Immunol. 198:157-174, 2009.

[0698] In some embodiments where ABPC is a single polypeptide and includes two ABDs, both the first ABD and the second ABD can be VHH domains, or at least one ABD can be a VHH domain. In some embodiments where ABPC is a single polypeptide and includes two ABDs, both the first ABD and the second ABD can be VHH domains. NAR A structural domain, or at least one ABD, is V. NAR Domains. In some embodiments where ABPC is a single polypeptide, the first ABD is an scFv domain. In some embodiments where ABPC is a single polypeptide and includes two ABDs, both the first and second ABDs can be scFv domains, or at least one ABD can be an scFv domain.

[0699] In some embodiments, ABPC may include two or more polypeptides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 polypeptides). In s...

Claims

1. An antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain (ABD), the first ABD being capable of specifically binding to TROP2 or an epitope of TROP2 presented on the surface of a target mammalian cell, wherein: The first ABD dissociates at a rate of approximately 4.0–6.5 faster than at a rate of approximately 7.0–8.0; or the first ABD dissociates at a rate of approximately 4.0–6.5 with K D Greater than K at a pH of approximately 7.0-8.0 D .

2. The ABPC of claim 1, wherein the first ABD comprises an HCVD that is itself one of the following heavy chain variable domains (HCVDs): (a) sacituzumab; (b) datopotamab; (c) hu7E6SVG; and (d) A1,2X4, and / or an LCVD that is itself one of the following light chain variable domains (LCVDs): (a) sacituzumab; (b) datopotamab; (c) hu7E6SVG; and (d) A1,2X4, each HCVD or LCVD having one or more amino acids substituted with histidine.

3. The ABPC of claim 2, wherein the HCVD comprises one of the following: (a1) an HCVD of goxatozumab, the HCVD comprising SEQ ID NO: 4; (b1) an HCVD of dabrabutazine, the HCVD comprising SEQ ID NO: 80; (c1) an HCVD of hu7E6SVG, the HCVD comprising SEQ ID NO: 156; and (d1) an HCVD of A1,2X4, the HCVD comprising SEQ ID NO: 234; and one of the following correspondingly: (a2) an LCVD of goxatozumab, the LCVD comprising SEQ ID NO: 5; (b2) an LCVD of dabrabutazine, the LCVD comprising SEQ ID NO: 81; (c2) an LCVD of hu7E6SVG, the LCVD comprising SEQ ID NO: 157; and (d2) an LCVD of A1,2X4, the LCVD comprising SEQ ID NO:

5. NO: 235, wherein each HCVD and / or LCVD has one or more histidine substitutions.

4. The ABPC according to claim 3, wherein the first ABD comprises an HCVD, the HCVD comprising CDR1, CDR2, and CDR3 which are themselves one of (a) to (c): (a1) SEQ ID NO: 6, 7, and 8; (b1) SEQ ID NO: 82, 83, and 84; (c1) SEQ ID NO: 158, 159, and 160; and (d1) SEQ ID NO: 236, 237, and 238, and a corresponding LCVD comprising CDR1, CDR2, and CDR3 corresponding to one of the following: (a2) SEQ ID NO: 9, 10, and 11; (b2) SEQ ID NO: 85, 86, and 87; (c2) SEQ ID NO: 161, 162, and 163; and (d ...9, 10, and 11; (c2) SEQ ID NO: 9, 10, and 11; (d2) SEQ ID NO: 9, 10, and 11; (b2) SEQ ID NO: 9, 10, and 11; (c2) SEQ ID NO: 9, 10, and 11; (d2) SEQ ID NO: 9, 10, and 11; (b2) SEQ ID NO: 9, 10, and 11; (c2) SEQ ID NO: 9, 10, and 11; (d2) SEQ ID NO: 9, NO:239, 240 and 241, where each group of three CDRs shares one or more amino acid positions that are substituted by histidine.

5. The ABPC according to any one of claims 2 to 4, comprising an HCVD that is itself one of (a) to (c): (a) HCVD that is at least 90%, 95% or 98% identical to SEQ ID NO: 4, wherein the HCVD in SEQ ID NO: 4 comprises histidine at one or more of the following positions: 29, 32, 33, 50, 52, 53, 60, 61, 62, 63, 64, 65, 66, 99, 101, 104, 105 and 108; (b) HCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 80, wherein the HCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 29, 53, 55, 64, 65, 98, 101, 104, 105, 107, and 108; and (c) HCVD that is at least 90%, 95% or 98% identical to SEQ ID NO: 156, wherein the HCVD comprises histidine at one or more of the following positions in SEQ ID NO: 156: 26, 29, 30, 33, 34, 51, 54, 56, 57, 59, 102, 103 and 106.

6. The ABPC according to any one of claims 2 to 5, comprising an LCVD that is itself one of (a) to (d): (a) an LCVD that is at least 90%, 95% or 98% identical to SEQ ID NO: 5, wherein the LCVD comprises histidine at one or more of the following positions in SEQ ID NO: 5: 28, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 92, 93, 94, 95, 96 and 97; (b) At least 90%, 95% or 98% identical to SEQ ID NO: 80, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 80: 26, 28-31, 33, 34, 50-54, 89, 93, 94 and 95; (c) An LCVD that is at least 90%, 95%, or 98% identical to SEQ ID NO: 157, wherein the LCVD comprises histidine at one or more positions selected from the following in SEQ ID NO: 157: 25, 32, 34, 36, 54, 56, 57, 58, 59, 60, 93, 96, 97, 99, 100, and 101; and (d) An LCVD that is at least 90%, 95% or 98% identical to SEQ ID NO: 235, wherein the LCVD comprises histidine at one or more positions in SEQ ID NO:

235.

7. The ABPC according to claim 5 or 6, wherein the HCVD and / or the LCVD comprises histidine at two or more positions in its defined SEQ ID NO.

8. The ABPC of claim 1, wherein the first ABD comprises HCVD, and the HCVD comprises one sequence of SEQ ID NO:4, one sequence of SEQ ID NO:12-52, one sequence of SEQ ID NO:80, one sequence of SEQ ID NO:88-128, one sequence of SEQ ID NO:156, 164-202, one sequence of SEQ ID NO:234, SEQ ID NO:242-280, or one sequence of SEQ ID NO: One sequence from the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, SEQ ID NO: 81, SEQ ID NO: 129-15 ... 157, one sequence shown in SEQ ID NO: 203-233, one sequence shown in SEQ ID NO: 235, SEQ ID NO: 281-312, or SEQ ID NO: One of the sequences shown in 351, 352, 353, 354, 355, 359, 360, 361, 362, 365, 366, 367, 368, 370, 371, 372, 373, 376, 377, 383, 386, 387, 388, 389, 392, 393, 394, 395, 396, 411, 412, 417, 418, 423, 459, 460, 462, 464, 465, 466, 467, 468, 469, 470, 473, 474, 485, 488, 489, and 491.

9. The ABPC of claim 1, wherein the first ABD comprises one of (a) to (c): (a) an HCVD that is itself one of the sequences shown in SEQ ID NO: 4, SEQ ID NO: 12-52, or SEQ ID NO: 313-350, and / or an LCVD that is itself one of the sequences shown in SEQ ID NO: 5, SEQ ID NO: 53-79, or SEQ ID NO: 351-396, wherein the first ABD does not include (i) SEQ ID NO: 4 and 5; (ii) an HCVD that is itself SEQ ID NO: 4 and not SEQ ID NO: The LCVD of one of the sequences shown in 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 71, 74, 75, 76, 77, 78, 79, 351, 352, 353, 354, 355, 359, 360, 361, 362, 365, 366, 367, 368, 370, 371, 372, 373, 376, 377, 383, 386, 387, 388, 389, 392, 393, 394, 395, and 396; or (iii) the LCVD of itself being SEQ ID NO: 5 and not being SEQ ID NO: HCVD of one of the following: 15, 18, 19, 22, 24, 25, 32, 33, 34, 35, 36, 37, 38, 41, 43, 46, 47, 50, 318, 320, 322, 323, 324, 325, 328, 332, 333, 334, 336, 337, 343, 344, 345, 347, and 348; (b) an HCVD that is itself one of the sequences shown in SEQ ID NO: 80, SEQ ID NO: 88-128, SEQ ID NO: 397-406, or SEQ ID NO: 397-406, and / or an LCVD that is itself one of the sequences shown in SEQ ID NO: 81, SEQ ID NO: 129-155, or SEQ ID NO: 407-426, wherein the first ABD does not include (i) SEQ ID NO: 80 and 81; (ii) an HCVD that is itself SEQ ID NO: 80 and not SEQ ID NO: LCVDs of 131, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 147, 151, 152, 153, 411, 412, 417, 418, and 423; or (iii) LCVDs that are themselves SEQ ID NO: 81 and HCVDs that are not one of SEQ ID NOs: 91, 101, 103, 112, 113, 116, 119, 122, 123, 125, and 126; and (c) an HCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 156, SEQ ID NO: 164-202, or SEQ ID NO: 427-457, and / or an LCVD that is itself a sequence of one of the sequences shown in SEQ ID NO: 157, SEQ ID NO: 203-233, or SEQ ID NO: 458-492, wherein the first ABD does not include (i) SEQ ID NO: 156 and 157; (ii) an HCVD that is itself SEQ ID NO: 156 and not SEQ ID NO: LCVD of one of 204, 211, 213, 215, 218, 220, 221, 222, 223, 224, 225, 228, 229, 231, 232, 233, 459, 460, 462, 464, 465, 466, 467, 468, 469, 470, 473, 474, 485, 488, 489, and 491; or (iii) an LCVD that is itself SEQ ID NO: 157 and is not SEQ ID NO: HCVD of one of the sequences shown in sequences 164, 167, 168, 171, 172, 175, 178, 180, 181, 183, 196, 197, 200, 201, 427, 428, 429, 430, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 447, 449, 451, 454, 456 and 457.

10. The ABPC according to any one of claims 1 to 9, wherein the ABPC is degraded in the target mammalian cells after internalization; and / or wherein the ABPC further comprises a conjugated toxin, a radioisotope, a drug, or a small molecule; and / or wherein the ABPC provides an increase in toxin release in the target mammalian cells compared to the same amount of control ABPC.

11. The ABPC of claim 10, wherein the ABPC provides at least a 20%, 50%, 2-fold, or 5-fold increase in toxin release; and / or wherein the ABPC provides an increase in target mammalian cell killing compared to the same amount of control ABPC.

12. The ABPC of claim 11, wherein the composition provides at least a 20%, 50%, 2-fold, or 5-fold increase in killing of target mammalian cells compared to the same amount of control ABPC.

13. The ABPC according to any one of claims 1 to 12, wherein the ABPC provides an increase in lysosomal delivery in the target mammalian cells compared to the same amount of control ABPC; optionally, the increase is at least 20%, 50%, 2-fold, or 5-fold.

14. The ABPC according to any one of claims 1 to 13, wherein, compared with the same amount of control ABPC, the ABPC results in less or no detectable reduction in the level of TROP2 presented on the surface of the target mammalian cells.

15. The ABPC according to any one of claims 1 to 14, wherein the ABPC further comprises a second ABD.

16. The ABPC according to any one of claims 1 to 15, wherein the ABPC is conjugated with a drug.

17. A kit comprising at least one dose of ABPC according to any one of claims 1 to 16.

18. A method of treating cancer, wherein the cancer is characterized by a population of cancer cells having a predetermined level of TROP2 or an epitope of TROP2 presented on their surface, the method comprising administering a therapeutically effective amount of ABPC according to any one of claims 1 to 16 to a subject identified as having cancer, wherein the cancer is characterized by having the population of said cancer cells.

19. A method for reducing the volume of a tumor in a subject, wherein the tumor is characterized by having TROP2-positive cancer cells, the method comprising administering a therapeutically effective amount of ABPC according to any one of claims 1 to 16 to the subject identified as having cancer, wherein the cancer is characterized by the cancer cells.

20. A method for inducing cell death in TROP2-positive cancer cells of a subject, the method comprising administering a therapeutically effective amount of ABPC according to any one of claims 1 to 16 to the subject identified as having cancer.

21. A method for reducing the risk of metastasis or additional metastasis in a subject with TROP2-positive cancer, the method comprising administering a therapeutically effective amount of ABPC according to any one of claims 1 to 16 to the subject identified as having said cancer.

22. A TROP2-specific binding protein construct comprising a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD), wherein the HCVD and the LCVD comprise one of (a) to (f): (a) One of the HCVD and LCVD sequence pairs shown in one of the following SEQ ID NO: pairs: 18+59, 19+59, 32+59, 34+59, 35+59, 36+59, 37+59, 38+59, 18+62, 19+62, 38+62, 19+65, 18+66, 19+66, 35+71, 38+71, 34+73, 19+75, 35+75, 36+75, 37+75, 38+75, 19+366, 32+366, 35+366, 36+366, 18+376, 32+376, 34+376, 35+376, 36+376, 37+3 76, 38+376, 18+351, 19+351, 32+351, 34+351, 35+351, 36+351, 37+351, 38+351, 18+352, 19+352, 32+352, 34+352, 35+352, 36+352, 37+352, 38+352, 32+353, 34+353, 35+353, 37+353, 38+353, 18+361, 19+361, 32+361, 34+361, 35+361, 36+361, 37+361, 38+361, 18+365, 32+365, 3 4+365, 35+365, 36+365, 37+365, 38+365, 18+366, 19+366, 32+366, 34+366, 35+366, 36+366, 37+366, 38+366, 18+388, 32+388, 34+388, 35+388, 37+388, 38+388, 18+389, 19+389, 32+389, 34+389, 35+389, 36+389, 37+389, 38+389, 18+394, 32+394, 34+394, 35+394, 36+394, 37+39 4, 38+394, 101+134, 119+134, 122+134, 119+142, 119+143, 122+143, 116+148, 116+151, 119+151, 122+151, 196+223, 197+223, 200+223, 196+224, 197+224, 200+224, 196+225, 197+225, 200+225, 196+226, 197+226, 196+229, 197+229, 200+229, 196+233, 197+233, 197+460, 197+ 462, 197+460, and 197+462; (b) HCVD and LCVD sequences, each of which is identical to the HCVD and LCVD sequences listed in one of the SEQ ID NO: pairs listed in (a), and has HCDR and LCDR having at least 90%, at least 95%, or at least 98% identity with the HCVD and LCVD sequences. (c) HCVD and LCVD sequences, each having the same HCVD and LCVD sequences as shown in one of the SEQ ID NO: pairs listed in (a) (as determined by the Kabat system), and HCDR and LCDR having at least 90%, at least 95%, or at least 98% identity with the HCVD and LCVD sequences; (d) HCVD and LCVD sequences, each having the same HCVD and LCVD sequences as shown in one of the SEQ ID NO: pairs listed in (a) (as determined by the IMGT system), and HCDR and LCDR having at least 90%, at least 95%, or at least 98% identity with the HCVD and LCVD sequences; (e) HCVD and LCVD sequences, each having the same HCVD and LCVD sequences as shown in one of the SEQ ID NO: pairs listed in (a) (as determined by the additive Kabat-IMGT method), and HCDR and LCDR having at least 90%, at least 95%, or at least 98% identity with the HCVD and LCVD sequences; and (f) HCVD and LCVD sequences, each having the same HCVD and LCVD sequences as shown in one of the SEQ ID NO: pairs listed in (a) (as determined by the additive Kabat-IMGT method), and HCDR and LCDR having at least 98% identity with the HCVD and LCVD sequences.

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