PTK7-binding proteins and uses thereof

Abstract

Provided herein are antigen binding protein constructs (ABPCs) that bind PTK7 and uses thereof. The present invention is based on the concept that antigen binding protein (ABP) constructs can be generated that show enhanced efficacy in toxin release in target mammalian cells, increased cell killing, and increased endolysosomal delivery. As disclosed herein, applicants conducted a novel antibody screening campaign using the extracellular domain of PTK7 to immunize rabbits. From several hundred initial clones, applicants selected a diverse set of PTK7 binding proteins for subsequent pH manipulation.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 365,005, filed May 19, 2022, the entire contents of which are incorporated herein by reference. (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically as an XML file titled "45395-0057WO1_SL_ST26.XML". The XML file, created on May 15, 2023, is 1,242,742 bytes in size. The material within the XML file is hereby incorporated by reference in its entirety. (CROSS REFERENCE TO RELATED APPLICATIONS) The present disclosure relates to the field of antigen-binding molecules. (Technical field)

[0002] The present disclosure relates to the field of antigen-binding molecules. Summary of the Invention

[0003] The present invention is based on the concept that antigen binding protein (ABP) constructs can be generated that exhibit enhanced efficacy in toxin release, increased cell killing, and increased endolysosomal delivery in target mammalian cells.

[0004] Tyrosine protein kinase-like 7 (PTK7), also known as colon cancer kinase 4 (CCK4), is a receptor tyrosine kinase encoded by the PTK7 gene in humans. "PTK7" and "CCK4" are used interchangeably herein. PTK7 is overexpressed in many major cancers (e.g., ovarian, breast, and non-small cell lung cancer, and colon cancer), and the anti-PTK7 ADC, cofetuzumab peridotin, is currently being evaluated in clinical trials. Applicants sought to develop anti-PTK7 binding proteins as disclosed herein because pH manipulation of PTK7 antibodies could potentially reduce the uptake of the corresponding ADC in normal tissues. Such anti-PTK7 pH-ADCs hold the potential to reduce "on target" toxicity and widen the therapeutic window compared to non-pH-dependent anti-PTK7 ADCs. The pH-ADCs of the present disclosure can also improve efficacy by increasing tumor uptake and improving PK profiles, which may be particularly beneficial for patients with tumors characterized by low PTK7 expression.

[0005] As disclosed herein, Applicants conducted a novel antibody screening campaign using the extracellular domain of PTK7 to immunize rabbits. From several hundred initial clones, Applicants selected a diverse set of PTK7-binding proteins for subsequent pH manipulation. As detailed herein, Applicants produced over 500 variants of these initial rabbit monoclonal antibody (RabmAb) clones and tested them for their ability to exhibit greater PTK7-specific binding at pH 7.4 versus pH 5.4, as well as increased intracellular uptake by cancer cells expressing PTK7 on their surface. Provided herein are antigen binding protein constructs (ABPCs) and pharmaceutical compositions, comprising an effective amount of an ABPC comprising a first antigen binding domain (ABD) capable of specifically binding to PTK7 or an epitope of PTK7 present on the surface of a target mammalian cell, wherein (a) the dissociation rate of the first ABD at about pH 4.0 to about 6.5 is faster than the dissociation rate at about pH 7.0 to about 8.0, or (b) the dissociation constant (K D) at pH 7.0 to 8.0 D In certain embodiments, antigen binding protein constructs (ABPCs) and pharmaceutical compositions are provided that are greater than or equal to 100 μg / mL.

[0006] In addition to being the first to produce the aforementioned anti-PTK7 antibodies and variants thereof, each of which is disclosed herein, Applicants have also produced hundreds of variants starting from parent PTK7 binding proteins selected from cofetuzumab, 7C8, and 12C6.

[0007] In some embodiments, the first ABD comprises a heavy chain variable domain (HCVD) of cofetuzumab, 7C8, 12C6, MYT9345, MYT9359, MYT9361, MYT9412, MYT9460, MYT9792 or MYT9797, each HCVD optionally having at least one histidine substitution.

[0008] In some embodiments, the first ABD comprises a light chain variable domain (LCVD) of cofetuzumab, 7C8, 12C6, MYT9345, MYT9359, MYT9361, MYT9412, MYT9460, MYT9792 or MYT9797, each LCVD optionally having at least one histidine substitution.

[0009] In some embodiments, the first ABD is selected from the group consisting of: (a) an HCVD of MYT9345 and / or an LCVD of MYT9345; (b) an HCVD of MYT9359 and / or an LCVD of MYT9359; (c) an HCVD of MYT9361 and / or an LCVD of MYT9361; (d) an HCVD of MYT9412 and / or an LCVD of MYT9412; (e) an HCVD of MYT9460 and / or an LCVD of MYT9460; (f) an HCVD of MYT9361 and / or an LCVD of MYT9361; (g) the HCVD of MYT9792 and / or the LCVD of MYT9792, (h) the HCVD of cofetuzumab and / or the LCVD of cofetuzumab, (i) the HCVD of 7C8 and / or the LCVD of 7C8, (j) the HCVD of 12C6 and / or the LCVD of 12C6, each HCVD or LCVD optionally having one or more amino acids replaced with histidine.

[0010] In some embodiments, the HCVD comprises one of: (a) an HCVD of MYT9345 comprising SEQ ID NO:301; (b) an HCVD of MYT9359 comprising SEQ ID NO:375; (c) an HCVD of MYT9361 comprising SEQ ID NO:459; (d) an HCVD of MYT9412 comprising SEQ ID NO:542; (e) an HCVD of MYT9460 comprising SEQ ID NO:628; (f) an HCVD of MYT9792 comprising SEQ ID NO:710; (g) an HCVD of MYT9797 comprising SEQ ID NO:803; (h) an HCVD of cofetuzumab comprising SEQ ID NO:1; (i) an HCVD of 7C8 comprising SEQ ID NO:126; or (j) an HCVD of 12C6 comprising SEQ ID NO:229.

[0011] In some embodiments, the LCVD comprises one of: (a) an LCVD of MYT9345 comprising SEQ ID NO:302; (b) an LCVD of MYT9359 comprising SEQ ID NO:376; (c) an LCVD of MYT9361 comprising SEQ ID NO:460; (d) an LCVD of MYT9412 comprising SEQ ID NO:543; (e) an LCVD of MYT9460 comprising SEQ ID NO:629; (f) an LCVD of MYT9792 comprising SEQ ID NO:711; (g) an LCVD of MYT9797 comprising SEQ ID NO:804; (h) an LCVD of cofetuzumab comprising SEQ ID NO:1; (i) an LCVD of 7C8 comprising SEQ ID NO:127; or (j) an LCVD of 12C6 comprising SEQ ID NO:229.

[0012] In some embodiments, the first ABD comprises: (a) an HCVD optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively with one or more amino acids substituted with histidine; (b) an HCVD optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, collectively with one or more amino acids substituted with histidine; (c) an HCVD optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, collectively with one or more amino acids substituted with histidine; (d) optionally, an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 544, 545, and 546, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 461, 462, and 463 have been substituted with histidine; (e) optionally, an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 630, 631, and 632 have been substituted with histidine; (f) optionally, a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 712, 713, and 714 have been substituted with histidine; (g) optionally, a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 805, 806, and 807 have been substituted with histidine. (h) optionally, an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, respectively, in which collectively one or more amino acids in SEQ ID NOs: 3, 4, and 5 have been substituted with histidine; (i) optionally, an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, respectively, in which collectively one or more amino acids in SEQ ID NOs: 128, 129, and 130 have been substituted with histidine; (j) optionally, an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 231,HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, collectively with a total of one or more amino acids in SEQ ID NOs: 231, 232, and 233 substituted with histidine.

[0013] In some embodiments, the first ABD comprises: (a) an LCVD optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively with one or more amino acids substituted with histidine; (b) an LCVD optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively with one or more amino acids substituted with histidine; (c) an LCVD optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively with one or more amino acids substituted with histidine; (d) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 464, 465, and 466 have been substituted with histidine; (e) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 633, 634, and 635, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 633, 634, and 635 have been substituted with histidine; (f) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 715, 716, and 717, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 715, 716, and 717 have been substituted with histidine; (g) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 808, 809, and 810, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 808, 809, and 810 have been substituted with histidine. (h) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, in which collectively one or more amino acids in SEQ ID NOs: 6, 7, and 8 have been substituted with histidine; (i) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, in which collectively one or more amino acids in SEQ ID NOs: 131, 132, and 133 have been substituted with histidine; (j) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234,and LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, collectively with a total of one or more amino acids in SEQ ID NOs: 234, 235, and 236 substituted with histidine.

[0014] In some embodiments, the first ABD comprises: (a) an HCVD, optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively with one or more amino acids substituted with histidine; and / or an LCVD, optionally comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively with one or more amino acids substituted with histidine; (b) an optional and / or optionally a LCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, in which collectively one or more amino acids in SEQ ID NOs: 377, 378, and 379 have been substituted with histidine; (c) optionally a CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, in which collectively one or more amino acids in SEQ ID NOs: 461, 462, and 463 have been substituted with histidine; and / or optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, in which collectively one or more amino acids in SEQ ID NOs: 464, 465, and 466 have been substituted with histidine; (d) optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, in which collectively one or more amino acids in SEQ ID NOs: 544, 545, and 546 have been substituted with histidine; (e) an HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 544, 545 and 546, respectively, and / or an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 547, 548 and 549, respectively, optionally with a substitution of one or more amino acids collectively with histidine; (f) an HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 544, 545 and 546, respectively, optionally with a substitution of one or more amino acids collectively with histidine;(f) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, in which, collectively, one or more amino acids in SEQ ID NOs: 712, 713, and 714 have been substituted with histidine; and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 633, 634, and 635, respectively, in which, collectively, one or more amino acids in SEQ ID NOs: 633, 634, and 635 have been substituted with histidine; and / or optionally a LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 715, 716 and 717, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 715, 716 and 717 have been substituted with histidine; (g) optionally a HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 805, 806 and 807, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 805, 806 and 807 have been substituted with histidine; and / or optionally a LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 715, 716 and 717, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 805, 806 and 807 have been substituted with histidine; and 810, collectively in total, one or more amino acids have been substituted with histidine; (h) optionally, a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, respectively, collectively in total, one or more amino acids have been substituted with histidine; and / or optionally, a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, respectively, collectively in total, one or more amino acids have been substituted with histidine; and / or optionally, a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, collectively in total, one or more amino acids have been substituted with histidine. (i) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8, optionally with a substitution of one or more amino acids in SEQ ID NOs: 131, 132 and 133 in total with histidine; and / or an HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 131, 132 and 133 in total with histidine, optionally with a substitution of one or more amino acids in SEQ ID NOs: 134, 135 and 136 in total with histidine.and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 231, 232, and 233 have been substituted with histidine; and / or, optionally, a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, in which collectively, one or more amino acids in SEQ ID NOs: 234, 235, and 236 have been substituted with histidine.

[0015] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally including a histidine at one or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally including a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542. (e) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102, and 103 in SEQ ID NO: 628; (f) an HCVD at least 90% identical to SEQ ID NO: 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102, and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0016] In some embodiments, the first ABD is selected from (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 10 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD that is at least 90% identical to SEQ ID NO: 629, optionally comprising a histidine at one or more positions selected from 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD that is at least 90% identical to SEQ ID NO: 711, optionally comprising a histidine at one or more positions selected from 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95, 98 and 99 in SEQ ID NO: 711; and (g) an LCVD that is at least 90% identical to SEQ ID NO: 804, optionally comprising a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0017] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a histidine at two or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally including a histidine at two or more positions selected from 32, 99, 101, 102, 106, and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally including a histidine at two or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104, and 105 in SEQ ID NO: 542. (e) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at two or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102, and 103 in SEQ ID NO: 628; (f) an HCVD at least 90% identical to SEQ ID NO: 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102, and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at two or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0018] In some embodiments, the first ABD is selected from (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally comprising a histidine at two or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally comprising a histidine at two or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 10 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at two or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 629, optionally containing a histidine at two or more positions selected from 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally containing a histidine at two or more positions selected from 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95, 98 and 99 in SEQ ID NO: 711; and (g) an LCVD at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at two or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0019] In some embodiments, the first ABD is (a) an HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301, and / or an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52 in SEQ ID NO: 375; , 55, 58, 59, 63, 97, 99, and 108 of SEQ ID NO: 375, and / or a LCVD at least 90% identical to SEQ ID NO: 376, and optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) a histidine at one or more positions selected from 32, 99, 101, 102, 106, and 111 of SEQ ID NO: 459; and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 of SEQ ID NO: 460; (d) a HCVD which is at least 90% identical to SEQ ID NO: 542, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542, and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 3; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; and / or 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98 in SEQ ID NO: 629;(f) an LCVD at least 90% identical to SEQ ID NO: 629, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110 and 113 in SEQ ID NO: 710, and / or 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95 in SEQ ID NO: 711. (g) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100 and 107 in SEQ ID NO: 803, and / or an LCVD at least 90% identical to SEQ ID NO: 804, optionally including a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0020] In some embodiments, the first ABD is selected from the group consisting of (a) an HCVD of SEQ ID NO: 301, or one of 309-342; (b) an HCVD of SEQ ID NO: 375, or one of 383-423; (c) an HCVD of SEQ ID NO: 459, or one of 467-511; (d) an HCVD of SEQ ID NO: 542, or one of 550-592; (e) an HCVD of SEQ ID NO: 628, or one of 636-675; (f) an HCVD of SEQ ID NO: 710, or one of 718-767; (g) an HCVD of SEQ ID NO: 803, or one of 811-854; and and / or the first ABD comprises (a) an LCVD of SEQ ID NO: 302, or one of 343-374, (b) an LCVD of SEQ ID NO: 376, or one of 424-458, (c) an LCVD of SEQ ID NO: 460, or one of 512-541, (d) an LCVD of SEQ ID NO: 543, or one of 593-627, (e) an LCVD of SEQ ID NO: 629, or one of 676-709, (f) an LCVD of SEQ ID NO: 711, or one of 768-802, or (g) an LCVD of SEQ ID NO: 804, or one of 855-892.

[0021] (a) comprising an HCVD of SEQ ID NO: 301, or one of 309-342, and / or an LCVD of SEQ ID NO: 302, or one of 343-374, wherein the first ABD does not comprise (i) an HCVD of SEQ ID NO: 301 and an LCVD of SEQ ID NO: 302, (ii) an HCVD of SEQ ID NO: 301 and an LCVD that is not one of SEQ ID NOs: 344, 349-352, 354, 359-361, 363, 366-368, 370, and 373, or (iii) an LCVD of SEQ ID NO: 302 and an HCVD that is not one of SEQ ID NOs: 312, 313, 315, 319-323, 327, 329, 335, 340, and 341; (b) an HCVD of SEQ ID NO: 375, or one of 383 to 423, and / or an LCVD of SEQ ID NO: 376, or one of 424 to 458, wherein the first ABD does not include (i) an LCVD of SEQ ID NO: 375 and an LCVD of SEQ ID NO: 376, (ii) an HCVD of SEQ ID NO: 375 and an LCVD that is not one of SEQ ID NOs: 425, 429, 430, 431, 432, 433, 435, 436, 437, 438, 442, 444, 445, 446, 449, 450, 453, and 455, or (iii) an LCVD of SEQ ID NO: 376 and an HCVD that is not one of SEQ ID NOs: 383, 384, 387, 389, 391, 394, 395, 398, 401, 402, 406, 410, 412, and 421; (c) comprising an HCVD of SEQ ID NO: 459, or one of 467-511, and / or an LCVD of SEQ ID NO: 460, or one of 512-541, wherein the first ABD does not comprise (i) an HCVD of SEQ ID NO: 459 and an LCVD of SEQ ID NO: 460, (ii) an HCVD of SEQ ID NO: 459 and an LCVD that is not one of SEQ ID NOs: 518, 519, 521, 524, 533, and 536, or (iii) an LCVD of SEQ ID NO: 460 and an HCVD that is not one of SEQ ID NOs: 473, 496, 498, 499, 503, and 508; (d) comprising an HCVD of SEQ ID NO: 542, or one of 550-592, and / or an LCVD of SEQ ID NO: 543, or one of 593-627, wherein the first ABD does not comprise (i) an HCVD of SEQ ID NO: 542 and an LCVD of SEQ ID NO: 543, (ii) an HCVD of SEQ ID NO: 542 and an LCVD that is not one of SEQ ID NOs: 594, 598, 599, 600, 601, 611, 614, and 620, or (iii) an LCVD of SEQ ID NO: 543 and an HCVD that is not one of SEQ ID NOs: 551, 553, 554, 555, 556, 563, 565, 568, 582, 584, and 585; (e) comprising an HCVD of SEQ ID NO: 628, or one of SEQ ID NOs: 636-675, and / or an LCVD of SEQ ID NO: 629, or one of SEQ ID NOs: 676-709, wherein the first ABD does not comprise (i) an HCVD of SEQ ID NO: 628, and an LCVD of SEQ ID NO: 629, (ii) an HCVD of SEQ ID NO: 628, and an LCVD that is not one of SEQ ID NOs: 677, 678, 680, 681, 685, 688, 692, 694, 696, 700, 701, 702, 703, 704, and 705, or (iii) an LCVD of SEQ ID NO: 629, and an HCVD that is not one of SEQ ID NOs: 636, 638, 640, 646, 648, 649, 650, 651, 652, 653, 666, 667, 668, and 669; (f) an HCVD of SEQ ID NO: 710, or one of 718-767, and / or an LCVD of SEQ ID NO: 711, or one of 768-802, and the first ABD comprises (i) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NO: 711, (ii) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NO: 769, 771, 773, 774, 779, 780, 785, 786, 788, 790, , 791, 792, 795, and 796; or (iii) an LCVD of SEQ ID NO: 711 and an HCVD that is not one of SEQ ID NOs: 721, 722, 723, 725, 727, 728, 731, 735, 736, 743, 744, 745, 746, 748, 749, 751, 753, 755, 756, 757, 758, and 761; and (g) an HCVD of SEQ ID NO: 803, or one of 811-854, and / or an LCVD of SEQ ID NO: 804, or one of 855-892, and the first ABD does not include one of: (i) an HCVD of SEQ ID NO: 803 and an LCVD of SEQ ID NO: 804, (ii) an HCVD of SEQ ID NO: 803 and an LCVD that is not one of SEQ ID NOs: 862, 864-866, 868, 870, 881 and 882, or (iii) an LCVD of SEQ ID NO: 804 and an HCVD that is not one of SEQ ID NOs: 818, 821, 824, 826-829, 835, 841, 848 and 850.

[0022] In some embodiments, the first antigen binding domain (ABD) is selected from the group consisting of: (a) an HCVD that is at least 90% identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at one or more positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107; (b) an HCVD that is at least 90% identical to SEQ ID NO:126, wherein the HCVD comprises a histidine at one or more positions of SEQ ID NO:1 selected from the group consisting of 53, 54, 56, 57, 58, 64, 98, 100, 102, 103, and 107; and / or (c) an HCVD that is at least 90% identical to SEQ ID NO: 229, wherein the HCVD comprises a histidine at one or more positions in SEQ ID NO: 229 selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100. In some embodiments, the first ABD comprises one of: (a) an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 25, 29, 31, 35, 60, 93, and 94 of SEQ ID NO:2; (b) an LCVD that is at least 90% identical to SEQ ID NO:127, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94 of SEQ ID NO:127; or (c) an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99 in SEQ ID NO:230.

[0023] In some embodiments, the first ABD comprises one of: (a) an HCVD that is at least 90% identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at two or more positions of SEQ ID NO:1 selected from the group consisting of 27, 29, 31, 34, and 53; and (b) an HCVD that is at least 90% identical to SEQ ID NO:126, wherein the HCVD comprises a histidine at two or more positions of SEQ ID NO:126 selected from the group consisting of 53, 56, 57, 102, and 105. In some embodiments, the first ABD comprises one of: (a) an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at two or more positions of SEQ ID NO:2 selected from the group consisting of 31, 60, and 93; and (b) an LCVD that is at least 90% identical to SEQ ID NO:127, wherein the LCVD comprises a histidine at two or more positions of SEQ ID NO:127 selected from the group consisting of 28 and 90.

[0024] In some embodiments, the first ABD is (a) an HCVD at least 90% identical to SEQ ID NO:1 comprising a histidine at one or more positions selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107 of SEQ ID NO:1, and / or an LCVD at least 90% identical to SEQ ID NO:2 comprising a histidine at one or more positions selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94 of SEQ ID NO:2; (b) an LCVD at least 90% identical to SEQ ID NO:126 comprising a histidine at one or more positions selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, or 111 in SEQ ID NO:126. and (c) an HCVD that is at least 90% identical to SEQ ID NO: 229 comprising a histidine at one or more positions selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, or 100 in SEQ ID NO: 229, and / or an LCVD that is at least 90% identical to SEQ ID NO: 230 comprising a histidine at one or more positions selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99 in SEQ ID NO: 230.

[0025] In some embodiments, the first ABD is (a) a HCVD of SEQ ID NO: 1, 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105; 6, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, or 227; (c) one of the HCVDs of SEQ ID NOs: 229, 238, 243, 244, 245, 246, 248, 251, 253, 255, or 267.

[0026] In some embodiments, the first ABD comprises one of the following LCVDs: (a) an LCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122, 123, 124, or 125; (b) an LCVD of SEQ ID NO: 127, 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, or 228; and (c) an LCVD of SEQ ID NO: 230, 275, 276, 278, 281, 283, 287, 289, 290, 292, or 297.

[0027] In some embodiments, the first ABD is selected from the group consisting of (a) a HCVD of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105, and / or a HCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122,, 123, 124, or 125, and the first antigen-binding domain is selected from the group consisting of (i) an HCVD of SEQ ID NO: 1 and an LCVD of SEQ ID NO: 2, (ii) an HCVD of SEQ ID NO: 1 and an LCVD that is not one of SEQ ID NOs: 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, and 122 to 125, or (iii) an LCVD of SEQ ID NO: 2 and an LCVD that is not one of SEQ ID NOs: 14, 17 to 22, 24, 25, 29 to 31, 33, 34, 40, 44, 46, 48, 49, 53, 86 to 96, and 98 to 105. (b) an HCVD of SEQ ID NO: 147, 148, 150, 151, 154, 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, or 227, and / or an LCVD of SEQ ID NO: 127, 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, or 228, wherein the first ABD is (i) an HCVD of SEQ ID NO: 126 and an LCVD of SEQ ID NO: 127; (ii) an HCVD of SEQ ID NO: 126 and an LCVD other than one of SEQ ID NOs: 181, 182, 184, 185, 187-189, 191, 199, 201, 203, and 228; (iii) an LCVD of SEQ ID NO: 127 and an HCVD other than one of SEQ ID NOs: 147, 148, 150, 151, 154, 166-170, 172-175, 208-222, and 224-227; and (c) an HCVD of SEQ ID NOs: 238, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 300, 301, 302, 303, 304, 305, 306, 307 46, 248, 251, 253, 255, or 267, and / or a LCVD of SEQ ID NO:230, 275, 276, 278, 281, 283, 287, 289, 290, 292, or 297, wherein the first ABD comprises (i) a LCVD of SEQ ID NO:229 and a LCVD of SEQ ID NO:230, (ii) a HCVD of SEQ ID NO:229 and a LCVD that is not one of SEQ ID NOs:275, 276, 278, 281, 283, 287, 289, 290, 292, or 297, and (iii) a LCVD of SEQ ID NO:230 and a LCVD of SEQ ID NO:238, 243-246, 248, 251, 253, 255, and 267, which do not include HCVD.

[0028] In some embodiments, ABPC is degraded in the target mammalian cell after internalization of ABPC by the target mammalian cell. In some embodiments, ABPC comprises a conjugated toxin, radioisotope, drug, or small molecule.

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

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

[0031] In some embodiments, the composition provides an increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 20% to 50% increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 2 to 5 fold increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0032] In some embodiments, the composition causes less reduction in the level of PTK7 displayed on the surface of target mammalian cells compared to the composition that contains the same amount of control ABPC.In some embodiments, the composition does not cause detectable reduction in the level of PTK7 present on the surface of target mammalian cells.

[0033] Also provided herein is a pharmaceutical composition comprising an effective amount of an antigen binding protein construct (ABPC), comprising: a first ABD capable of specifically binding to PTK7 or an epitope of PTK7 present on the surface of a target mammalian cell; and a conjugated toxin, radioisotope, drug, or small molecule, wherein (a) the dissociation rate of the first ABD at about pH 4.0 to about 6.5 is faster than its dissociation rate at about pH 7.0 to about 8.0, or the dissociation constant (K D ) at pH 7.0 to 8.0 D and (b) the composition provides one or more of: 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 endolysosomal delivery in the target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0034] In some embodiments, the first ABD comprises one of: (a) an HCVD of MYT9345, (b) an HCVD of MYT9359, (c) an HCVD of MYT9361, (d) an HCVD of MYT9412, (e) an HCVD of MYT9460, (f) an HCVD of MYT9792, and (g) an HCVD of MYT9797, each HCVD optionally having one or more histidine substitutions. In some embodiments, the first ABD comprises one of: (a) an LCVD of MYT9345, (b) an LCVD of MYT9359, (c) an LCVD of MYT9361, (d) an LCVD of MYT9412, (e) an LCVD of MYT9460, (f) an LCVD of MYT9792, and (g) an LCVD of MYT9797, each LCVD optionally having one or more histidine substitutions.

[0035] In some embodiments, the first ABD comprises at least one of: (a) an HCVD of MYT9345 and / or an LCVD of MYT9345; (b) an HCVD of MYT9359 and / or an LCVD of MYT9359; (c) an HCVD of MYT9361 and / or an LCVD of MYT9361; (d) an HCVD of MYT9412 and / or an LCVD of MYT9412; (e) an HCVD of MYT9460 and / or an LCVD of MYT9460; (f) an HCVD of MYT9792 and / or an LCVD of MYT9792; and (g) an HCVD of MYT9797 and / or an LCVD of MYT9797, each HCVD and / or LCVD optionally having one or more histidine substitutions.

[0036] In some embodiments, the HCVD comprises one of: (a) an HCVD of MYT9345 comprising SEQ ID NO: 301; (b) an HCVD of MYT9359 comprising SEQ ID NO: 375; (c) an HCVD of MYT9361 comprising SEQ ID NO: 459; (d) an HCVD of MYT9412 comprising SEQ ID NO: 542; (e) an HCVD of MYT9460 comprising SEQ ID NO: 628; (f) an HCVD of MYT9792 comprising SEQ ID NO: 710; and (g) an HCVD of MYT9797 SEQ ID NO: 803. In some embodiments, the LCVD comprises one of: (a) an LCVD of MYT9345 comprising SEQ ID NO: 302; (b) an LCVD of MYT9359 comprising SEQ ID NO: 376; (c) an LCVD of MYT9361 comprising SEQ ID NO: 460; (d) an LCVD of MYT9412 comprising SEQ ID NO: 543; (e) an LCVD of MYT9460 comprising SEQ ID NO: 629; (f) an LCVD of MYT9792 comprising SEQ ID NO: 711; and (g) an LCVD of MYT9797 SEQ ID NO: 804.

[0037] In some embodiments, the first ABD is (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively with one or more amino acids substituted with histidine; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, collectively with one or more amino acids substituted with histidine; (c) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively, collectively with one or more amino acids substituted with histidine; (d) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 544, 545, and 546, collectively with one or more amino acids substituted with histidine; (e) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, in which collectively one or more amino acids in SEQ ID NOs: 630, 631, and 632 have been substituted with histidine; (f) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, in which collectively one or more amino acids in SEQ ID NOs: 712, 713, and 714 have been substituted with histidine; (g) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, in which collectively one or more amino acids in SEQ ID NOs: 805, 806, and 807 have been substituted with histidine.

[0038] In some embodiments, the first ABD is (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively with one or more amino acids substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively with one or more amino acids substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, collectively with one or more amino acids substituted with histidine; (d) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, collectively with one or more amino acids substituted with histidine; (e) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 633, 634 and 635, respectively, in which collectively one or more amino acids in SEQ ID NOs: 633, 634 and 635 have been substituted with histidine; (f) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 715, 716 and 717, respectively, in which collectively one or more amino acids in SEQ ID NOs: 715, 716 and 717 have been substituted with histidine; (g) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 808, 809 and 810, respectively, in which collectively one or more amino acids in SEQ ID NOs: 808, 809 and 810 have been substituted with histidine.

[0039] In some embodiments, the first ABD is selected from the group consisting of: (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 303, 304, and 305 substituted with histidine; and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine; and 379, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 377, 378, and 379 substituted with histidine; and / or LCVD, comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 380, 381, and 382 substituted with histidine; (c) LCVD, comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 462, 463, and 464, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 463, 464, and 465, collectively having one or more total amino acid positions of SEQ ID NOs: 464, 465, and 466, collectively having one or more total amino acid positions of SEQ ID NOs: 465, 466, and 467, collectively having one or more total amino acid positions of SEQ ID NOs: 466, 467, and 468, collectively having one or more total amino acid positions of SEQ ID NOs: 467, 468, and 469 ... and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, collectively, having one or more amino acid positions substituted with histidine; (d) LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 544, 545, and 546, respectively, collectively, having one or more amino acid positions substituted with histidine; and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 547, 548, and 549 substituted with histidine; (e) HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 630, 631, and 632 substituted with histidine; and / or SEQ ID NO: 633;(f) LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 633, 634, and 635, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 633, 634, and 635 substituted with histidine; (g) HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 712, 713, and 714 substituted with histidine; and / or CDR1, CDR2, and CDR3 of SEQ ID NOs: 715, 716, and 717, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 715, 716, and 717 substituted with histidine. (g) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 805, 806, and 807 substituted with histidine; and / or an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 808, 809, and 810, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 808, 809, and 810 substituted with histidine.

[0040] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally including a histidine at one or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally including a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) a HCVD at least 90% identical to SEQ ID NO: 542; (f) a HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; (g) a HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102 and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0041] In some embodiments, the first ABD is selected from (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally including a histidine at one or more positions selected from 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 25, 27, 29, 30, 35, 36, 38, 40, 42, 44, 46, 48, 49, 50, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 711; and (g) an LCVD that is at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0042] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally comprising a histidine at two or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally comprising a histidine at two or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an HCVD at least 90% identical to SEQ ID NO: 542; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at two or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; (g) an HCVD at least 90% identical to SEQ ID NO: 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102 and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at two or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0043] In some embodiments, the first ABD is selected from (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally comprising a histidine at two or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally comprising a histidine at two or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at two or more positions selected from the group consisting of 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at two or more positions selected from the group consisting of 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at positions 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally containing a histidine at positions 25, 27, 29, 30, 35, 36, 40, 42, 46, 48, 49, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; , 56, 57, 91, 93, 94, 95, 98 and 99 in SEQ ID NO: 711, and optionally containing a histidine at two or more positions selected from the group consisting of: 56, 57, 91, 93, 94, 95, 98 and 99 in SEQ ID NO: 804, and (g) an LCVD at least 90% identical to SEQ ID NO: 804, and optionally containing a histidine at two or more positions selected from the group consisting of 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0044] In some embodiments, the first ABD is (a) an HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301, and / or an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52 in SEQ ID NO: 375; , 55, 58, 59, 63, 97, 99, and 108 of SEQ ID NO: 375, and / or a LCVD at least 90% identical to SEQ ID NO: 376, and optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) a histidine at one or more positions selected from 32, 99, 101, 102, 106, and 111 of SEQ ID NO: 459; and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 of SEQ ID NO: 460; (d) a HCVD which is at least 90% identical to SEQ ID NO: 542, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542, and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 3; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; and / or 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98 in SEQ ID NO: 629;(f) an LCVD at least 90% identical to SEQ ID NO: 629, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110 and 113 in SEQ ID NO: 710, and / or 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95 in SEQ ID NO: 711. (g) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100 and 107 in SEQ ID NO: 803, and / or an LCVD at least 90% identical to SEQ ID NO: 804, optionally including a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0045] In some embodiments, the first ABD comprises (a) an HCVD of SEQ ID NO: 301, or one of 309-342, (b) an HCVD of SEQ ID NO: 375, or one of 383-423, (c) an HCVD of SEQ ID NO: 459, or one of 467-511, (d) an HCVD of SEQ ID NO: 542, or one of 550-592, (e) an HCVD of SEQ ID NO: 628, or any of 636-675, (f) an HCVD of SEQ ID NO: 710, or any of 718-767, and (g) an HCVD of SEQ ID NO: 803, or any of 811-854. In some embodiments, the first ABD comprises one of: (a) an LCVD of SEQ ID NO: 302, or one of 343-374; (b) an LCVD of SEQ ID NO: 376, or one of 424-458; (c) an LCVD of SEQ ID NO: 460, or one of 512-541; (d) an LCVD of SEQ ID NO: 543, or one of 593-627; (e) an LCVD of SEQ ID NO: 629, or one of 676-709; (f) an LCVD of SEQ ID NO: 711, or one of 768-802; and (g) an LCVD of SEQ ID NO: 804 or one of 855-892.

[0046] In some embodiments, the first ABD is (a) any one of SEQ ID NOs: 301, 309 to 342, and / or any one of SEQ ID NOs: 302, or any one of SEQ ID NOs: 343 to 374, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 301 and an LCVD of SEQ ID NO: 302, (ii) an HCVD of SEQ ID NO: 301 and an LCVD other than one of SEQ ID NOs: 344, 349 to 352, 354, 359 to 361, 363, 366 to 368, 370 and 373, or (iii) an HCVD other than one of SEQ ID NOs: 312, 313, 315, 319 to 323, 327, 329, 335, 340 and 341 and SEQ ID NO: 302; (b) any one of SEQ ID NOs: 375, 383 to 423, and / or any one of SEQ ID NOs: 376, or any one of SEQ ID NOs: 424 to 458, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 375 and an LCVD of SEQ ID NO: 376, (ii) an LCVD of SEQ ID NO: 375 and not one of SEQ ID NOs: 425, 429, 430, 431, 432, 433, 435, 436, 437, 438, 442, 444, 445, 446, 449, 450, 453, and 455, or (iii) an HCVD of SEQ ID NOs: 383, 384, 387, 389, 391, 394, 395, 398, 401, 402, 406, 410, 412, and 421, and not one of SEQ ID NO: 376; (c) any one of SEQ ID NOs: 459, 467 to 511, and / or any one of SEQ ID NOs: 460, or any one of SEQ ID NOs: 512 to 541, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 459 and an LCVD other than SEQ ID NO: 460, (ii) an HCVD of SEQ ID NO: 459 and an LCVD other than one of SEQ ID NOs: 518, 519, 521, 524, 533, and 536, or (iii) an HCVD other than one of SEQ ID NOs: 473, 496, 498, 499, 503, and 508 and an LCVD of SEQ ID NO: 460; (d) any one of SEQ ID NOs: 542, 550 to 592, and / or any one of SEQ ID NOs: 543, or any one of SEQ ID NOs: 593 to 627, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 542 and an LCVD of SEQ ID NO: 543, (ii) an HCVD of SEQ ID NO: 542 and an LCVD other than one of SEQ ID NOs: 594, 598, 599, 600, 601, 611, 614, and 620, or (iii) an HCVD other than one of SEQ ID NOs: 551, 553, 554, 555, 556, 563, 565, 568, 582, 584, and 585, and an LCVD of SEQ ID NO: 543; (e) any one of SEQ ID NOs: 628, 636-675, and / or any one of SEQ ID NOs: 629, or any one of SEQ ID NOs: 676-709, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 628 and an LCVD of SEQ ID NO: 629, (ii) an HCVD of SEQ ID NO: 628 and an LCVD that is not one of SEQ ID NOs: 677, 678, 680, 681, 685, 688, 692, 694, 696, 700, 701, 702, 703, 704, and 705, or (iii) an HCVD that is not one of SEQ ID NOs: 636, 638, 640, 646, 648, 649, 650, 651, 652, 653, 666, 667, 668, and 669, and an LCVD of SEQ ID NO: 629; (f) any one of SEQ ID NOs: 710, or any one of SEQ ID NOs: 718 to 767, and / or any one of SEQ ID NOs: 711, or any one of SEQ ID NOs: 768 to 802, wherein the first ABD is (i) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NO: 711, (ii) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NOs: 769, 771, 773, 774, 779, 780, 785 , 786, 788, 790, 791, 792, 795, and 796; or (iii) an HCVD other than one of SEQ ID NOs: 721, 722, 723, 725, 727, 728, 731, 735, 736, 743, 744, 745, 746, 748, 749, 751, 753, 755, 756, 757, 758, and 761, and an LCVD of SEQ ID NO: 711; and (g) an HCVD of any one of SEQ ID NOs: 803, or 811 to 854, and / or an LCVD of any one of SEQ ID NOs: 804, or 855 to 892, wherein the first ABD comprises one of: (i) an HCVD of SEQ ID NO: 803 and SEQ ID NO: 804, (ii) an HCVD of SEQ ID NO: 803 and an LCVD other than one of SEQ ID NOs: 862, 864 to 866, 868, 870, 881, and 882, or (iii) an HCVD other than one of SEQ ID NOs: 818, 821, 824, 826 to 829, 835, 841, 848, and 850 and an LCVD of SEQ ID NO: 804.

[0047] In some embodiments, the composition results in increased toxin release in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition increases toxin release in target mammalian cells by at least 20% or 50% compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition increases toxin release in target mammalian cells by at least 2-5 fold compared to a composition comprising the same amount of control ABPC.

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

[0049] In some embodiments, the composition provides increased endolysosomal delivery, including at least a 20% or 50% increase in endolysosomal delivery, compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition provides at least a 2-5 fold increase in endolysosomal delivery in target mammalian cells, compared to a composition comprising the same amount of control ABPC.

[0050] In some embodiments, the composition causes less reduction in the level of PTK7 displayed on the surface of target mammalian cell compared with the composition that contains the same amount of control ABPC.In some embodiments, the composition causes no detectable reduction in the level of PTK7 present on the surface of target mammalian cell.In some embodiments, the target mammalian cell is cancer cell.

[0051] 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 KD of the ABD at a pH of about 4.0 to about 6.5 is at least 10 times faster than the KD of the ABD at a pH of about 7.0 to about 8.0. D In some embodiments, the KD of the ABD at a pH of about 4.0 to about 6.5 is at least 10% greater than the KD of the ABD at a pH of about 7.0 to about 8.0. D In some embodiments, the KD of the ABD at a pH of about 4.0 to about 6.5 is at least three times greater than the KD of the ABD at a pH of about 7.0 to about 8.0. D is at least 10 times larger than

[0052] In some embodiments, ABPC is cytotoxic or cytostatic to target mammalian cells.

[0053] In some embodiments, ABPC is cross-reactive with non-human primate PTK7 and human PTK7.In some embodiments, ABPC is cross-reactive with non-human primate PTK7, human PTK7, and one or both of rat PTK7 and mouse PTK7.In some embodiments, ABPC is cross-reactive with non-human primate PTK7, human PTK7, rat PTK7, and mouse PTK7.In some embodiments, ABD binds to the epitope of PTK7 present on the surface of cells from Old World monkeys.

[0054] In some embodiments, the ABPC comprises a single polypeptide. In some embodiments, the ABD is selected from a VH domain, a VHH domain, a VNAR domain, and a scFv. In some embodiments, the ABPC is BiTe, (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a scFv-CH-CL-scFv, a HSAbody, a scDiabody-HSA, or a tandem-scFv.

[0055] In some embodiments, the ABPC comprises two or more polypeptides. In some embodiments, the ABPC comprises an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes construct, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, an Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv-(H)IgG, an IgG(L)-scFv, a scFv-(L)IgG, an IgG(L,H)-Fv, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, a KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, F(ab') 2 -scFv 2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, Diabody-Fc, tandem scFv-Fc, VHH-Fc, tandem VHH-Fc, VHH-Fc KiH, Fab-VHH-Fc, Intrabody, dock and lock, ImmTAC, IgG-IgG conjugate, Cov-X-Body, scFv1-PEG-scFv2, Adnectin, DARPin, fibronectin, and DEP conjugate.

[0056] In some embodiments, at least one polypeptide of ABPC is linked to a toxin, radioisotope, drug, or small molecule via a cleavable linker. In some embodiments, at least one polypeptide of ABPC is linked to a toxin, radioisotope, drug, or small molecule via a non-cleavable linker.

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

[0058] In some embodiments, the control ABPC is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, 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 about 7.0 to about 8.0, and (c) the dissociation constant (K D ) at pH levels of about 7.0 to about 8.0 D Not more than three times larger than

[0059] In some embodiments, the control ABPC is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, 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 about 7.0 to about 8.0; and (c) the dissociation constant (K D ) is K at pH of about 7.0 to about 8.0 D Not more than twice as large as

[0060] In some embodiments, the control ABPC is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, (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 about 7.0 to about 8.0, and (c) the dissociation constant (K D ) is K at pH of about 7.0 to about 8.0 D not more than one time greater than

[0061] In some embodiments, the control ABPC is selected from MYT9345, MYT9359, MYT9361, MYT9412, MYT9460, MYT9792, MYT9797, cofetuzumab, 7C8, and 12C6.

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

[0063] Also provided herein are kits comprising at least one dose of any of the pharmaceutical compositions comprising any of the PCs described herein.

[0064] Also provided herein is a compound having (a) a dissociation rate of the first ABD at a pH of about 4.0 to about 6.5 that is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or (b) a dissociation constant (K D ) at a pH of about 7.0 to about 8.0 D and a first ABD capable of specifically binding PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, the first ABD being greater than 1.

[0065] In some embodiments, the first ABD comprises one of: (a) an HCVD of MYT9345, (b) an HCVD of MYT9359, (c) an HCVD of MYT9361, (d) an HCVD of MYT9412, (e) an HCVD of MYT9460, (f) an HCVD of MYT9792, (g) an HCVD of MYT9797, (h) an HCVD of cofetuzumab, (i) an HCVD of 7C8, and (j) an HCVD of 12C6, each HCVD optionally having one or more amino acids substituted with histidine.

[0066] In some embodiments, the first ABD comprises one of: (a) an LCVD of MYT9345, (b) an LCVD of MYT9359, (c) an LCVD of MYT9361, (d) an LCVD of MYT9412, (e) an LCVD of MYT9460, (f) an LCVD of MYT9792, (g) an LCVD of MYT9797, (h) an LCVD of cofetuzumab, (i) an LCVD of 7C8, and (j) an LCVD of 12C6, each LCVD optionally having one or more amino acids substituted with histidine.

[0067] In some embodiments, the first ABD is (a) an HCVD of MYT9345 and / or an LCVD of MYT9345, either or both of which have one or more amino acids optionally substituted with histidine; (b) an HCVD of MYT9359 and / or an LCVD of MYT9359, either or both of which have one or more amino acids optionally substituted with histidine; (c) an HCVD of MYT9361 and / or an LCVD of MYT9361, either or both of which have one or more amino acids optionally substituted with histidine; (d) an HCVD of MYT9361 and / or an LCVD of MYT9361, either or both of which have one or more amino acids optionally substituted with histidine; (e) an HCVD of MYT9460 and / or an LCVD of MYT9460, either or both of which have one or more amino acids optionally substituted with histidine; (f) an HCVD of MYT9792 and / or an LCVD of MYT9792, either or both of which have one or more amino acids optionally substituted with histidine; and (g) an HCVD of MYT9797 and / or an LCVD of MYT9797, either or both of which have one or more amino acids optionally substituted with histidine.

[0068] In some embodiments, the HCVD comprises one of: (a) an HCVD of MYT9345 comprising SEQ ID NO:301; (b) an HCVD of MYT9359 comprising SEQ ID NO:375; (c) an HCVD of MYT9361 comprising SEQ ID NO:459; (d) an HCVD of MYT9412 comprising SEQ ID NO:542; (e) an HCVD of MYT9460 comprising SEQ ID NO:628; (f) an HCVD of MYT9792 comprising SEQ ID NO:710; and (g) an HCVD of MYT9797 comprising SEQ ID NO:803.

[0069] In some embodiments, the LCVD comprises one of: (a) an LCVD of MYT9345 comprising SEQ ID NO: 302; (b) an LCVD of MYT9359 comprising SEQ ID NO: 376; (c) an LCVD of MYT9361 comprising SEQ ID NO: 460; (d) an LCVD of MYT9412 comprising SEQ ID NO: 543; (e) an LCVD of MYT9460 comprising SEQ ID NO: 629; (f) an LCVD of MYT9792 comprising SEQ ID NO: 711; and (g) an LCVD of MYT9797 comprising SEQ ID NO: 804.

[0070] In some embodiments, the first ABD is (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively with one or more amino acids substituted with histidine; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, collectively with one or more amino acids substituted with histidine; (c) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively, collectively with one or more amino acids substituted with histidine; (d) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 544, 545, and 546, collectively with one or more amino acids substituted with histidine; (e) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, in which collectively one or more amino acids in SEQ ID NOs: 630, 631, and 632 have been substituted with histidine; (f) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, in which collectively one or more amino acids in SEQ ID NOs: 712, 713, and 714 have been substituted with histidine; (g) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, in which collectively one or more amino acids in SEQ ID NOs: 805, 806, and 807 have been substituted with histidine.

[0071] In some embodiments, the first ABD is (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively with one or more amino acids substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively with one or more amino acids substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, collectively with one or more amino acids substituted with histidine; (d) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, collectively with one or more amino acids substituted with histidine; (e) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 633, 634 and 635, respectively, in which collectively one or more amino acids in SEQ ID NOs: 633, 634 and 635 have been substituted with histidine; (f) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 715, 716 and 717, respectively, in which collectively one or more amino acids in SEQ ID NOs: 715, 716 and 717 have been substituted with histidine; (g) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 808, 809 and 810, respectively, in which collectively one or more amino acids in SEQ ID NOs: 808, 809 and 810 have been substituted with histidine.

[0072] In some embodiments, the first ABD is selected from the group consisting of: (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 303, 304, and 305 substituted with histidine; and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine; and 379, collectively having one or more amino acid positions of SEQ ID NOs: 377, 378, and 379, optionally substituted with histidine; and / or LCVDs, comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively having one or more amino acid positions of SEQ ID NOs: 380, 381, and 382, ​​optionally substituted with histidine; (c) CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively. and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, and collectively having one or more amino acid positions of SEQ ID NOs: 464, 465, and 466 substituted with histidine; (d) SEQ ID NOs: 544, 545, and 546, respectively, and collectively having one or more amino acid positions of SEQ ID NOs: 544, 545, and 546 substituted with histidine; and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 547, 548, and 549 substituted with histidine; (e) HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 630, 631, and 632 optionally substituted with histidine;and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 633, 634, and 635, respectively, collectively having one or more of the total amino acid positions of SEQ ID NOs: 633, 634, and 635 substituted with histidine; (f) HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, collectively having one or more of the total amino acid positions of SEQ ID NOs: 712, 713, and 714 substituted with histidine; and / or CDR1, CDR2, and CDR3 of SEQ ID NOs: 715, 716, and 717, respectively, collectively having (g) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, and collectively, one or more amino acid positions of SEQ ID NOs: 805, 806, and 807, substituted with histidine; and / or an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 808, 809, and 810, respectively, and collectively, one or more amino acid positions of SEQ ID NOs: 808, 809, and 810, substituted with histidine.

[0073] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally including a histidine at one or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally including a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) a HCVD at least 90% identical to SEQ ID NO: 542; (f) a HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; (g) a HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102 and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0074] In some embodiments, the first ABD is (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally comprising a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally comprising a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally including a histidine at one or more positions selected from 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 25, 27, 29, 30, 35, 36, and (g) an LCVD that is at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0075] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally comprising a histidine at two or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally comprising a histidine at two or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an HCVD at least 90% identical to SEQ ID NO: 542; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at two or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; (g) an HCVD at least 90% identical to SEQ ID NO: 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102 and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at two or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0076] In some embodiments, the first ABD is (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally containing a histidine at two or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at two or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally including a histidine at positions 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at positions 25, 27, 29, 30, 35, 36, and (g) an LCVD that is at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at two or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0077] In some embodiments, the first ABD is (a) an HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301, and / or an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52 in SEQ ID NO: 375; , 55, 58, 59, 63, 97, 99, and 108 of SEQ ID NO: 375, and / or a LCVD at least 90% identical to SEQ ID NO: 376, and optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) a histidine at one or more positions selected from 32, 99, 101, 102, 106, and 111 of SEQ ID NO: 459; and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 of SEQ ID NO: 460; (d) a HCVD which is at least 90% identical to SEQ ID NO: 542, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542, and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 3; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; and / or 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98 in SEQ ID NO: 629;(f) an LCVD at least 90% identical to SEQ ID NO: 629, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110 and 113 in SEQ ID NO: 710, and / or 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95 in SEQ ID NO: 711. (g) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100 and 107 in SEQ ID NO: 803, and / or an LCVD at least 90% identical to SEQ ID NO: 804, optionally including a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0078] In some embodiments, the first ABD is selected from the group consisting of (a) an HCVD of SEQ ID NO: 301, or one of 309-342; (b) an HCVD of SEQ ID NO: 375, or one of 383-423; (c) an HCVD of SEQ ID NO: 459, or one of 467-511; (d) an HCVD of SEQ ID NO: 542, or one of 550-592; (e) an HCVD of SEQ ID NO: 628, or one of 636-675; (f) an HCVD of SEQ ID NO: 710, or one of 718-767; (g) an HCVD of SEQ ID NO: 803, or one of 811-854; and / or or the first ABD comprises (a) an LCVD of SEQ ID NO: 302, or one of 343-374, (b) an LCVD of SEQ ID NO: 376, or one of 424-458, (c) an LCVD of SEQ ID NO: 460, or one of 512-541, (d) an LCVD of SEQ ID NO: 543, or one of 593-627, (e) an LCVD of SEQ ID NO: 629, or one of 676-709, (f) an LCVD of SEQ ID NO: 711, or one of 768-802, or (g) an HCVD of an LCVD of SEQ ID NO: 804, or one of 855-892.

[0079] In some embodiments, the first ABD is (a) an HCVD of SEQ ID NO: 301, or an HCVD of SEQ ID NO: 309 to 342, and / or an LCVD of any one of SEQ ID NOs: 302, or an LCVD of any one of SEQ ID NOs: 343 to 374, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 301 and an LCVD of SEQ ID NO: 302, (ii) an HCVD of SEQ ID NO: 301 and an LCVD other than one of SEQ ID NOs: 344, 349 to 352, 354, 359 to 361, 363, 366 to 368, 370 and 373, or (iii) an HCVD other than one of SEQ ID NOs: 312, 313, 315, 319 to 323, 327, 329, 335, 340 and 341, and SEQ ID NO: 302; (b) an HCVD of SEQ ID NO: 375, or an HCVD of SEQ ID NO: 383 to 423, and / or an LCVD of any one of SEQ ID NOs: 376, or an LCVD of any one of SEQ ID NOs: 424 to 458, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 375 and an LCVD of SEQ ID NO: 376, (ii) an LCVD of SEQ ID NO: 375 and not one of SEQ ID NOs: 425, 429, 430, 431, 432, 433, 435, 436, 437, 438, 442, 444, 445, 446, 449, 450, 453, and 455, or (iii) an HCVD of SEQ ID NOs: 383, 384, 387, 389, 391, 394, 395, 398, 401, 402, 406, 410, 412, and 421, and not one of SEQ ID NO: 376; (c) an HCVD of SEQ ID NO: 459, or an HCVD of 467 to 511, and / or an LCVD of any one of SEQ ID NOs: 460, or an LCVD of any one of SEQ ID NOs: 512 to 541, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 459 and an LCVD other than one of SEQ ID NOs: 518, 519, 521, 524, 533, and 536, or (iii) an HCVD other than one of SEQ ID NOs: 473, 496, 498, 499, 503, and 508 and an LCVD of SEQ ID NO: 460; (d) an HCVD of SEQ ID NO: 542, or an HCVD of any one of SEQ ID NOs: 550 to 592, and / or an LCVD of any one of SEQ ID NOs: 543, or an LCVD of any one of SEQ ID NOs: 593 to 627, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 542 and an LCVD of SEQ ID NO: 543, (ii) an HCVD of SEQ ID NO: 542 and an LCVD other than one of SEQ ID NOs: 594, 598, 599, 600, 601, 611, 614, and 620, or (iii) an HCVD other than one of SEQ ID NOs: 551, 553, 554, 555, 556, 563, 565, 568, 582, 584, and 585, and an LCVD of SEQ ID NO: 543; (e) an HCVD of SEQ ID NO: 628, or an HCVD of SEQ ID NO: 636 to 675, and / or an LCVD of any one of SEQ ID NOs: 629, or an LCVD of any one of SEQ ID NOs: 676 to 709, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 628 and an LCVD of SEQ ID NO: 629, (ii) an HCVD of SEQ ID NO: 628 and an LCVD that is not one of SEQ ID NOs: 677, 678, 680, 681, 685, 688, 692, 694, 696, 700, 701, 702, 703, 704, and 705, or (iii) an HCVD that is not one of SEQ ID NOs: 636, 638, 640, 646, 648, 649, 650, 651, 652, 653, 666, 667, 668, and 669, and an LCVD of SEQ ID NO: 629; (f) an HCVD of SEQ ID NO: 710, or an HCVD of SEQ ID NO: 718 to 767, and / or an LCVD of any one of SEQ ID NOs: 711, or an LCVD of any one of SEQ ID NOs: 768 to 802, wherein the first ABD is (i) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NO: 711, (ii) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NOs: 769, 771, 773, 774, 779, 780, 785, 786, 787, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 8, 790, 791, 792, 795, and 796; or (iii) an HCVD other than one of SEQ ID NOs: 721, 722, 723, 725, 727, 728, 731, 735, 736, 743, 744, 745, 746, 748, 749, 751, 753, 755, 756, 757, 758, and 761, and an LCVD of SEQ ID NO: 711; and (g) an HCVD of SEQ ID NO: 803, or one of 811-854, and / or an LCVD of SEQ ID NO: 804, or one of 855-892, and the first ABD comprises one of: (i) an HCVD of SEQ ID NO: 803 and an LCVD of SEQ ID NO: 804, (ii) an HCVD of SEQ ID NO: 803 and an LCVD other than one of SEQ ID NOs: 862, 864-866, 868, 870, 881 and 882, or (iii) an HCVD other than one of SEQ ID NOs: 818, 821, 824, 826-829, 835, 841, 848 and 850 and not an LCVD of SEQ ID NO: 804.

[0080] In some embodiments, the first antigen binding domain comprises one of: (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, respectively, collectively with one or more amino acids substituted with histidine in total; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, respectively, collectively with one or more amino acids substituted with histidine in total; or (c) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, collectively with one or more amino acids substituted with histidine in total. In some embodiments, the first CCK4 binding domain comprises one of: (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, in which collectively one or more amino acids in total have been substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, in which collectively one or more amino acids in total have been substituted with histidine; or (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, in which collectively one or more amino acids in total have been substituted with histidine.

[0081] In some embodiments, the first CCK4 binding domain is (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, collectively substituted with histidine, one or more of the amino acid positions of SEQ ID NOs: 3, 4, and 5, respectively, and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, collectively substituted with histidine, one or more of the amino acid positions of SEQ ID NOs: 128, 129, and 130 ... collectively substituted with histidine, one or more of the amino acid positions or a LCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, wherein all of the amino acid positions of one or more of SEQ ID NOs: 131, 132, and 133, respectively, have been collectively substituted with histidine; (c) a HCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, wherein all of the amino acid positions of one or more of SEQ ID NOs: 231, 232, and 233, respectively, have been collectively substituted with histidine; and a LCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, wherein all of the amino acid positions of one or more of SEQ ID NOs: 234, 235, and 236, respectively, have been collectively substituted with histidine.

[0082] In some embodiments, the first antigen binding domain (ABD) is selected from the group consisting of: (a) an HCVD that is at least 90% identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at one or more positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107; (b) an HCVD that is at least 90% identical to SEQ ID NO:126, wherein the HCVD comprises a histidine at one or more positions of SEQ ID NO:1 selected from the group consisting of 53, 54, 56, 57, 58, 64, 98, 100, 102, 103, and 107; and / or (c) an HCVD that is at least 90% identical to SEQ ID NO: 229, wherein the HCVD comprises a histidine at one or more positions in SEQ ID NO: 229 selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100. In some embodiments, the first antigen-binding domain comprises one of: (a) an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 25, 29, 31, 35, 60, 93, and 94 of SEQ ID NO:2; (b) an LCVD that is at least 90% identical to SEQ ID NO:127, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94 of SEQ ID NO:127; or (c) an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99 in SEQ ID NO:230.

[0083] In some embodiments, the first antigen-binding domain comprises one of: (a) an HCVD that is at least 90% identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at two or more positions of SEQ ID NO:1 selected from the group consisting of 27, 29, 31, 34, and 53; and (b) an HCVD that is at least 90% identical to SEQ ID NO:126, wherein the HCVD comprises a histidine at two or more positions of SEQ ID NO:126 selected from the group consisting of 53, 56, 57, 102, and 105.

[0084] In some embodiments, the first antigen-binding domain is selected from the group consisting of: (a) an HCVD at least 90% identical to SEQ ID NO:1 comprising a histidine at one or more positions selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107 of SEQ ID NO:1; and / or an LCVD at least 90% identical to SEQ ID NO:2 comprising a histidine at one or more positions selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94 of SEQ ID NO:2; (b) an LCVD at least 90% identical to SEQ ID NO:126 comprising a histidine at one or more positions selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, or 111 in SEQ ID NO:126. and (c) an HCVD that is at least 90% identical to SEQ ID NO: 229 comprising a histidine at one or more positions selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, or 100 in SEQ ID NO: 229; and / or an LCVD that is at least 90% identical to SEQ ID NO: 230 comprising a histidine at one or more positions selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99 in SEQ ID NO: 230.

[0085] In some embodiments, the first antigen binding domain is selected from the group consisting of (a) a HCVD of SEQ ID NO: 1, 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105; , 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, or 227; (c) an HCVD of one of the HCVDs of SEQ ID NOs: 229, 238, 243, 244, 245, 246, 248, 251, 253, 255, or 267.

[0086] In some embodiments, the first antigen binding domain comprises one of the following LCVDs: (a) an LCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122, 123, 124, or 125; (b) an LCVD of SEQ ID NO: 127, 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, or 228; and (c) an LCVD of SEQ ID NO: 230, 275, 276, 278, 281, 283, 287, 289, 290, 292, or 297.

[0087] In some embodiments, the first antigen binding domain comprises one of the following: (a) a HCVD of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105, and / or a HCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105, and / or a HCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105, and / or a HCVD of SEQ ID NO: 2, 56, 6 or (iii) a LCVD of SEQ ID NO: 2, and a LCVD of SEQ ID NO: 7, 78, 110, 113, 114, 119, 122, 123, 124, or 125, wherein the first antigen-binding domain is selected from the group consisting of (i) a HCVD of SEQ ID NO: and a LCVD of SEQ ID NO:; (ii) a HCVD of SEQ ID NO: and a LCVD that is not one of the SEQ ID NOs: 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, and 122-125; or (iii) a LCVD of SEQ ID NO: 2, and a LCVD of SEQ ID NO: NO: HCVD that is not one of 14, 17-22, 24, 25, 29-31, 33, 34, 40, 44, 46, 48, 49, 53, 86-96, and 98-105; (b) SEQ ID NOs: 147, 148, 150, 151, 154, 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 22 0, 221, 222, 224, 225, 226, or 227; and / or SEQ ID NOs: 127, 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, or 228, wherein the first antigen-binding domain does not comprise: (i) an HCVD of SEQ ID NO: 126 and an LCVD of SEQ ID NO: 127; (ii) an HCVD of SEQ ID NO: 126 and an LCVD that is not one of the SEQ ID NOs: (iii) an LCVD of SEQ ID NO:127 and an HCVD of SEQ ID NO:147, 148, 150, 151, 154, 166-170, 172-175, 208-222, and 224-227; and (c) an HCVD of SEQ ID NO:238, 243, 244, 245, 246, 248, 251, 253, 255, or 267;and / or an LCVD of SEQ ID NO: 230, 275, 276, 278, 281, 283, 287, 289, 290, 292, or 297, wherein the first antigen-binding domain is selected from (i) an HCVD of SEQ ID NO: 229 and an LCVD of SEQ ID NO: 230; (ii) an HCVD of SEQ ID NO: 229 and an LCVD that is not one of SEQ ID NO: 275, 276, 278, 281, 283, 287, 289, 290, 292, and 297; and (iii) an LCVD of SEQ ID NO: 230 and an HCVD that is not one of SEQ ID NO: 238, 243-246, 248, 251, 253, 255, and 267.

[0088] In some embodiments, ABPC is degraded in the target mammalian cell after internalization of ABPC by the target mammalian cell. In some embodiments, ABPC comprises a conjugated toxin, radioisotope, drug, or small molecule.

[0089] In some embodiments, the composition comprising ABPC results in increased toxin release in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC increases toxin release in target mammalian cells by at least 20% or 50% compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC increases toxin release in target mammalian cells by at least 2-5 fold compared to a composition comprising the same amount of control ABPC.

[0090] In some embodiments, a composition comprising ABPC provides increased killing of target mammalian cells compared to a composition comprising an equivalent amount of control ABPC. In some embodiments, a composition comprising ABPC provides at least a 20% to 50% increase in killing of target mammalian cells compared to a composition comprising an equivalent amount of control ABPC. In some embodiments, a composition comprising ABPC provides at least a 2 to 5 fold increase in killing of target mammalian cells compared to a composition comprising an equivalent amount of control ABPC.

[0091] In some embodiments, the composition comprising ABPC provides increased endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, ABPC provides at least a 20% increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC provides at least a 50% increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC provides at least a 2-fold increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC provides at least a 5-fold increase in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control ABPC.

[0092] In some embodiments, the composition that comprises ABPC does not cause the level of PTK7 displayed on the surface of target mammalian cells to be significantly reduced compared with the composition that comprises the same amount of control ABPC.In some embodiments, the composition that comprises ABPC does not cause the level of PTK7 displayed on the surface of target mammalian cells to be significantly reduced.

[0093] Also provided herein is an antigen binding protein construct (ABPC) comprising: a first ABD capable of specifically binding to PTK7 or an epitope of PTK7 present on the surface of a target mammalian cell; and a conjugated toxin, radioisotope, drug, or small molecule, wherein (a) the dissociation rate of the first ABD at about pH 4.0 to about 6.5 is faster than its dissociation rate at about pH 7.0 to about 8.0, or the dissociation constant (K D ) at pH 7.0 to 8.0 Dand (b) the composition provides one or more of: 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 endolysosomal delivery in the target mammalian cell compared to a composition comprising the same amount of a control ABPC.

[0094] In some embodiments, the first ABD comprises one of (a) an HCVD of MYT9345, (b) an HCVD of MYT9359, (c) an HCVD of MYT9361, (d) an HCVD of MYT9412, (e) an HCVD of MYT9460, (f) an HCVD of MYT9792, (g) an HCVD of MYT9797, (h) an HCVD of cofetuzumab, (i) an HCVD of 7C8, and (j) an HCVD of 12C6, each of which has one or more amino acids optionally substituted with histidine. In some embodiments, the first ABD comprises one of (a) an LCVD of MYT9345, (b) an LCVD of MYT9359, (c) an LCVD of MYT9361, (d) an LCVD of MYT9412, (e) an LCVD of MYT9460, (f) an LCVD of MYT9792, (g) an LCVD of MYT9797, (h) an LCVD of cofetuzumab, (i) an LCVD of 7C8, and (j) an LCVD of 12C6, each of which has an LCVD substituted with one or more amino acids, optionally substituted with histidine.

[0095] In some embodiments, the first ABD is (a) an HCVD of MYT9345 and an LCVD of MYT9345, (b) an HCVD of MYT9359 and an LCVD of MYT9359, (c) an HCVD of MYT9361 and an LCVD of MYT9361, (d) an HCVD of MYT9412 and an LCVD of MYT9412, (e) an HCVD of MYT9460 and an LCVD of MYT9460, (f) an HCVD of MYT9792 and an LCVD of MYT9792, (g) an HCVD of MYT9361 and an LCVD of MYT9361, (h) an HCVD of MYT9412 and an LCVD of MYT9412, (i) an HCVD of MYT9460 and an LCVD of MYT9460, (j) an HCVD of MYT9792 and an LCVD of MYT9792, (k) an HCVD of MYT9361 and an LCVD of MYT9361, (l) an HCVD of MYT9361 and an LCVD of MYT9361, (l) an HCVD of MYT9412 and an LCVD of MYT9412, (l) an HCVD of MYT9460 and an LCVD of MYT9460, (l) an HCVD of MYT9792 and an LCVD of MYT9792, (l) an HCVD of MYT9361 and an LCVD of MYT9361, (l) an HCVD of MYT9361 and an LCVD of MYT9361, (l) an HCVD of MYT9412 and an LCVD of MYT9412, (l) an HCVD of MYT9460 and an (g) the HCVD of MYT9797 and the LCVD of MYT9797; (h) the HCVD of cofetuzumab and the LCVD of cofetuzumab; (i) the HCVD of 7C8 and the LCVD of 7C8; (j) the HCVD of 12C6 and the LCVD of 12C6, each or any of the domains optionally having one or more amino acids substituted with histidine.

[0096] In some embodiments, the HCVD comprises one of: (a) an HCVD of MYT9345 comprising SEQ ID NO:301; (b) an HCVD of MYT9359 comprising SEQ ID NO:375; (c) an HCVD of MYT9361 comprising SEQ ID NO:459; (d) an HCVD of MYT9412 comprising SEQ ID NO:542; (e) an HCVD of MYT9460 comprising SEQ ID NO:628; (f) an HCVD of MYT9792 comprising SEQ ID NO:710; and (g) an HCVD of MYT9797 comprising SEQ ID NO:803. In some embodiments, the LCVD comprises one of: (a) an LCVD of MYT9345 comprising SEQ ID NO: 302; (b) an LCVD of MYT9359 comprising SEQ ID NO: 376; (c) an LCVD of MYT9361 comprising SEQ ID NO: 460; (d) an LCVD of MYT9412 comprising SEQ ID NO: 543; (e) an LCVD of MYT9460 comprising SEQ ID NO: 629; (f) an LCVD of MYT9792 comprising SEQ ID NO: 711; and (g) an LCVD of MYT9797 comprising SEQ ID NO: 804.

[0097] In some embodiments, the first ABD is (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively with one or more amino acids substituted with histidine; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, collectively with one or more amino acids substituted with histidine; (c) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively, collectively with one or more amino acids substituted with histidine; (d) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 544, 545, and 546, collectively with one or more amino acids substituted with histidine; (e) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, in which collectively one or more amino acids in SEQ ID NOs: 630, 631, and 632 have been substituted with histidine; (f) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, in which collectively one or more amino acids in SEQ ID NOs: 712, 713, and 714 have been substituted with histidine; (g) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, in which collectively one or more amino acids in SEQ ID NOs: 805, 806, and 807 have been substituted with histidine.

[0098] In some embodiments, the first ABD is (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively with one or more amino acids substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively with one or more amino acids substituted with histidine; (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, collectively with one or more amino acids substituted with histidine; (d) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, collectively with one or more amino acids substituted with histidine; (e) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 633, 634 and 635, respectively, in which collectively one or more amino acids in SEQ ID NOs: 633, 634 and 635 have been substituted with histidine; (f) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 715, 716 and 717, respectively, in which collectively one or more amino acids in SEQ ID NOs: 715, 716 and 717 have been substituted with histidine; (g) an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NOs: 808, 809 and 810, respectively, in which collectively one or more amino acids in SEQ ID NOs: 808, 809 and 810 have been substituted with histidine.

[0099] In some embodiments, the first ABD is selected from the group consisting of: (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 303, 304, and 305 substituted with histidine; and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, collectively having one or more total amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine; and 379, collectively having one or more amino acid positions of SEQ ID NOs: 377, 378, and 379, optionally substituted with histidine; and / or LCVDs, comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, collectively having one or more amino acid positions of SEQ ID NOs: 380, 381, and 382, ​​optionally substituted with histidine; (c) CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively. and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, and collectively having one or more amino acid positions of SEQ ID NOs: 464, 465, and 466 substituted with histidine; (d) SEQ ID NOs: 544, 545, and 546, respectively, and collectively having one or more amino acid positions of SEQ ID NOs: 544, 545, and 546 substituted with histidine; and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 547, 548, and 549 substituted with histidine; (e) HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 630, 631, and 632, respectively, collectively having one or more amino acid positions of SEQ ID NOs: 630, 631, and 632 optionally substituted with histidine;and / or LCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 633, 634, and 635, respectively, collectively having one or more of the total amino acid positions of SEQ ID NOs: 633, 634, and 635 substituted with histidine; (f) HCVDs comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 712, 713, and 714, respectively, collectively having one or more of the total amino acid positions of SEQ ID NOs: 712, 713, and 714 substituted with histidine; and / or CDR1, CDR2, and CDR3 of SEQ ID NOs: 715, 716, and 717, respectively, collectively having (g) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 805, 806, and 807, respectively, and collectively, one or more amino acid positions of SEQ ID NOs: 805, 806, and 807, substituted with histidine; and / or an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 808, 809, and 810, respectively, and collectively, one or more amino acid positions of SEQ ID NOs: 808, 809, and 810, substituted with histidine.

[0100] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally including a histidine at one or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally including a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) a HCVD at least 90% identical to SEQ ID NO: 542; (f) a HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; (g) a HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102 and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0101] In some embodiments, the first ABD is selected from (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally including a histidine at one or more positions selected from 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 25, 27, 29, 30, 35, 36, 38, 40, 42, 44, 46, 48, 49, 50, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 711; and (g) an LCVD that is at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0102] In some embodiments, the first ABD is (a) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301; (b) a HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 in SEQ ID NO: 375. (c) an HCVD at least 90% identical to SEQ ID NO: 459, optionally comprising a histidine at two or more positions selected from 32, 99, 101, 102, 106 and 111 in SEQ ID NO: 459; (d) an HCVD at least 90% identical to SEQ ID NO: 542, optionally comprising a histidine at two or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an HCVD at least 90% identical to SEQ ID NO: 542; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at two or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; (g) an HCVD at least 90% identical to SEQ ID NO: 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 102 and 103 in SEQ ID NO: 710; and (g) an HCVD that is at least 90% identical to SEQ ID NO: 803, optionally containing a histidine at two or more positions selected from 33, 50, 53, 55-58, 64, 100, and 107 in SEQ ID NO: 803.

[0103] In some embodiments, the first ABD is (a) an LCVD at least 90% identical to SEQ ID NO: 302, optionally containing a histidine at two or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) an LCVD at least 90% identical to SEQ ID NO: 376, optionally containing a histidine at two or more positions selected from 30, 31, 33, 51, 92 and 95 in SEQ ID NO: 460; (d) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 543. (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally including a histidine at positions 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99 and 100 in SEQ ID NO: 629; (f) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at positions 25, 27, 29, 30, 35, 36, and (g) an LCVD that is at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at two or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0104] In some embodiments, the first ABD is (a) an HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at one or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301, and / or an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at one or more positions selected from 26, 27, 30, 32, 34, 51, 52 in SEQ ID NO: 375; , 55, 58, 59, 63, 97, 99, and 108 of SEQ ID NO: 375, and / or a LCVD at least 90% identical to SEQ ID NO: 376, and optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 in SEQ ID NO: 376; (c) a histidine at one or more positions selected from 32, 99, 101, 102, 106, and 111 of SEQ ID NO: 459; and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 30, 31, 33, 51, 92 and 95 of SEQ ID NO: 460; (d) a HCVD which is at least 90% identical to SEQ ID NO: 542, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542, and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at one or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at one or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 3; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at one or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; and / or 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98 in SEQ ID NO: 629;(f) an LCVD at least 90% identical to SEQ ID NO: 629, optionally containing a histidine at one or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110 and 113 in SEQ ID NO: 710, and / or 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95 in SEQ ID NO: 711. (g) an LCVD at least 90% identical to SEQ ID NO: 711, optionally including a histidine at one or more positions selected from 33, 50, 53, 55-58, 64, 100 and 107 in SEQ ID NO: 803, and / or an LCVD at least 90% identical to SEQ ID NO: 804, optionally including a histidine at one or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0105] In some embodiments, the first ABD is (a) an HCVD at least 90% identical to SEQ ID NO: 301, optionally including a histidine at two or more positions selected from 29, 30, 32, 50-54, 58, 60, 96, and 101 in SEQ ID NO: 301, and / or an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at two or more positions selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98 in SEQ ID NO: 302; (b) an LCVD at least 90% identical to SEQ ID NO: 302, optionally including a histidine at two or more positions selected from 26, 27, 30, 32, 34, 51, 52 in SEQ ID NO: 375; , 55, 58, 59, 63, 97, 99, and 108 of SEQ ID NO: 375, and / or LCVDs at least 90% identical to SEQ ID NO: 376, and optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102 of SEQ ID NO: 376; (c) HCVDs at least 90% identical to SEQ ID NO: 375, and optionally containing a histidine at two or more positions selected from 32, 99, 101, 102, 106, and 111 of SEQ ID NO: 459; and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at two or more positions selected from 30, 31, 33, 51, 92 and 95 of SEQ ID NO: 460; (d) a HCVD which is at least 90% identical to SEQ ID NO: 542, optionally containing a histidine at two or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542, and / or a LCVD which is at least 90% identical to SEQ ID NO: 460, optionally containing a histidine at two or more positions selected from 27, 29, 30, 31, 32, 53, 55, 58, 102, 104 and 105 in SEQ ID NO: 542; (e) an LCVD at least 90% identical to SEQ ID NO: 543, optionally containing a histidine at two or more positions selected from 25, 29, 30, 31, 32, 89, 92 and 98 in SEQ ID NO: 3; (f) an HCVD at least 90% identical to SEQ ID NO: 628, optionally containing a histidine at two or more positions selected from 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102 and 103 in SEQ ID NO: 628; and / or 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98 in SEQ ID NO: 629;(f) an LCVD at least 90% identical to SEQ ID NO: 629, optionally containing a histidine at two or more positions selected from 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110 and 113 in SEQ ID NO: 710, and / or 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95 in SEQ ID NO: 711. (g) an LCVD at least 90% identical to SEQ ID NO: 711, optionally containing a histidine at two or more positions selected from 33, 50, 53, 55-58, 64, 100 and 107 in SEQ ID NO: 803, and / or an LCVD at least 90% identical to SEQ ID NO: 804, optionally containing a histidine at two or more positions selected from 31, 33-35, 52, 54, 98 and 99 in SEQ ID NO: 804.

[0106] In some embodiments, the first ABD comprises (a) an HCVD of SEQ ID NO: 301, or one of 309-342, (b) an HCVD of SEQ ID NO: 375, or one of 383-423, (c) an HCVD of SEQ ID NO: 459, or one of 467-511, (d) an HCVD of SEQ ID NO: 542, or one of 550-592, (e) an HCVD of SEQ ID NO: 628, or any of 636-675, (f) an HCVD of SEQ ID NO: 710, or any of 718-767, and (g) an HCVD of SEQ ID NO: 803, or any of 811-854.

[0107] In some embodiments, the first ABD comprises one of: (a) an LCVD of SEQ ID NO: 302, or one of 343-374; (b) an LCVD of SEQ ID NO: 376, or one of 424-458; (c) an LCVD of SEQ ID NO: 460, or one of 512-541; (d) an LCVD of SEQ ID NO: 543, or one of 593-627; (e) an LCVD of SEQ ID NO: 629, or one of 676-709; (f) an LCVD of SEQ ID NO: 711, or one of 768-802; and (g) an LCVD of SEQ ID NO: 804 or one of 855-892.

[0108] In some embodiments, the first ABD is (a) an HCVD of SEQ ID NO: 301, or an HCVD of SEQ ID NO: 309 to 342, and / or an LCVD of any one of SEQ ID NOs: 302, or an LCVD of any one of SEQ ID NOs: 343 to 374, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 301 and an LCVD of SEQ ID NO: 302, (ii) an HCVD of SEQ ID NO: 301 and an LCVD other than one of SEQ ID NOs: 344, 349 to 352, 354, 359 to 361, 363, 366 to 368, 370 and 373, or (iii) an HCVD other than one of SEQ ID NOs: 312, 313, 315, 319 to 323, 327, 329, 335, 340 and 341 and an LCVD of SEQ ID NO: 302; (b) an HCVD of SEQ ID NO: 375, or an HCVD of SEQ ID NO: 383 to 423, and / or an LCVD of any one of SEQ ID NOs: 376, or an LCVD of any one of SEQ ID NOs: 424 to 458, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 375 and an LCVD of SEQ ID NO: 376, (ii) an LCVD of SEQ ID NO: 375 and not one of SEQ ID NOs: 425, 429, 430, 431, 432, 433, 435, 436, 437, 438, 442, 444, 445, 446, 449, 450, 453, and 455, or (iii) an HCVD of SEQ ID NOs: 383, 384, 387, 389, 391, 394, 395, 398, 401, 402, 406, 410, 412, and 421, and not one of SEQ ID NO: 376; (c) an HCVD of SEQ ID NO: 459, or an HCVD of 467 to 511, and / or an LCVD of any one of SEQ ID NOs: 460, or an LCVD of any one of SEQ ID NOs: 512 to 541, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 459 and an LCVD other than one of SEQ ID NOs: 518, 519, 521, 524, 533, and 536, or (iii) an HCVD other than one of SEQ ID NOs: 473, 496, 498, 499, 503, and 508 and an LCVD of SEQ ID NO: 460; (d) an HCVD of SEQ ID NO: 542, or an HCVD of any one of SEQ ID NOs: 550 to 592, and / or an LCVD of any one of SEQ ID NOs: 543, or an LCVD of any one of SEQ ID NOs: 593 to 627, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 542 and an LCVD of SEQ ID NO: 543, (ii) an HCVD of SEQ ID NO: 542 and an LCVD other than one of SEQ ID NOs: 594, 598, 599, 600, 601, 611, 614, and 620, or (iii) an HCVD other than one of SEQ ID NOs: 551, 553, 554, 555, 556, 563, 565, 568, 582, 584, and 585, and an LCVD of SEQ ID NO: 543; (e) an HCVD of SEQ ID NO: 628, or an HCVD of SEQ ID NO: 636 to 675, and / or an LCVD of any one of SEQ ID NOs: 629, or an LCVD of any one of SEQ ID NOs: 676 to 709, wherein the first ABD does not include (i) an HCVD of SEQ ID NO: 628 and an LCVD of SEQ ID NO: 629, (ii) an HCVD of SEQ ID NO: 628 and an LCVD that is not one of SEQ ID NOs: 677, 678, 680, 681, 685, 688, 692, 694, 696, 700, 701, 702, 703, 704, and 705, or (iii) an HCVD that is not one of SEQ ID NOs: 636, 638, 640, 646, 648, 649, 650, 651, 652, 653, 666, 667, 668, and 669, and an LCVD of SEQ ID NO: 629; (f) an HCVD of SEQ ID NO: 710, or an HCVD of SEQ ID NO: 718 to 767, and / or an LCVD of any one of SEQ ID NOs: 711, or an LCVD of any one of SEQ ID NOs: 768 to 802, wherein the first ABD is (i) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NO: 711, (ii) an HCVD of SEQ ID NO: 710 and an LCVD of SEQ ID NOs: 769, 771, 773, 774, 779, 780, 785, 786, 787, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 8, 790, 791, 792, 795, and 796; or (iii) an HCVD other than one of SEQ ID NOs: 721, 722, 723, 725, 727, 728, 731, 735, 736, 743, 744, 745, 746, 748, 749, 751, 753, 755, 756, 757, 758, and 761, and an LCVD of SEQ ID NO: 711; and (g) an HCVD of SEQ ID NO: 803, or one of 811-854, and / or an LCVD of SEQ ID NO: 804, or one of 855-892, and the first ABD comprises one of: (i) an HCVD of SEQ ID NO: 803 and an LCVD of SEQ ID NO: 804, (ii) an HCVD of SEQ ID NO: 803 and an LCVD other than one of SEQ ID NOs: 862, 864-866, 868, 870, 881 and 882, or (iii) an HCVD other than one of SEQ ID NOs: 818, 821, 824, 826-829, 835, 841, 848 and 850 and not an LCVD of SEQ ID NO: 804.

[0109] In some embodiments, the first antigen binding domain comprises one of: (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, respectively, collectively with one or more amino acids substituted with histidine in total; (b) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, respectively, collectively with one or more amino acids substituted with histidine in total; or (c) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, collectively with one or more amino acids substituted with histidine in total. In some embodiments, the first CCK4 binding domain comprises one of: (a) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, in which collectively one or more amino acids in total have been substituted with histidine; (b) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, in which collectively one or more amino acids in total have been substituted with histidine; or (c) an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, in which collectively one or more amino acids in total have been substituted with histidine.

[0110] In some embodiments, the first CCK4 binding domain is (a) an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 3, 4, and 5, collectively substituted with histidine, one or more of the amino acid positions of SEQ ID NOs: 3, 4, and 5, respectively, and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 6, 7, and 8, respectively, and / or an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, collectively substituted with histidine, one or more of the amino acid positions of SEQ ID NOs: 128, 129, and 130 ... collectively substituted with histidine, one or more of the amino acid positions or a LCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, wherein all of the amino acid positions of one or more of SEQ ID NOs: 131, 132, and 133, respectively, have been collectively substituted with histidine; (c) a HCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, wherein all of the amino acid positions of one or more of SEQ ID NOs: 231, 232, and 233, respectively, have been collectively substituted with histidine; and a LCVD comprising the CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, wherein all of the amino acid positions of one or more of SEQ ID NOs: 234, 235, and 236, respectively, have been collectively substituted with histidine.

[0111] In some embodiments, the first antigen-binding domain is selected from the group consisting of: (a) an HCVD that is at least 90% identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at one or more positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107; (b) an HCVD that is at least 90% identical to SEQ ID NO:126, wherein the HCVD comprises a histidine at one or more positions of SEQ ID NO:1 selected from the group consisting of 53, 54, 56, 57, 58, 64, 98, 100, 102, 103, and 107; , 60, 102, 103, 104, 105, 106, 108, 109, 110 or 111; and / or (c) an HCVD that is at least 90% identical to SEQ ID NO: 229, wherein the HCVD comprises a histidine at one or more positions in SEQ ID NO: 229 selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58 or 100. In some embodiments, the first antigen-binding domain comprises one of: (a) an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 25, 29, 31, 35, 60, 93, and 94 of SEQ ID NO:2; (b) an LCVD that is at least 90% identical to SEQ ID NO:127, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94 of SEQ ID NO:127; or (c) an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at one or more positions selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99 in SEQ ID NO:230.

[0112] In some embodiments, the first antigen-binding domain comprises one of: (a) an HCVD that is at least 90% identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at two or more positions of SEQ ID NO:1 selected from the group consisting of 27, 29, 31, 34, and 53; and (b) an HCVD that is at least 90% identical to SEQ ID NO:126, wherein the HCVD comprises a histidine at two or more positions of SEQ ID NO:126 selected from the group consisting of 53, 56, 57, 102, and 105.

[0113] In some embodiments, the first antigen-binding domain comprises one of: (a) an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at two or more positions of SEQ ID NO:2 selected from the group consisting of 31, 60, and 93; and (b) an LCVD that is at least 90% identical to SEQ ID NO:127, wherein the LCVD comprises a histidine at two or more positions of SEQ ID NO:127 selected from the group consisting of 28 and 90.

[0114] In some embodiments, the first antigen-binding domain is selected from the group consisting of: (a) an HCVD at least 90% identical to SEQ ID NO:1 comprising a histidine at one or more positions selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107 of SEQ ID NO:1; and / or an LCVD at least 90% identical to SEQ ID NO:2 comprising a histidine at one or more positions selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94 of SEQ ID NO:2; (b) an LCVD at least 90% identical to SEQ ID NO:126 comprising a histidine at one or more positions selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, or 111 in SEQ ID NO:126. and (c) an HCVD that is at least 90% identical to SEQ ID NO: 229 comprising a histidine at one or more positions selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, or 100 in SEQ ID NO: 229; and / or an LCVD that is at least 90% identical to SEQ ID NO: 230 comprising a histidine at one or more positions selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99 in SEQ ID NO: 230.

[0115] In some embodiments, the first antigen binding domain is selected from the group consisting of (a) a HCVD of SEQ ID NO: 1, 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105; , 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, or 227; (c) an HCVD of one of the HCVDs of SEQ ID NOs: 229, 238, 243, 244, 245, 246, 248, 251, 253, 255, or 267. In some embodiments, the first antigen binding domain comprises one of the following LCVDs: (a) an LCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122, 123, 124, or 125; (b) an LCVD of SEQ ID NO: 127, 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, or 228; and (c) an LCVD of SEQ ID NO: 230, 275, 276, 278, 281, 283, 287, 289, 290, 292, or 297.

[0116] In some embodiments, the first antigen-binding domain comprises (a) an HCVD of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, or 105, and / or an LCVD of SEQ ID NO: 2, 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122, 123, 124, or 125; (i) an HCVD of SEQ ID NO: 1 and an LCVD of SEQ ID NO: 2; (ii) an HCVD of SEQ ID NO: 1 and an LCVD other than one of SEQ ID NOs: 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, and 122 to 125; or (iii) an LCVD of SEQ ID NO: 2 and an HCVD other than one of SEQ ID NOs: 14, 17 to 22, 24, 25, 29 to 31, 33, 34, 40, 44, 46, 48, 49, 53, 86 to 96, and 98 to 105; (b) an HCVD of SEQ ID NOs: 147, 148, 150, 151, 154, , 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, or 227, and / or a LCVD of SEQ ID NO: 127, 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, or 228, and the first ABD comprises (i) an HCVD of SEQ ID NO: 126, and a LCVD of SEQ ID NO: 127, (ii) an HCV of SEQ ID NO: 126 D and an LCVD other than one of SEQ ID NOs: 181, 182, 184, 185, 187-189, 191, 199, 201, 203, and 228; (iii) an LCVD of SEQ ID NO: 127 and an HCVD other than one of SEQ ID NOs: 147, 148, 150, 151, 154, 166-170, 172-175, 208-222, and 224-227; and (c) an HCVD of SEQ ID NOs: 238, 243, 244, 245, 246, 248, 251, 253, 255, or 267, and / or SEQ ID NOs: 230, 275, 276,278, 281, 283, 287, 289, 290, 292, or 297, and the first ABD comprises one of: (i) an LCVD of SEQ ID NO: 229 and an LCVD of SEQ ID NO: 230; (ii) an HCVD of SEQ ID NO: 229 and an LCVD that is not one of SEQ ID NOs: 275, 276, 278, 281, 283, 287, 289, 290, 292, and 297; and (iii) an LCVD of SEQ ID NO: 230 and an HCVD that is not one of SEQ ID NOs: 238, 243-246, 248, 251, 253, 255, and 267.

[0117] In some embodiments, the composition comprising ABPC results in an increase in toxin release in target mammalian cells compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC increases toxin release in target mammalian cells by at least 20% compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC increases toxin release in target mammalian cells by at least 50% compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC increases toxin release in target mammalian cells by at least 2-fold compared to a composition comprising the same amount of control ABPC. In some embodiments, the composition comprising ABPC increases toxin release in target mammalian cells by at least 5-fold compared to a composition comprising the same amount of control ABPC.

[0118] In some embodiments, a composition comprising ABPC provides increased killing of target mammalian cells compared to a composition comprising an equivalent amount of control ABPC. In some embodiments, a composition comprising ABPC provides at least a 20% to 50% increase in killing of target mammalian cells compared to a composition comprising an equivalent amount of control ABPC. In some embodiments, a composition comprising ABPC provides at least a 2 to 5 fold increase in killing of target mammalian cells compared to a composition comprising an equivalent amount of control ABPC.

[0119] In some embodiments, the composition comprising ABPC provides 50% increase in endolysosomal delivery in target mammalian cells compared to the composition comprising the same amount of control ABPC.In some embodiments, the composition comprising ABPC provides at least 20% or 50% increase in endolysosomal delivery in target mammalian cells compared to the composition comprising the same amount of control ABPC.In some embodiments, the composition comprising ABPC increases at least 2-fold or 5-fold increase in endolysosomal delivery in target mammalian cells compared to the composition comprising the same amount of control ABPC.

[0120] In some embodiments, the composition comprising ABPC does not cause the level of PTK7 displayed on the surface of target mammalian cell to be significantly reduced compared with the composition comprising the same amount of control ABPC.In some embodiments, the composition comprising ABPC does not cause the level of PTK7 displayed on the surface of target mammalian cell to be detectably reduced.In some embodiments, the target mammalian cell is cancer cell.

[0121] 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 KD of the ABD at a pH of about 4.0 to about 6.5 is at least 10% greater than the KD of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the KD of the ABD at a pH of about 4.0 to about 6.5 is at least 3 times greater than the KD of the ABD at a pH of about 7.0 to about 8.0. In some embodiments, the KD of the ABD at a pH of about 4.0 to about 6.5 is at least 10-fold greater than the KD of the ABD at a pH of about 7.0 to about 8.0.

[0122] In some embodiments, ABPC is cytotoxic or cytostatic to target mammalian cells.

[0123] In some embodiments, ABPC is cross-reactive with non-human primate PTK7 and human PTK7.In some embodiments, ABPC is cross-reactive with non-human primate PTK7, human PTK7, and one or both of rat PTK7 and mouse PTK7.In some embodiments, ABPC is cross-reactive with non-human primate PTK7, human PTK7, rat PTK7, and mouse PTK7.In some embodiments, ABD binds to the epitope of PTK7 present on the surface of cells from Old World monkeys.

[0124] In some embodiments, the ABPC comprises a single polypeptide. In some embodiments, the ABD is selected from a VH domain, a VHH domain, a VNAR domain, and a scFv. In some embodiments, the ABPC is BiTe, (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a scFv-CH-CL-scFv, a HSAbody, a scDiabody-HSA, or a tandem-scFv.

[0125] In some embodiments, the ABPC comprises two or more polypeptides. In some embodiments, the ABPC comprises an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes construct, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, an Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv-(H)IgG, an IgG(L)-scFv, a scFv-(L)IgG, an IgG(L,H)-Fv, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, a KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, Diabody-Fc, tandem scFv-Fc, VHH-Fc, tandem VHH-Fc, VHH-Fc KiH, Fab-VHH-Fc, intrabody, dock and lock lock), ImmTAC, IgG-IgG conjugate, Cov-X-Body, scFv1-PEG-scFv2, Adnectin, DARPin, fibronectin, and DEP conjugate.

[0126] In some embodiments, at least one polypeptide of ABPC is linked to a toxin, radioisotope, drug, or small molecule via a cleavable linker. In some embodiments, at least one polypeptide of ABPC is linked to a toxin, radioisotope, drug, or small molecule via a non-cleavable linker.

[0127] In some embodiments, the half-life of ABPC in vivo is increased compared to the half-life of control ABPC in vivo. In some embodiments, the half-life of ABPC in vivo is decreased by about 5% to 95% compared to the half-life of control ABPC in vivo. In some embodiments, the half-life of ABPC in vivo is decreased by about 10% to 95% compared to the half-life of control ABPC in vivo. In some embodiments, the half-life of ABPC in vivo is decreased by about 30% to 95% compared to the half-life of control ABPC in vivo. In some embodiments, the half-life of ABPC in vivo is decreased by about 50% to 95% compared to the half-life of control ABPC in vivo. In some embodiments, the half-life of ABPC in vivo is decreased by about 70% to 95% compared to the half-life of control ABPC in vivo.

[0128] In some embodiments, the control ABPC is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, and (a) the control ABPC comprises a first ABD; (b) the dissociation rate of the first ABD of the control ABPC is within 3-fold at a pH of about 4.0 to about 6.5 compared to the dissociation rate at a pH of about 7.0 to about 8.0; and (c) the dissociation constant (K D ) is the K when the pH is about 4.0 to about 6.5 and when the pH is about 7.0 to about 8.0. D not more than three times as much.

[0129] In some embodiments, the control ABPC is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, (a) the control ABPC comprises a first ABD, (b) the dissociation rate of the first ABD of the control ABPC is within 2-fold at a pH of about 4.0 to about 6.5 compared to the dissociation rate at a pH of about 7.0 to about 8.0, and (c) the dissociation constant (K D ) is the K when the pH is about 4.0 to about 6.5 and when the pH is about 7.0 to about 8.0. D not more than twice as much.

[0130] In some embodiments, the control ABPC is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a target mammalian cell, 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 not more than 1-fold faster than its dissociation rate at a pH of about 7.0 to about 8.0, and (c) the dissociation constant (K D ) is the K at pH 7.0 to 8.0 D It is not more than one time.

[0131] In some embodiments, the control ABPC is MYT9345, MYT9359, MYT9361, MYT9412, MYT9460, MYT9792, MYT9797, cofetuzumab, 7C8, or 12C6.

[0132] In some embodiments, the ABPC comprises a second ABD.

[0133] Also provided herein are kits that include at least one dose of any of the ABPCs described herein.

[0134] Also provided herein is a method of treating a cancer characterized by having a population of cancer cells having PTK7 or an epitope of PTK7 present on the surface of the cancer cells, comprising administering a therapeutically effective amount of any of the pharmaceutical compositions described herein or any of the ABPCs described herein to a subject identified as having a cancer characterized by having the population of cancer cells.

[0135] Also provided herein is a method of reducing tumor volume in a subject, wherein the tumor is characterized by having a population of cancer cells that have PTK7 or an epitope of PTK7 present on their surface, the method comprising administering a therapeutically effective amount of any of the pharmaceutical compositions described herein or any of the ABPCs described herein to a subject identified as having a cancer characterized by having said population of cancer cells.

[0136] Also provided herein is a method of inducing cell death of cancer cells in a subject, wherein the cancer cells have PTK7 or an epitope of PTK7 present on their surface, the method comprising administering a therapeutically effective amount of any one of the pharmaceutical compositions described herein or any of the ABPCs described herein to a subject identified as having a cancer characterized by having a population of said cancer cells.

[0137] In some embodiments, the cancer is a primary tumor. In some embodiments, the cancer is a metastasis. In some embodiments, the cancer is a non-T cell infiltrating tumor. In some embodiments, the cancer is a T cell infiltrating tumor.

[0138] Also provided herein is a method of reducing the risk of developing metastases or reducing the risk of developing further metastases in a subject having a cancer characterized by having a population of cancer cells that have PTK7 or an epitope of PTK7 present on their surface, the method comprising administering a therapeutically effective amount of any one of the pharmaceutical compositions described herein or any of the ABPCs described herein to a subject identified as having a cancer characterized by having said population of cancer cells.

[0139] In some embodiments, the cancer is a non-T cell infiltrating tumor. In some embodiments, the cancer is a T cell infiltrating tumor.

[0140] As used herein, the term "antigen-binding protein construct" refers to (i) a single polypeptide comprising at least one antigen-binding domain, or (ii) a complex of two or more polypeptides (e.g., the same or different polypeptides) that together form at least one antigen-binding domain. Non-limiting examples and embodiments of antigen-binding protein constructs are described herein. Further examples and embodiments of antigen-binding protein constructs are known in the art.

[0141] A "multispecific ABPC" is an ABPC that includes two or more different ABDs that collectively 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 the surface of a cell) or on different antigens (e.g., different proteins present on the surface of the same cell or on the surface of different cells). In some embodiments, the antigens are present on the surface of a cell. In some embodiments, a multispecific ABPC binds to two different epitopes (i.e., a "bispecific ABPC"). In some embodiments, a multispecific ABPC binds to three different epitopes (i.e., a "trispecific ABPC"). In some embodiments, a multispecific ABPC binds to four different epitopes (i.e., a "tetraspecific ABPC"). In some embodiments, a multispecific ABPC binds to five different epitopes (i.e., a "quintuplet specific ABPC"). Each binding specificity can be present in any suitable valency. Non-limiting examples of multispecific ABPCs are described herein.

[0142] An "antibody binding protein" or "ABD" is one or more protein domains (e.g., formed from amino acids from a single polypeptide or formed from amino acids from two or more polypeptides (e.g., the same or different polypeptides) that can specifically bind to one or more different antigens). In some examples, the ABD can bind to an antigen or epitope with specificity and affinity similar to that of a naturally occurring antibody. In some embodiments, the ABD can be an antibody or a fragment thereof. In some embodiments, the ABD can include an alternative scaffold. Non-limiting examples of ABDs are described herein. Further examples of ABDs are known in the art. In some examples, the ABD can bind to a single antigen.

[0143] The term "antibody" is used herein in its broadest sense and includes a specific type of immunoglobulin molecule that contains one or more ABDs that specifically bind to an antigen or epitope. Antibodies include, for example, intact antibodies (e.g., intact immunoglobulins, e.g., human IgG (e.g., human IgG1, human IgG2, human IgG3, human IgG4)), antibody fragments, and multispecific antibodies, among others. One example of an ABD is an ABD formed by a VH-VL dimer. Further examples of antibodies are described herein. Further examples of antibodies are known in the art.

[0144] The phrase "endosomal / lysosomal pathway" refers to the network of endosomes (early endosomes, multivesicular bodies, late endosomes, and lysosomes) in the cytoplasm of mammalian cells, where molecules are sorted for internalization via cell-mediated internalization processes, e.g., pinocytosis, micropinocytosis, receptor-mediated endocytosis, and / or phagocytosis.

[0145] Once endosomes of the endosomal / lysosomal pathway have been purified or isolated, assays of the target protein (e.g., the antigen-binding protein constructs described herein) can be performed using methods known in the art (ELISA, Western blot, immunofluorescence, and immunoprecipitation followed by assays of protein concentration) and can be used to determine the concentration or relative levels of the target protein in the endosome. Alternatively, endosomes of the endosomal / lysosomal pathway can be imaged by immunofluorescence microscopy using a detectably labeled antibody (e.g., a fluorescently, dye-, or GFP-labeled antibody, such as CellLight™ Early Endosome-GFP) that specifically binds to a characteristic protein present in the endosome (e.g., EEA1 in early endosomes) and a fluorescently labeled antibody that specifically binds to the protein of interest (e.g., ABCP), and the level of the target protein in the endosome can be determined by quantifying the overlap of the fluorescence emission of the two different antibodies.

[0146] The phrase "endolysosomal delivery" refers to the rate of accumulation over time or the total amount of accumulation at a particular time point of ABPC (e.g., any of the ABPCs described herein) within the endosomal / lysosomal pathway in a mammalian cell (e.g., any of the exemplary target mammalian cells described herein).

[0147] An exemplary method for calculating the increased endolysosomal delivery of a pH engineered ABPC variant compared to the corresponding starting ABPC from the cytofluorescence data is to measure the ratio of the mean fluorescence intensity of the variant minus the mean fluorescence intensity of the non-binding IgG control, and then divide all by the mean fluorescence intensity of the variant's corresponding starting ABPC minus the mean fluorescence intensity of the IgG control.

[0148] An exemplary assay for measuring the endolysosomal delivery of any of the ABPCs described herein involves labeling ABPC with a fluorescent dye, then incubating the labeled ABPC with cells, and measuring cellular fluorescence as an indicator of endolysosomal delivery of ABPC (e.g., as generally described in Wustner, Traffic 7(6):699-715, 2006). Alternatively, any of the ABPCs described herein can be labeled with a pH-sensitive dye that fluoresces preferentially at acidic pH but not at neutral pH, and then incubated with cells to measure cellular fluorescence as an indicator of delivery of ABPC to acidic endolysosomal compartments.

[0149] When the term "population" is used before a noun, it means two or more of that particular noun. For example, the phrase "a population of cancer cells" means "two or more cancer cells." Non-limiting examples of cancer cells are described herein.

[0150] The phrase "cytostatic to a cell" refers to a direct or indirect reduction in the proliferation (cell division) of the cell (e.g., a cancer cell) in vivo or in vitro. When a therapeutic agent is cytostatic to a cell, the therapeutic agent can, for example, directly or indirectly cause cell cycle arrest of the cell (e.g., a cancer cell). In some examples, a therapeutic agent that is cytostatic to a cell can reduce the number of cells in a population of cells that are in S phase (compared to the number of cells in the population of cells that are in S phase before contact with the therapeutic agent). In some examples, a therapeutic agent that is cytostatic to a cell can reduce the percentage of cells in 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 population of cells that are in S phase before contact with the therapeutic agent).

[0151] The phrase "cytotoxicity to a cell" refers to the direct or indirect induction of death (eg, necrosis or apoptosis) of a cell (eg, a mammalian cell, eg, a cancer cell).

[0152] "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 indicated, as used herein, "affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between a member of the ABD and an antigen or epitope. The affinity of a molecule X for its partner Y is determined by the dissociation equilibrium constant (K D ). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®). Further methods for determining affinity for ABDs and their corresponding antigens or epitopes are known in the art. The term "epitope" refers to a portion of an antigen that is specifically bound by an ABD through a series of physical interactions between: (i) all monomers (e.g., individual amino acid residues, sugar side chains, post-translationally 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-translationally modified amino acid residues) on the portion of the antigen that is specifically bound by the ABD. Epitopes can consist of, for example, surface accessible amino acid residues, sugar side chains, phosphorylated amino acid residues, methylated amino acid residues, and / or acetylated amino acid residues, and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that binding to the former, but not the latter, can 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 3-6 amino acids, or about 10-15 amino acids. In some embodiments, an epitope refers to a portion of a full-length protein or a portion thereof that is defined by a three-dimensional structure (e.g., protein folding). In some embodiments, an epitope is defined by a non-contiguous amino acid sequence that is held together through protein folding. In some embodiments, an epitope is defined by a non-contiguous amino acid sequence that is held together by a quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequence between the residues that define the epitope may not be important to the three-dimensional structure of the epitope. Conformational epitopes may be determined and screened using an assay that compares the binding of an antigen-binding protein construct to a denatured version of the antigen of interest so that linear epitopes are generated. An epitope may include amino acid residues that are directly involved in binding, as well as other amino acid residues.

[0153] Methods for identifying the epitope to which an ABD specifically binds are known in the art, such as structure-based analyses (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g., of the antigen and / or antigen-ABD complex), and / or mutagenesis-based analyses in which variants are measured in binding assays with binding partners (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis), many of which are known in the art.

[0154] The term "paratope" refers to a portion of the ABD that specifically binds to an antigen through a series of physical interactions between: (i) all monomers (e.g., individual amino acid residues, sugar side chains, post-translationally 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-translationally modified amino acid residues) on the portion of the antigen that is specifically bound by the ABD. A paratope can consist of, for example, surface accessible amino acid residues and can have specific three-dimensional structural characteristics as well as specific charge characteristics. In some embodiments, a paratope refers to a portion of a full-length ABD or a portion thereof that is defined by a three-dimensional structure (e.g., protein folding). In some embodiments, a paratope is defined by discontinuous amino acid sequences that are held together through protein folding. In some embodiments, an epitope is defined by discontinuous amino acid sequences that are held together by a quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequence between the residues that define the paratope may not be important to the three-dimensional structure of the paratope. The paratope may include amino acid residues that are directly involved in binding as well as other amino acid residues.

[0155] Methods for identifying the paratope to which an ABD specifically binds are known in the art, such as structure-based analysis (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g., of the ABD and / or the ABD-antigen complex), and / or mutagenesis-based analysis in which variants are measured in binding assays with binding partners (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis), many of which are known in the art.

[0156] The phrase "present on the surface of a mammalian cell" refers to (1) an antigen that is physically associated with or at least partially incorporated into the plasma membrane of a mammalian cell (e.g., a transmembrane protein, a peripheral membrane protein, a lipid-binding protein (e.g., a GPI anchor), an N-myristolyated protein, or an S-palmitoylated protein), or (2) an antigen that is stably bound to its cognate receptor that is physically associated with the plasma membrane of the cell (e.g., a ligand bound to its cognate receptor that physically attaches the cognate receptor to the plasma membrane). Non-limiting methods for determining the presence of an antigen on the surface of a mammalian cell include fluorescence activated cell sorting (FACS), immunohistochemistry, cell fractionation assays, and Western blot.

[0157] The phrase "control ABPC" or "control antigen binding protein construct" means any one of the following: (1) An ABPC that is capable of specifically binding to PTK7 or an epitope of PTK7 displayed on the surface of a mammalian cell (e.g., a target mammalian cell), where one or both of the following are true: (a) a dissociation rate of the first ABD at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein); is ≦3-fold (e.g., ≦2.8-fold, ≦2.6-fold, ≦2.5-fold, ≦2.4-fold, ≦2.2-fold, ≦2.0-fold, ≦1.8-fold, ≦1.6-fold, ≦1.5-fold, ≦1.4-fold, ≦1.2-fold, ≦1.0-fold, ≦0.8-fold, ≦0.6-fold, ≦0.5-fold, ≦0.4-fold, ≦0.3-fold ≦0.2-fold, or ≦0.1-fold) at a pH of about 7.0 to about 8.0 (e.g., any of the subranges of this range described herein); or (b) a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein) is ≦3-fold (e.g., ≦2.8-fold, ≦2.6-fold, ≦2.5-fold) at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein). , ≦2.4x, ≦2.2x, ≦2.0x, ≦1.8x, ≦1.6x, ≦1.5x, ≦1.4x, ≦1.2x, ≦1.0x, ≦0.8x, ≦0.6x, ≦0.5x, ≦0.4x, ≦0.3x ≦0.2x, or ≦0.1x) at a pH of about 7.0 to about 8.0 (e.g., any of the subranges of this range described herein), (2) MYT9345, (3) MYT9359, (4) MYT9361, (5) MYT9412, (6) MYT9460, (7) MYT9792, (8) MYT9797, (9) cofetuzumab, (10) 7C8, or (11) 12C6.

[0158] The term "extracellular space" refers to the fluid outside the plasma membrane of a mammalian cell. If the mammalian cell is in vitro, the extracellular space can be liquid culture medium. If the mammalian cell is in vivo, the extracellular space can be, for example, plasma, serum, blood, interstitial fluid, or lymph.

[0159] The term "endolysosomal space" refers to the fluid enclosed by the vesicles and organelles that make up the endosomal / lysosomal pathway in mammalian cells.

[0160] The phrase "reduced level" or "diminished level" can be a decrease or reduction of at least 1% (e.g., ≧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 ≧99%) as compared to a reference level or value.

[0161] The term "cell killing ability" refers to the ability of an agent (e.g., any ABPC described herein) to directly or indirectly induce apoptosis and / or necrosis of mammalian cells (e.g., cancer cells), measured as a percentage over time or at relevant time points. Methods for determining the cell killing ability of a cell are known in the art (e.g., trypan blue staining, microscopy, fluorescence-assisted cell sorting, and assays that detect markers of apoptosis (e.g., Annexin V)). In non-limiting examples, cell killing ability 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 of the agent that achieves half of the maximum cell killing ability), or by the ratio of the dissociation constant KD of the agent in mammalian cells divided by its IC50. In some non-limiting examples, the IC50 and / or KD ratios described herein are compared to those of a control ABPC (as defined herein), optionally demonstrating that the ABPC described herein has a higher cell killing ability compared to the control ABPC.

[0162] The term "toxin release" refers to the ability of a mammalian cell (e.g., a non-cancerous mammalian cell or a cancer cell) to internalize (e.g., via pinocytosis and / or receptor-mediated endocytosis) any of the ABPCs described herein (e.g., any of the ABPCs described herein or control ABPCs) conjugated to a toxin and then release the toxin conjugated to the ABPC, measured as a percentage over time or at a specific time point. 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.

[0163] The phrases "target cell" or "target mammalian cell" or "mammalian target cell" refer to a mammalian cell having at least one PTK7 present on its surface. In some examples, the mammalian target cell can be a cancer cell. In some embodiments, the target mammalian cell can have the following values ​​in total (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, 1-500, 1-100, 1-50, or 1-10, or any of the number ranges recited in U.S. Patent Application Publication No. 2022 / 0281984, referring to the identities of PTK7 present on the plasma membrane of the target mammalian cell.

[0164] The phrase "antigen density" refers to the number of PTK7 present on the surface of a target mammalian cell, or the average number of PTK7 on the surface of a population of target mammalian cells of a particular type, which can be measured, for example, using a Quantibright bead kit or radiolabeling (e.g., BD Biosciences PE pHYcoerYthrin Fluorescence Quantitation Kit, Catalog No. 340495).

[0165] The phrase "amino acid substituted with histidine" refers to the substitution of a non-histidine amino acid residue in a reference polypeptide sequence with histidine. Non-limiting methods for substituting an amino acid residue in a reference polypeptide with histidine are described herein. Additional methods for substituting an amino acid residue in a reference polypeptide with histidine are known in the art.

[0166] The phrase "amino acid substituted with alanine" refers to the substitution of an amino acid residue that is a histidine in a reference polypeptide sequence with an alanine. Non-limiting methods for substituting a histidine in a reference polypeptide with an alanine are described herein. Additional methods for substituting a histidine in a reference polypeptide with an alanine are known in the art.

[0167] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Methods and materials for use in the present invention are described herein, and other suitable methods and materials known in the art can 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 described herein are incorporated by reference in their entirety.In case of conflict, the present specification, including definitions, will control.

[0168] Other features and advantages of the invention will become apparent from the following detailed description and figures, and from the claims. [Brief description of the drawings]

[0169] [Figure 1] SDS PAGE of cofetuzumab histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of cofetuzumab and its histidine scanning and alanine scanning mutants. The arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT6002 is cofetuzumab, and MYT6152 to MYT6193 are cofetuzumab heavy chain histidine scanning and alanine scanning mutants. [Figure 2a] Binding of cofetuzumab starting ABPC and histidine-scanning and alanine-scanning variants to PTK7 by biolayer interferometry. Histidine-scanning and alanine-scanning variants of the heavy chain, MYT6002 (cofetuzumab) and MYT6152-MYT6193, were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 2b] Same as above. [Figure 2c] Same as above. [Figure 2d] Same as above. [Figure 2e] Same as above. [Figure 2f] Same as above. [Figure 2g] Same as above. [Figure 2h] Same as above. [Figure 2i] Same as above. [Figure 2j] Same as above. [Figure 2k] Same as above. [Figure 2l] Same as above. [Figure 2m] Same as above. [Figure 2n]Same as above. [Figure 2o] Same as above. [Figure 2p] Same as above. [Figure 2q] Same as above. [Figure 2r] Same as above. [Figure 2s] Same as above. [Figure 2t] Same as above. [Figure 2u] Same as above. [Figure 2v] Same as above. [Figure 2w] Same as above. [Figure 2x] Same as above. [Figure 2y] Same as above. [Figure 2z] Same as above. [Figure 2aa] Same as above. [Figure 2ab] Same as above. [Figure 2ac] Same as above. [Figure 2ad] Same as above. [Figure 2ae] Same as above. [Figure 2af] Same as above. [Figure 2ag] Same as above. [Figure 2ah] Same as above. [Figure 2ai] Same as above. [Figure 2aj] Same as above. [Figure 2ak] Same as above. [Figure 2al] Same as above. [Figure 2am] Same as above. [Figure 2an] Same as above. [Figure 2ao] Same as above. [Figure 2ap] Same as above. [Figure 2aq] Same as above. [Diagram 3] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Construct heavy chain histidine scanning and alanine scanning variants are listed in the first column of the table with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 4] SDS PAGE of cofetuzumab histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of the cofetuzumab histidine scanning and alanine scanning mutants. The arrows indicate the sizes corresponding to IgG on the non-reducing SDS PAGE gel. MYT6194 to MYT6224 are histidine scanning and alanine scanning mutants of the light chain of cofetuzumab. [Figure 5a] Binding of cofetuzumab starting ABPC and histidine-scanning and alanine-scanning variants to PTK7 by biolayer interferometry. MYT6002 (cofetuzumab) and MYT6194-MYT6224, histidine-scanning and alanine-scanning variants of the 7 light chain, were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 5b] Same as above. [Figure 5c] Same as above. [Figure 5d] Same as above. [Figure 5e] Same as above. [Figure 5f] Same as above. [Figure 5g] Same as above. [Figure 5h] Same as above. [Figure 5i] Same as above. [Figure 5j] Same as above. [Figure 5k] Same as above. [Figure 5l] Same as above. [Figure 5m] Same as above. [Figure 5n] Same as above. [Figure 5o] Same as above. [Figure 5p] Same as above. [Figure 5q] Same as above. [Figure 5r] Same as above. [Figure 5s] Same as above. [Figure 5t] Same as above. [Figure 5u] Same as above. [Figure 5v] Same as above. [Figure 5w] Same as above. [Figure 5x] Same as above. [Figure 5y] Same as above. [Figure 5z] Same as above. [Figure 5aa] Same as above. [Figure 5ab] Same as above. [Figure 5ac] Same as above. [Figure 5ad] Same as above. [Figure 5ae] Same as above. [Figure 5af] Same as above. [Figure 6] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine-scanning and alanine-scanning variants of the light chain are listed in the first column of the table, with SEQ ID NOs listed and corresponding for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 7] SDS PAGE of cofetuzumab histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of histidine scanning and alanine scanning variants of cofetuzumab. The arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT7837 to MYT7856 are histidine scanning and alanine scanning variants of the heavy chain combination of cofetuzumab. [Figure 8a]Binding of histidine-scanning and alanine-scanning variants of cofetuzumab to PTK7 by biolayer interferometry. Heavy chain combined histidine-scanning and alanine-scanning variants, MYT6002 (cofetuzumab) and MYT7837-MYT7856, were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 8b] Same as above. [Figure 8c] Same as above. [Figure 8d] Same as above. [Figure 8e] Same as above. [Figure 8f] Same as above. [Figure 8g] Same as above. [Figure 8h] Same as above. [Figure 8i] Same as above. [Figure 8j] Same as above. [Figure 8k] Same as above. [Figure 8l] Same as above. [Figure 8m] Same as above. [Figure 8n] Same as above. [Figure 8o] Same as above. [Figure 8p] Same as above. [Figure 8q] Same as above. [Figure 8r] Same as above. [Figure 8s] Same as above. [Figure 8t] Same as above. [Figure 8u] Same as above. [Figure 9] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine scanning and alanine scanning mutants of heavy chain combinations are listed in the first column of the table, with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 10]SDS PAGE of cofetuzumab histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of histidine scanning and alanine scanning variants of cofetuzumab. The arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT7857-MYT7876 are histidine scanning and alanine scanning variants of the light chain combination of cofetuzumab. [Figure 11a] Binding of histidine-scanning and alanine-scanning variants of cofetuzumab to PTK7 by biolayer interferometry. Histidine-scanning and alanine-scanning variants of the light chain combinations MYT6002 (cofetuzumab) and MYT7857-MYT7876 were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 11b] Same as above. [Figure 11c] Same as above. [Figure 11d] Same as above. [Figure 11e] Same as above. [Figure 11f] Same as above. [Figure 11g] Same as above. [Figure 11h] Same as above. [Figure 11i] Same as above. [Figure 11j] Same as above. [Figure 11k] Same as above. [Figure 11l] Same as above. [Figure 11m] Same as above. [Figure 11n] Same as above. [Figure 11o] Same as above. [Figure 11p] Same as above. [Figure 11q] Same as above. [Figure 11r] Same as above. [Figure 11s] Same as above. [Figure 11t] Same as above. [Figure 11u] Same as above. [Figure 12] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine scanning and alanine scanning mutants of light chain combinations are listed in the first column of the table, with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 13] SDS PAGE of 7C8 histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of 7C8 and histidine scanning and alanine scanning variants. Arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT6003 is 7C8, and the remaining lanes (MYT6225-MYT6270) are 7C8 heavy chain histidine scanning and alanine scanning variants. [Figure 14a] Binding of 7C8 starting ABPC and histidine-scanning and alanine-scanning variants to PTK7 by biolayer interferometry. MYT6003 (7C8) and MYT6225-MYT6270 heavy chain histidine-scanning and alanine-scanning variants were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 14b] Same as above. [Figure 14c] Same as above. [Figure 14d] Same as above. [Figure 14e] Same as above. [Figure 14f] Same as above. [Figure 14g] Same as above. [Figure 14h] Same as above. [Figure 14i] Same as above. [Figure 14j] Same as above. [Figure 14k]Same as above. [Figure 14l] Same as above. [Figure 14m] Same as above. [Figure 14n] Same as above. [Figure 14o] Same as above. [Figure 14p] Same as above. [Figure 14q] Same as above. [Figure 14r] Same as above. [Figure 14s] Same as above. [Figure 14t] Same as above. [Figure 14u] Same as above. [Figure 14v] Same as above. [Figure 14w] Same as above. [Fig. 14x] Same as above. [Figure 14y] Same as above. [Figure 14z] Same as above. [Figure 14aa] Same as above. [Figure 14ab] Same as above. [Figure 14ac] Same as above. [Figure 14ad] Same as above. [Fig. 14ae] Same as above. [Fig. 14af] Same as above. [Figure 14ag] Same as above. [Figure 14ah] Same as above. [Figure 14ai] Same as above. [Figure 14aj] Same as above. [Figure 14ak] Same as above. [Figure 14al] Same as above. [Figure 14am] Same as above. [Figure 14an] Same as above. [Figure 14ao] Same as above. [Figure 14ap] Same as above. [Figure 14aq] Same as above. [Figure 14ar] Same as above. [Figure 14a] Same as above. [Figure 14at] Same as above. [Figure 14au] Same as above. [Figure 15] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Construct heavy chain histidine scanning and alanine scanning mutants are listed in the first column of the table with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 16] SDS PAGE of 7C8 histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of 7C8 histidine scanning and alanine scanning variants. The arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT6271 to MYT6298 are 7C8 light chain histidine scanning and alanine scanning variants. [Figure 17a] Binding of 7C8 starting ABPC and histidine-scanning and alanine-scanning variants to PTK7 by biolayer interferometry. MYT6003 (7C8) and MYT6271-MYT6298 light chain histidine-scanning and alanine-scanning variants were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 17b] Same as above. [Figure 17c] Same as above. [Figure 17d] Same as above. [Figure 17e] Same as above. [Fig. 17f] Same as above. [Figure 17g] Same as above. [Figure 17h] Same as above. [Figure 17i] Same as above. [Figure 17j] Same as above. [Figure 17k] Same as above. [Figure 17l] Same as above. [Figure 17m] Same as above. [Figure 17n] Same as above. [Figure 17o] Same as above. [Figure 17p] Same as above. [Figure 17q] Same as above. [Figure 17r] Same as above. [Figure 17s] Same as above. [Figure 17t] Same as above. [Figure 17u] Same as above. [Figure 17v] Same as above. [Figure 17w] Same as above. [Fig. 17x] Same as above. [Figure 17y] Same as above. [Fig.17z] Same as above. [Figure 17aa] Same as above. [Figure 17ab] Same as above. [Figure 17ac] Same as above. [Figure 18] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine-scanning and alanine-scanning variants of the light chain are listed in the first column of the table, with SEQ ID NOs listed and corresponding for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 19] SDS PAGE of 7C8 histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of 7C8 histidine scanning and alanine scanning variants. The arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT7816 to MYT7835 are histidine scanning and alanine scanning variants of the combination of the heavy chain of 7C8. [Figure 20a]Binding of histidine-scanning and alanine-scanning mutants of 7C8 to PTK7 by biolayer interferometry. Heavy chain combinations of histidine-scanning and alanine-scanning mutants of 7C8, MYT6003 (7C8) and MYT7816-MYT7835, were captured on an anti-human Fc biosensor and allowed to bind to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 20b] Same as above. [Figure 20c] Same as above. [Figure 20d] Same as above. [Figure 20e] Same as above. [Fig. 20f] Same as above. [Figure 20g] Same as above. [Figure 20h] Same as above. [Figure 20i] Same as above. [Figure 20j] Same as above. [Figure 20k] Same as above. [Figure 20l] Same as above. [Figure 20m] Same as above. [Figure 20n] Same as above. [Figure 20o] Same as above. [Figure 20p] Same as above. [Figure 20q] Same as above. [Figure 20r] Same as above. [Figure 20s] Same as above. [Figure 20t] Same as above. [Figure 20u] Same as above. [Figure 21] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine scanning and alanine scanning mutants of heavy chain combinations are listed in the first column of the table, with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 22]SDS PAGE of 7C8 histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of 7C8 histidine scanning and alanine scanning variants. The arrow indicates the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT7836 is a combination of the light chain histidine scanning and alanine scanning variants of 7C8. [Figure 23a] Binding of histidine-scanning and alanine-scanning mutants of 7C8 to PTK7 by biolayer interferometry. MYT6003 (7C8) and MYT7836, histidine-scanning and alanine-scanning mutants of 7C8 in light chain combinations, were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 23b] Same as above. [Figure 24] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine scanning and alanine scanning mutants of light chain combinations are listed in the first column of the table, with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Diagram 25] SDS PAGE of 12C6 histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of 12C6 and histidine scanning and alanine scanning variants. Arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT7959 is 12C6, and the remaining lanes (MYT7960-MYT7991) are 12C6 heavy chain histidine scanning and alanine scanning variants. [Figure 26a]Binding of 12C6 starting ABPC and histidine-scanning and alanine-scanning variants to PTK7 by biolayer interferometry. Histidine-scanning and alanine-scanning variants of the heavy chain, MYT7959 (12C6) and MYT7960-MYT7991, were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 26b] Same as above. [Figure 26c] Same as above. [Figure 26d] Same as above. [Figure 26e] Same as above. [Fig. 26f] Same as above. [Figure 26g] Same as above. [Figure 26h] Same as above. [Figure 26i] Same as above. [Figure 26j] Same as above. [Figure 26k] Same as above. [Figure 26l] Same as above. [Figure 26m] Same as above. [Figure 26n] Same as above. [Figure 26o] Same as above. [Figure 26p] Same as above. [Figure 26q] Same as above. [Figure 26r] Same as above. [Figure 26s] Same as above. [Figure 26t] Same as above. [Figure 26u] Same as above. [Figure 26v] Same as above. [Figure 26w] Same as above. [Fig. 26x] Same as above. [Figure 26y] Same as above. [Fig.26z] Same as above. [Figure 26aa] Same as above. [Fig. 26ab] Same as above. [Figure 26ac] Same as above. [Figure 26ad] Same as above. [Fig. 26ae] Same as above. [Fig. 26af] Same as above. [Figure 26ag] Same as above. [Figure 27] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Construct heavy chain histidine scanning and alanine scanning variants are listed in the first column of the table with corresponding SEQ ID NOs listed for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 28] SDS PAGE of 12C6 histidine scanning and alanine scanning. Harvested Expi293 cell culture supernatant was loaded onto a non-reducing SDS PAGE gel to confirm the expression of 12C6 histidine scanning and alanine scanning variants. The arrows indicate the size equivalent to IgG on the non-reducing SDS PAGE gel. MYT7992 to MYT8020 are 12C6 light chain histidine scanning and alanine scanning variants. [Figure 29a] Binding of 12C6 starting ABPC and histidine-scanning and alanine-scanning variants to PTK7 by biolayer interferometry. MYT7959 (12C6) and MYT7992-MYT8020, histidine-scanning and alanine-scanning variants of the light chain of 12C6, were captured on an anti-human Fc biosensor and bound to PTK7 at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (grey trace). [Figure 29b] Same as above. [Figure 29c] Same as above. [Figure 29d] Same as above. [Figure 29e] Same as above. [Fig. 29f] Same as above. [Figure 29g] Same as above. [Figure 29h] Same as above. [Figure 29i] Same as above. [Figure 29j] Same as above. [Figure 29k] Same as above. [Figure 29l] Same as above. [Figure 29m] Same as above. [Figure 29n] Same as above. [Figure 29o] Same as above. [Figure 29p] Same as above. [Figure 29q] Same as above. [Figure 29r] Same as above. [Figure 29s] Same as above. [Figure 29t] Same as above. [Figure 29u] Same as above. [Figure 29v] Same as above. [Figure 29w] Same as above. [Fig. 29x] Same as above. [Figure 29y] Same as above. [Fig.29z] Same as above. [Figure 29aa] Same as above. [Figure 29ab] Same as above. [Figure 29ac] Same as above. [Fig. 29ad] Same as above. [Diagram 30] 1 is a table of construct identifiers corresponding to SEQ ID NOs. Constructs, histidine-scanning and alanine-scanning variants of the light chain are listed in the first column of the table, with SEQ ID NOs listed and corresponding for the construct on the left and the appropriate heavy and / or light chain category along the top. [Figure 31a]Intracellular uptake of anti-PTK7 mAb in cells. Anti-PTK7 pH engineered antibody variants, corresponding starting ABPC antibody, control IgG1 isotype control (BP0297, Bioxcell), and vehicle control as specified in FIG. 31 were assayed for intracellular uptake and endolysosomal delivery as measured by median fluorescence intensity on cells at 25 nM after 24 hours. Error bars, if present, represent standard deviation. Each number above the bar represents the fold change relative to the corresponding starting ABPC. [Figure 31b] Same as above. [Fig. 31c] Same as above. [Fig. 31d] Same as above. [Figure 32a] Intracellular uptake of anti-PTK7 mAb in cells. Anti-PTK7 pH engineered antibody variants, corresponding starting ABPC antibodies, control IgG1 isotype control (BPO297, Bioxcell), and vehicle controls as specified in FIG. 32 were assayed for intracellular uptake and endolysosomal delivery as measured by median fluorescence intensity on cells at 25 nM after 24 hours. Error bars, if present, represent standard deviation. Each number above the bar represents the fold change relative to the corresponding starting ABPC. [Figure 32b] Same as above. [Figure 33a] Intracellular uptake of anti-PTK7 mAb in cells. Anti-PTK7 pH engineered antibody variants, corresponding starting ABPC antibodies, control IgG1 isotype control (BPO297, Bioxcell), and vehicle controls as specified in FIG. 33 were assayed for intracellular uptake and endolysosomal delivery as measured by median fluorescence intensity on cells at 25 nM after 24 hours. Error bars, if present, represent standard deviation. Each number above the bar represents the fold change relative to the corresponding starting ABPC. [Figure 33b] Same as above. [Figure 34a-1]Octet plots of MYT9345 HC and LC variants are presented. For each of Figures 34-40, the y-axis (nm) array of the plots was either (A) fixed or (B) automatically set by the software to maximize the vertical spread of the data. For each fixed y-axis, the major ticks are 0.4 nm and the minor ticks are 0.1 nm. [Figure 34a-2] Same as above. [Figure 34b-1] Same as above. [Figure 34b-2] Same as above. [Figure 35a-1] Octet plots of MYT9359 HC and LC variants are presented. [Figure 35a-2] Same as above. [Figure 35b-1] Same as above. [Figure 35b-2] Same as above. [Figure 36a-1] Octet plots of MYT9361 HC and LC variants are presented. [Figure 36a-2] Same as above. [Figure 36b-1] Same as above. [Figure 36b-2] Same as above. [Figure 37a-1] Octet plots of MYT9412 HC and LC variants are presented. [Figure 37a-2] Same as above. [Figure 37b-1] Same as above. [Figure 37b-2] Same as above. [Figure 38a-1] Octet plots of MYT9460 HC and LC variants are presented. [Figure 38a-2] Same as above. [Figure 38b-1] Same as above. [Figure 38b-2] Same as above. [Figure 39a-1] Octet plots of MYT9792 HC and LC variants are presented. [Figure 39a-2] Same as above. [Figure 39b-1] Same as above. [Figure 39b-2]Same as above. [Figure 40a-1] Octet plots of MYT9797 HC and LC variants are presented. [Figure 40a-2] Same as above. [Figure 40b-1] Same as above. [Figure 40b-2] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0170] Provided herein is an antigen binding protein construct (ABPC) comprising a first ABD (ABD) capable of specifically binding to PTK7 or an epitope of PTK7 present on the surface of a target mammalian cell, wherein (a) the dissociation rate of the first ABD at about pH 4.0 to about 6.5 is faster than the dissociation rate at about pH 7.0 to about 8.0, and / or (b) the dissociation constant (K D ) at pH 7.0 to 8.0 D Provided herein are antigen binding protein constructs (ABPCs) that are greater than 10 ...

[0171] Also provided is an antigen binding protein construct (ABPC) comprising a first ABD capable of specifically binding to PTK7 or an epitope of PTK7 present on the surface of a target mammalian cell; and a conjugated toxin, radioisotope, drug or small molecule, wherein (a) the dissociation rate of the first ABD at about pH 4.0 to about 6.5 is faster than its dissociation rate at about pH 7.0 to about 8.0, and / or the dissociation constant (K D ) at pH 7.0 to 8.0 Dand (b) a composition comprising the ABPC results in one or more (e.g., two or three) of: increased (e.g., a detectable increase) in toxin release in a target mammalian cell compared to a composition comprising an equivalent amount of a control ABPC; increased (e.g., a detectable increase) in killing of a target mammalian cell compared to a composition comprising an equivalent amount of the control ABPC; and increased (e.g., a detectable increase) in endolysosomal delivery in a target mammalian cell compared to a composition comprising an equivalent amount of the control ABPC.

[0172] In some embodiments of any ABPC described herein, the first ABD comprises an HCVD of cofetuzumab with one or more amino acids substituted with histidine. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD of cofetuzumab with one or more amino acids substituted with histidine. In some embodiments of any ABPC described herein, the first ABD comprises an HCVD of cofetuzumab with one or more amino acids substituted with histidine and an LCVD of cofetuzumab with one or more amino acids substituted with histidine. In some embodiments of any ABPC described herein, the HCVD of cofetuzumab comprises SEQ ID NO: 1. In some embodiments of any ABPC described herein, the LCVD of cofetuzumab comprises SEQ ID NO: 2.

[0173] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively, whereby collectively one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid positions in SEQ ID NO:3, 4, and 5 have been substituted with histidine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, whereby collectively one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid positions in SEQ ID NO:6, 7, and 8 have been substituted with histidine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NO:3, 4, and 5, respectively, are collectively substituted with histidine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NO:6, 7, and 8, respectively, are collectively substituted with histidine.

[0174] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, and the LCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:2 selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1 and comprises a histidine at one or more amino acid positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2 and comprises a histidine at one or more amino acid positions of SEQ ID NO:2 selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94.

[0175] In some embodiments of any of the ABPCs described herein, the HCVD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0176] In some examples of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, where the HCVD comprises an alanine at position 35 of SEQ ID NO:1.

[0177] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1 and comprises an alanine at position 35 of SEQ ID NO:1, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2 and comprises a histidine at one or more amino acid positions selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94 of SEQ ID NO:2.

[0178] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0179] In some embodiments of any of the ABPCs described herein, the LCVD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, and the LCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:2 listed in Table 2.

[0180] In some examples of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, and the LCVD comprises an alanine at position 38 of SEQ ID NO:2.

[0181] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2 and comprises an alanine at position 38 of SEQ ID NO:2, and an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1 and comprises a histidine at one or more amino acid positions selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, or 107 of SEQ ID NO:1.

[0182] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:2 selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94, and the LCVD comprises an alanine at position 38 of SEQ ID NO:2. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:2 selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94, and the LCVD comprises an alanine at position 38 of SEQ ID NO:2; and an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, or 107.

[0183] In some embodiments of any of the ABPCs described herein, the first ABD is an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, and comprises a histidine at one or more amino acid positions of SEQ ID NO:2 selected from the group consisting of 25, 29, 31, 35, 60, 93, or 94, and wherein the LCVD comprises an alanine at position 38 of SEQ ID NO:2. , an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and which comprises a histidine at one or more amino acid positions of SEQ ID NO:1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, or 107, and which comprises an alanine at position 35.

[0184] In some embodiments of any of the ABPCs described herein, the LCVD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, the LCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:2 listed in Table 2, and the LCVD comprises an alanine at position 38 of SEQ ID NO:2.

[0185] [Table 2-1] [Table 2-2]

[0186] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1 and includes a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2 and includes a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:2 listed in Table 2.

[0187] In any of the exemplary ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at any of the specific combinations of one or more amino acid positions listed in Table 2 of SEQ ID NO:2, wherein the LCVD comprises an alanine at position 38 of SEQ ID NO:2, and wherein the HCVD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions listed in Table 1 of SEQ ID NO:1.

[0188] In some embodiments of any of the ABPCs described herein, the first ABD includes an LCVD comprising SEQ ID NO:2 and an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1 and includes a histidine at any of the specific combinations of one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NO:1 listed in Table 1.

[0189] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 25 of SEQ ID NO:2, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0190] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 29 of SEQ ID NO:2, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0191] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 31 of SEQ ID NO:2, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0192] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 35 of SEQ ID NO:2 and an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0193] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 60 of SEQ ID NO:2, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0194] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 93 of SEQ ID NO:2, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0195] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:2, wherein the LCVD comprises a histidine at position 94 of SEQ ID NO:2, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:1, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:1 listed in Table 1.

[0196] In some embodiments of any ABPC described herein, the first ABD comprises an HCVD of cofetuzumab with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD of cofetuzumab with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the first ABD comprises an HCVD of cofetuzumab with one or more histidine(s) substituted with alanine and an LCVD of cofetuzumab with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the HCVD of cofetuzumab comprises SEQ ID NO: 1. In some embodiments of any ABPC described herein, the LCVD of cofetuzumab comprises SEQ ID NO: 2.

[0197] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively, whereby collectively one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) histidines in SEQ ID NO:3, 4, and 5 have been replaced with alanine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, whereby collectively one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) histidines in SEQ ID NO:6, 7, and 8 have been replaced with alanine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) histidines of SEQ ID NO:3, 4, and 5, respectively, have been collectively replaced with alanine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) histidines of SEQ ID NO:6, 7, and 8, respectively, have been collectively replaced with alanine.

[0198] In some embodiments of any ABPC described herein, the first ABD comprises an HCVD of SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD of SEQ ID NO: 2, or one of 55-85, or one of 106-125.

[0199] In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO:2 and an HCVD comprising SEQ ID NO:1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO:55 and an HCVD comprising SEQ ID NO:1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO:56 and an HCVD comprising SEQ ID NO:1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO:57 and an HCVD comprising SEQ ID NO:1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 58 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 59 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 60 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 61 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 62 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 63 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 64 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 65 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 66 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 67 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 68 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 69 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 70 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 71 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 72 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 73 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 74 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 75 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 76 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 77 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 78 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 79 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 80 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 81 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 82 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 83 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 84 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 85 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 106 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 107 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 108 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 109 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 110 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 111 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 112 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 113 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 114 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 115 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 116 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 117 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 118 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 119 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 120 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 121 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 122 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 123 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 124 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105. The present invention. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 125 and an HCVD comprising SEQ ID NO: 1, or one of 13-54, or one of 86-105.

[0200] In some embodiments of any of the ABPCs described herein, the first ABD comprises a HCVD of 7C8 with one or more amino acids substituted with histidine. In some embodiments of any of the ABPCs described herein, the first ABD comprises a LCVD of 7C8 with one or more amino acids substituted with histidine. In some embodiments of any of the ABPCs described herein, the first ABD comprises a HCVD of 7C8 with one or more amino acids substituted with histidine and a LCVD of 7C8 with one or more amino acids substituted with histidine. In some examples of any of the ABPCs described herein, the HCVD of 7C8 comprises SEQ ID NO: 126. In some examples of any of the ABPCs described herein, the LCVD of 7C8 comprises SEQ ID NO: 127.

[0201] In some embodiments of any of the ABPCs described herein, the first ABD comprises a HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO: 128, SEQ ID NO: 129, and SEQ ID NO: 130, respectively, wherein a total of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid positions in SEQ ID NO: 128, 129, and 130 are substituted with histidine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that includes CDR1, CDR2 and CDR3 of SEQ ID NO: 131, SEQ ID NO: 132, and SEQ ID NO: 133, respectively, and that collectively include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid positions in SEQ ID NOs: 131, 132 and 133 substituted with histidine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NOs: 128, 129, and 130 are collectively substituted with histidine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NOs: 131, 132, and 133 are collectively substituted with histidine.

[0202] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and the HCVD comprises a histidine at one or more amino acid positions of SEQ ID NO: 126 selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, and 111. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 127, and the LCVD comprises a histidine at one or more amino acid positions of SEQ ID NO: 127 selected from the group of 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and comprises a histidine at one or more amino acid positions of SEQ ID NO: 126 selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, and 111, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 127, and comprises a histidine at one or more amino acid positions of SEQ ID NO: 127 selected from the group consisting of 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94.

[0203] In some embodiments of any of the ABPCs described herein, the HCVD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0204] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0205] In some examples of any of the ABPCs described herein, the LCVD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 127 listed in Table 4.

[0206] [Table 4]

[0207] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126 and includes a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 127 and includes a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 127 listed in Table 4.

[0208] In some examples of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 127 and an HCVD that is at least 90% identical (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) to SEQ ID NO: 126, and the HCVD comprises a histidine at any of the specific combinations of one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0209] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 25 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0210] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 26 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0211] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 28 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0212] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 29 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0213] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 31 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0214] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 32 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0215] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 33 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0216] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 50 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0217] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 90 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0218] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 92 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0219] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 127, wherein the LCVD comprises a histidine at position 94 of SEQ ID NO: 127, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO: 126, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO: 126 listed in Table 3.

[0220] In some embodiments of any ABPC described herein, the first ABD comprises a HCVD of 7C8 with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the first ABD comprises a LCVD of 7C8 with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the first ABD comprises a HCVD of 7C8 with one or more histidine(s) substituted with alanine and a LCVD of 7C8 with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the HCVD of 7C8 comprises SEQ ID NO: 126. In some embodiments of any ABPC described herein, the LCVD of 7C8 comprises SEQ ID NO: 127.

[0221] In some embodiments of any of the ABPCs described herein, the first ABD comprises a HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO: 128, SEQ ID NO: 129, and SEQ ID NO: 130, respectively, in which a total of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) histidines in SEQ ID NOs: 128, 129 and 130 are substituted with alanine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that includes CDR1, CDR2 and CDR3 of SEQ ID NO: 131, SEQ ID NO: 132, and SEQ ID NO: 133, respectively, in which a total of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) histidines in SEQ ID NO: 131, 132 and 133 are substituted with alanine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 128, 129, and 130, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) histidines of SEQ ID NOs: 128, 129, and 130 have been collectively replaced with alanine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 131, 132, and 133, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) histidines of SEQ ID NOs: 131, 132, and 133 have been collectively replaced with alanine.

[0222] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD of SEQ ID NO: 126, or one of 134-179, or one of 208-227.

[0223] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD of one of SEQ ID NOs: 127, or 180-207, or 228.

[0224] In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 127, and an HCVD comprising one of SEQ ID NO: 126, or one of SEQ ID NO: 134-179, or one of SEQ ID NO: 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 180, and an HCVD comprising SEQ ID NO: 126, or one of SEQ ID NO: 134-179, or one of SEQ ID NO: 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 181, and an HCVD comprising SEQ ID NO: 126, or one of SEQ ID NO: 134-179, or one of SEQ ID NO: 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 182, and an HCVD comprising SEQ ID NO: 126, or one of SEQ ID NO: 134-179, or one of SEQ ID NO: 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 183, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 184, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 185, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 186, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 187, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 188, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 189, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 190, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 191, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 192, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 193, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 194, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 195, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 196, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 197, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 198, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 199, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 200, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 201, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 202, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 203, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 204, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 205, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 206, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 207, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 228, and an HCVD comprising SEQ ID NO: 126, or one of 134-179, or one of 208-227.

[0225] In some embodiments of any ABPC described herein, the first ABD comprises a HCVD of 12C6 with one or more amino acids substituted with histidine. In some embodiments of any ABPC described herein, the first ABD comprises a LCVD of 12C6 with one or more amino acids substituted with histidine. In some embodiments of any ABPC described herein, the first ABD comprises a HCVD of 12C6 with one or more amino acids substituted with histidine and a LCVD of 12C6 with one or more amino acids substituted with histidine. In some embodiments of any ABPC described herein, the HCVD of 12C6 comprises SEQ ID NO: 229. In some embodiments of any ABPC described herein, the LCVD of 12C6 comprises SEQ ID NO: 230.

[0226] In some examples of any of the ABPCs described herein, the first ABD comprises a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, collectively substituted with histidine at a total of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NOs: 231, 232, and 233. In some embodiments of any of the ABPCs described herein, the first ABD comprises a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, collectively substituted with histidine at a total of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NOs: 234, 235, and 236. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NO:231, SEQ ID NO:232, and SEQ ID NO:233, respectively, wherein one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions in total of SEQ ID NO:231, 232, and 233 have been substituted with histidine; and an LCVD consisting of CDR1, CDR2, and CDR3 of SEQ ID NO:234, SEQ ID NO:235, and SEQ ID NO:236, respectively, wherein one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) amino acid positions in SEQ ID NO:234, SEQ ID NO:235, and SEQ ID NO:236 collectively have been substituted with histidine.

[0227] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, wherein the HCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:229 selected from the group of 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at one or more amino acid positions of SEQ ID NO:230 selected from the group of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229 and comprises a histidine at one or more amino acid positions of SEQ ID NO:229 selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:230 and comprises a histidine at one or more amino acid positions of SEQ ID NO:230 selected from the group consisting of 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99. In some embodiments of any of the ABPCs and antibodies described herein, the HCVD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0228] [Table 5-1] [Table 5-2]

[0229] In some embodiments of any of the ABPCs and antibodies described herein, the LCVD comprises an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:230, and the LCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:230 listed in Table 6.

[0230] [Table 6-1] [Table 6-2]

[0231] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229 and includes a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5, and an LCVD that is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:230 and includes a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:230 listed in Table 6.

[0232] In some examples of any of the ABPCs described herein, the first ABD has an LCVD comprising SEQ ID NO:230 and an HCVD that is at least 90% identical (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) to SEQ ID NO:229, wherein the HCVD comprises a histidine at any of the specific combinations of one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid positions of SEQ ID NO:229 listed in Table 5.

[0233] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 30 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0234] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 31 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0235] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 33 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0236] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 51 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0237] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 53 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0238] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 57 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0239] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 91 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0240] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 92 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0241] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 94 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0242] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:230, wherein the LCVD comprises a histidine at position 99 of SEQ ID NO:230, and the HCVD is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100%) identical to SEQ ID NO:229, and wherein the HCVD comprises a histidine at any of the specific combinations of one or more amino acid positions of SEQ ID NO:229 listed in Table 5.

[0243] In some embodiments of any ABPC described herein, the first ABD comprises a HCVD of 12C6 with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the first ABD comprises a LCVD of 12C6 with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the first ABD comprises a HCVD of 12C6 with one or more histidine(s) substituted with alanine and a LCVD of 12C6 with one or more histidine(s) substituted with alanine. In some embodiments of any ABPC described herein, the HCVD of 12C6 comprises SEQ ID NO: 229. In some embodiments of any ABPC described herein, the LCVD of 12C6 comprises SEQ ID NO: 230.

[0244] In some embodiments of any of the ABPCs described herein, the first ABD comprises a HCVD comprising CDR1, CDR2 and CDR3 of SEQ ID NO:231, SEQ ID NO:232, and SEQ ID NO:233, respectively, in which a total of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) histidines in SEQ ID NOs:231, 232 and 233 are substituted with alanine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD that includes CDR1, CDR2 and CDR3 of SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 236, respectively, in which a total of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) histidines in SEQ ID NOs: 234, 235 and 236 are substituted with alanine. In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 231, 232, and 233, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) histidines of SEQ ID NOs: 231, 232, and 233 have been collectively replaced with alanine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 234, 235, and 236, respectively, in which one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) histidines of SEQ ID NOs: 234, 235, and 236 have been collectively replaced with alanine.

[0245] In some embodiments of any of the ABPCs described herein, the first ABD comprises an HCVD of SEQ ID NO: 229, or SEQ ID NOs: 237-268.

[0246] In some embodiments of any of the ABPCs described herein, the first ABD comprises a LCVD having the sequence of one of SEQ ID NOs: 230, or 269-297.

[0247] In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 230 and an HCVD comprising one of SEQ ID NOs: 237-268.

[0248] In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 269 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 270 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 271 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 272 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 273 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 274 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 275 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 276 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 277 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 278 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 279 and an HCVD comprising one of SEQ ID NOs: 229, or 237-268.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 280 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 281 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 282 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 283 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 284 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 285 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 286 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 287 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 288 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 289 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any of the ABPCs described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 290 and an HCVD comprising one of SEQ ID NOs: 229, or 237-268.In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 291 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 292 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 293 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 294 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 295 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NO: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 296 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NOs: 237-268. In some embodiments of any ABPC described herein, the first ABD comprises an LCVD comprising SEQ ID NO: 297 and an HCVD comprising SEQ ID NO: 229, or one of SEQ ID NOs: 237-268.

[0249] In some embodiments, the first ABD comprises a HCVD of MYT9345 with one or more amino acids optionally substituted with histidine. In some embodiments, the first ABD comprises a LCVD of MYT9345 with one or more amino acids optionally substituted with histidine. In some embodiments, the first ABD comprises a HCVD of MYT9345 with one or more amino acids optionally substituted with histidine and a LCVD of MYT9345 with one or more amino acids optionally substituted with histidine. In some embodiments, the HCVD of MYT9345 comprises SEQ ID NO: 301. In some embodiments, the LCVD of MYT9345 comprises SEQ ID NO: 302.

[0250] In some embodiments, the first ABD comprises a HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, and optionally having the sum of one or more amino acid positions of SEQ ID NOs: 303, 304, and 305 substituted with histidine. In some embodiments, the first ABD comprises a LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, and optionally having the sum of one or more amino acid positions of SEQ ID NOs: 306, 307, and 308 collectively substituted with histidine. In some embodiments, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 303, 304, and 305, respectively, and optionally all of one or more amino acid positions of SEQ ID NOs: 303, 304, and 305 substituted with histidine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 306, 307, and 308, respectively, and optionally all of one or more amino acid positions of SEQ ID NOs: 306, 307, and 308 substituted with histidine.

[0251] In some embodiments, the first ABD comprises an HCVD that is at least 90% identical to SEQ ID NO:301, where the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:301 selected from among 29, 30, 32, 50-54, 58, 60, 96, and 101. In some embodiments, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:302, where the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:302 selected from among 25, 30-33, 35, 55-57, 91, 94-96, and 98. In some embodiments, the first ABD comprises an HCVD at least 90% identical to SEQ ID NO: 301, the HCVD optionally comprising a histidine at one or more amino acid positions of SEQ ID NO: 301 selected from 29, 30, 32, 50-54, 58, 60, 96, and 101, and the LCVD comprises an LCVD at least 90% identical to SEQ ID NO: 302, the LCVD optionally comprising a histidine at one or more amino acid positions of SEQ ID NO: 302 selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98.

[0252] In some embodiments, the HCVD comprises an HCVD that is at least 90% identical to SEQ ID NO: 301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 301 listed in Table 7.

[0253] In some embodiments, the first ABD comprises a HCVD that is ≧90% (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) identical to SEQ ID NO:301, and the HCVD comprises an alanine at position 52 of SEQ ID NO:301.

[0254] In some embodiments, the first ABD comprises an HCVD that is ≧90% (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) identical to SEQ ID NO:301, where the HCVD comprises an alanine at position 52 of SEQ ID NO:301, and an LCVD that is ≧90% (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) identical to SEQ ID NO:302, where the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:302 selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98.

[0255] [Table 7-1] [Table 7-2]

[0256] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:302 listed in Table 8, and / or the LCVD comprises an alanine at position 95 of SEQ ID NO:302.

[0257] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises an alanine at position 95 of SEQ ID NO:302.

[0258] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, the LCVD comprising an alanine at position 95 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, the HCVD optionally comprising a histidine at one or more amino acid positions of SEQ ID NO:301 selected from 29, 30, 32, 50-54, 58, 60, 96, and 101.

[0259] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, and the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:302 selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98, and / or the LCVD comprises an alanine at position 95 of SEQ ID NO:302. In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:302 selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98, and / or the LCVD comprises an alanine at position 95 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:301 selected from 29, 30, 32, 50-54, 58, 60, 96, and 101.

[0260] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:302 selected from 25, 30-33, 35, 55-57, 91, 94-96, and 98, and / or the LCVD comprises an alanine at position 95 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:301 selected from 29, 30, 32, 50-54, 58, 60, 96, and 101, and / or the HCVD comprises an alanine at position 52.

[0261] [Table 8-1] [Table 8-2]

[0262] In some embodiments, the first ABD comprises an HCVD that is ≧90% identical to SEQ ID NO: 301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 301 listed in Table 7, and an LCVD that is ≧90% identical to SEQ ID NO: 302, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 302 listed in Table 8.

[0263] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:302 listed in Table 7, and / or the LCVD comprises an alanine at position 95 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 8. In some embodiments, the first ABD comprises an LCVD that comprises SEQ ID NO:302 and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0264] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 25 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0265] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 30 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0266] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 31 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0267] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises an alanine at position 95 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0268] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 32 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0269] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 33 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0270] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 35 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0271] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 55 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0272] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 56 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0273] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 57 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0274] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 91 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0275] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 94 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0276] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 95 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0277] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 96 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0278] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at position 98 of SEQ ID NO:302, and an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:301 listed in Table 7.

[0279] In some embodiments, the first ABD comprises an HCVD that is ≧90% identical to SEQ ID NO:301, wherein the HCVD comprises a histidine at any one of positions 29, 30, 32, 50-54, 58, 60, 96, and 101 of SEQ ID NO:301, and the LCVD comprises an LCVD that is ≧90% identical to SEQ ID NO:302, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:302 listed in Table 8.

[0280] In some embodiments, the first ABD comprises an HCVD of SEQ ID NO: 301, or one of 309-342, and / or the first ABD comprises an LCVD of SEQ ID NO: 302, or one of 343-374.

[0281] In some embodiments of the ABPC, the first ABD comprises an LCVD comprising any one of SEQ ID NOs: 302, or one of 343-374, and an HCVD comprising any one of SEQ ID NOs: 301, or one of 309-342.

[0282] In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 343, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 344, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 345, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 346, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 347, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 348, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 349, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 350, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 351, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 352, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 353, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 354, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 355, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 356, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342.In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 357, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 358, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 359, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 360, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 361, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 362, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 363, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 364, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 365, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 366, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 367, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 368, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 369, and an HCVD comprising SEQ ID NO: 301, or one of SEQ ID NOs: 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 370, and an HCVD comprising SEQ ID NO: 301, or one of SEQ ID NOs: 309-342.In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 371, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 372, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 373, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 374, and an HCVD comprising one of SEQ ID NOs: 301, or 309-342.

[0283] In some embodiments, the first ABD comprises an HCVD of MYT9359 having one or more amino acids substituted with histidine. In some embodiments, the first ABD comprises an LCVD of MYT9359 having one or more amino acids substituted with histidine. In some embodiments, the first ABD comprises an HCVD of MYT9359 having one or more amino acids optionally substituted with histidine and an LCVD of MYT9359 having one or more amino acids substituted with histidine. In some embodiments, the HCVD of MYT9359 comprises SEQ ID NO: 375. In some embodiments, the LCVD of MYT9359 comprises SEQ ID NO: 376.

[0284] In some embodiments, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, and optionally having one or more amino acid positions of SEQ ID NOs: 377, 378, and 379 collectively substituted with histidine. In some embodiments, the first ABD comprises an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, and optionally having one or more amino acid positions of SEQ ID NOs: 380, 381, and 382 collectively substituted with histidine. In some embodiments, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 377, 378, and 379, respectively, and optionally all of one or more amino acid positions of SEQ ID NOs: 377, 378, and 379, collectively, optionally substituted with histidine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 380, 381, and 382, ​​respectively, and optionally all of one or more amino acid positions of SEQ ID NOs: 380, 381, and 382, ​​collectively, optionally substituted with histidine.

[0285] In some embodiments, the first ABD comprises an HCVD that is at least 90% identical to SEQ ID NO:375, where the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:375 selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108. In some embodiments, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:376, where the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:376 selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102. In some embodiments, the first ABD comprises an HCVD that is at least 90% identical to SEQ ID NO: 375, optionally comprising a histidine at one or more amino acid positions of SEQ ID NO: 375 selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108, and the LCVD comprises an LCVD that is at least 90% identical to SEQ ID NO: 376, optionally comprising a histidine at one or more amino acid positions of SEQ ID NO: 376 selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102.

[0286] In some embodiments, the HCVD comprises an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0287] In some embodiments, the first ABD comprises a HCVD that is ≧90% (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) identical to SEQ ID NO:375, and the HCVD comprises an alanine at position 107 of SEQ ID NO:375.

[0288] In some embodiments, the first ABD comprises an HCVD that is ≧90% (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) identical to SEQ ID NO:375, wherein the HCVD comprises an alanine at position 107 of SEQ ID NO:375, and an LCVD that is ≧90% (e.g., ≧92%, ≧94%, ≧96%, ≧98%, ≧99%, or 100%) identical to SEQ ID NO:376, wherein the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:376 selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108.

[0289] [Table 9-1] [Table 9-2]

[0290] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:376 listed in Table 10, and / or the LCVD comprises an alanine at position 98 of SEQ ID NO:376. In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises an alanine at position 98 of SEQ ID NO:376. In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, where the LCVD comprises an alanine at position 98 of SEQ ID NO:376, and an HCVD that is ≧90% identical to SEQ ID NO:375, where the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:375 selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108.

[0291] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, and the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:376 selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100 and 102, and / or the LCVD comprises an alanine at position 98 of SEQ ID NO:376. In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:376 selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102, and / or the LCVD comprises an alanine at position 98 of SEQ ID NO:376, and an HCVD that is ≧90% identical to SEQ ID NO:375, wherein the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:375 selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108.

[0292] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:376 selected from 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102, and / or the LCVD comprises an alanine at position 98 of SEQ ID NO:376, and an HCVD that is ≧90% identical to SEQ ID NO:375, wherein the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:375 selected from 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108, and / or the HCVD comprises an alanine at position 107.

[0293] [Table 10-1] [Table 10-2]

[0294] In some embodiments, the first ABD comprises an HCVD that is ≧90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9, and an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 376 listed in Table 10.

[0295] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:376 listed in Table 10, and / or the LCVD comprises an alanine at position 98 of SEQ ID NO:376, and an HCVD that is ≧90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0296] In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 376 and an HCVD that is ≧90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0297] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 25 of SEQ ID NO:376, and an HCVD that is ≧90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0298] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 29 of SEQ ID NO:376, and the HCVD comprises an HCVD that is ≧90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0299] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 30 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0300] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises an alanine at position 98 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0301] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 31 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0302] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 33 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0303] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 50 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0304] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 51 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0305] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 52 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0306] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 53 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0307] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 89 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0308] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 91 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0309] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 92 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0310] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at position 93 of SEQ ID NO:376, and an HCVD that is at least 90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:375 listed in Table 9.

[0311] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 96 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0312] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 97 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0313] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 100 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0314] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 376, wherein the LCVD comprises a histidine at position 102 of SEQ ID NO: 376, and an HCVD that is at least 90% identical to SEQ ID NO: 375, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 375 listed in Table 9.

[0315] In some embodiments, the first ABD comprises an HCVD that is ≧90% identical to SEQ ID NO:375, wherein the HCVD comprises a histidine at any one of positions 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108 of SEQ ID NO:375, and the LCVD comprises an LCVD that is ≧90% identical to SEQ ID NO:376, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:376 listed in Table 10.

[0316] In some embodiments, the first ABD comprises an HCVD of SEQ ID NO: 375, or one of 383-423, and / or the first ABD comprises an LCVD of SEQ ID NO: 376, or one of 424-458. In some embodiments of the ABPC, the first ABD comprises an LCVD comprising any one of SEQ ID NO: 376, or one of 424-458, and an HCVD comprising any one of SEQ ID NO: 375, or one of 383-423.

[0317] In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 424 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 425 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 426 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 427 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 428 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 429 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 430, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 431, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 432, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 433, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 434, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 435, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 436, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 437, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423.In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 438, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 439, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 440, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 441, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 442, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 443, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 444, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 445, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 446, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 447, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 448, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 449, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 450 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 451 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423.In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 452 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 453 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 454 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 455 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 456 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 457 and an HCVD comprising one of SEQ ID NOs: 375, or 383-423. In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 458, and an HCVD comprising one of SEQ ID NOs: 375, or 383-423.

[0318] In some embodiments, the first ABD comprises an HCVD of MYT9361 having one or more amino acids substituted with histidine. In some embodiments, the first ABD comprises an LCVD of MYT9361 having one or more amino acids substituted with histidine. In some embodiments, the first ABD comprises an HCVD of MYT9361 having one or more amino acids optionally substituted with histidine and an LCVD of MYT9361 having one or more amino acids substituted with histidine. In some embodiments, the HCVD of MYT9361 comprises SEQ ID NO: 459. In some embodiments, the LCVD of MYT9361 comprises SEQ ID NO: 460.

[0319] In some embodiments, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively, and optionally having one or more amino acid positions of SEQ ID NOs: 461, 462, and 463 substituted with histidine. In some embodiments, the first ABD comprises an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, and optionally having one or more amino acid positions of SEQ ID NOs: 464, 465, and 466 substituted with histidine. In some embodiments, the first ABD comprises an HCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 461, 462, and 463, respectively, collectively comprising all of one or more amino acid positions of SEQ ID NOs: 461, 462, and 463, optionally substituted with histidine, and an LCVD comprising CDR1, CDR2, and CDR3 of SEQ ID NOs: 464, 465, and 466, respectively, collectively comprising all of one or more amino acid positions of SEQ ID NOs: 464, 465, and 466, optionally substituted with histidine.

[0320] In some embodiments, the first ABD comprises an HCVD that is at least 90% identical to SEQ ID NO:459, where the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:459 selected from 32, 99, 101, 102, 106, and 111. In some embodiments, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO:460, where the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:460 selected from 30, 31, 33, 51, 92, and 95. In some embodiments, the first ABD comprises an HCVD that is at least 90% identical to SEQ ID NO: 459, the HCVD optionally comprising a histidine at one or more amino acid positions of SEQ ID NO: 459 selected from 32, 99, 101, 102, 106, and 111, and an LCVD comprises an HCVD that is at least 90% identical to SEQ ID NO: 460, the LCVD optionally comprising a histidine at one or more amino acid positions of SEQ ID NO: 460 selected from 30, 31, 33, 51, 92, and 95.

[0321] In some embodiments, the HCVD comprises an HCVD that is at least 90% identical to SEQ ID NO: 459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 459 listed in Table 11.

[0322] [Table 11]

[0323] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 460, and the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 460 listed in Table 12.

[0324] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:460, where the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:460 selected from 30, 31, 33, 51, 92, and 95. In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:460, where the LCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:460 selected from 30, 31, 33, 51, 92, and 95, and an HCVD that is ≧90% identical to SEQ ID NO:459, where the HCVD optionally comprises a histidine at one or more amino acid positions of SEQ ID NO:459 selected from 32, 99, 101, 102, 106, and 111.

[0325] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:460, optionally comprising a histidine at one or more amino acid positions of SEQ ID NO:460 selected from 30, 31, 33, 51, 92, and 95, and an HCVD that is ≧90% identical to SEQ ID NO:459, optionally comprising a histidine at one or more amino acid positions of SEQ ID NO:459 selected from 32, 99, 101, 102, 106, and 111.

[0326] [Table 12-1] [Table 12-2]

[0327] In some embodiments, the first ABD comprises an HCVD that is ≧90% identical to SEQ ID NO:459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:459 listed in Table 11, and the LCVD comprises an LCVD that is ≧90% identical to SEQ ID NO:460, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:460 listed in Table 12.

[0328] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO: 460, wherein the LCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 460 listed in Table 12, and the HCVD comprises an HCVD that is ≧90% identical to SEQ ID NO: 459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 459 listed in Table 11.

[0329] In some embodiments, the first ABD comprises an LCVD comprising SEQ ID NO: 460 and an HCVD that is ≧90% identical to SEQ ID NO: 459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 459 listed in Table 11. In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:460, wherein the LCVD comprises a histidine at position 30 of SEQ ID NO:460, and an HCVD that is ≧90% identical to SEQ ID NO:459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:459 listed in Table 11.

[0330] In some embodiments, the first ABD comprises an LCVD that is ≧90% identical to SEQ ID NO:460, wherein the LCVD comprises a histidine at position 31 of SEQ ID NO:460, and an HCVD that is ≧90% identical to SEQ ID NO:459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO:459 listed in Table 11.

[0331] In some embodiments, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 460, wherein the LCVD comprises a histidine at position 33 of SEQ ID NO: 460, and an HCVD that is at least 90% identical to SEQ ID NO: 459, wherein the HCVD comprises a histidine at any of the specific combinations of two or more amino acid positions of SEQ ID NO: 459 listed in Table 11.

[0332] In some embodiments, the first ABD comprises an LCVD that is at least 90% identical to SEQ ID NO: 460, wherein the LCVD comprises a histidine at position 51 of SEQ ID NO: 460, and an HCVD that is at least 90% identical to SEQ ID NO: 459, wherein the HCVD comprises a histidine at any of the specific...

Claims

1. The first antigen-binding domain (ABD) is capable of specifically binding to PTK7 or an epitope of PTK7 present on the surface of target mammalian cells, wherein the dissociation rate of the first ABD at pH approximately 4.0 to approximately 6.5 is faster than the dissociation rate at pH approximately 7.0 to approximately 8.0, or the K of the first ABD at pH approximately 4.0 to approximately 6.5 Ｄ However, K at pH approximately 7.0 to 8.0 Ｄ Larger than, and The first antigen-binding domain is (a) to (q): (a) Heavy chain variable domains containing CDRs of sequence numbers 303 to 305, and light chain variable domains containing CDRs of sequence numbers 306 to 308, (b) Heavy chain variable domains containing CDRs of sequence numbers 377-379, and light chain variable domains containing CDRs of sequence numbers 380-382, (c) Heavy chain variable domains containing CDRs of sequence numbers 461 to 463, and light chain variable domains containing CDRs of sequence numbers 464 to 466, (d) Heavy chain variable domains containing CDRs of sequence numbers 544 to 546, and light chain variable domains containing CDRs of sequence numbers 547 to 549, (e) Heavy chain variable domains containing CDRs of sequence numbers 630 to 632, and light chain variable domains containing CDRs of sequence numbers 633 to 635, (f) Heavy chain variable domains containing CDRs of sequence numbers 712-714, and light chain variable domains containing CDRs of sequence numbers 715-717, (g) Heavy chain variable domains containing CDRs of sequence numbers 805-807, and light chain variable domains containing CDRs of sequence numbers 808-810, (h) A heavy chain variable domain of SEQ ID NO: 301, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 301 selected from the group consisting of 29, 30, 32, 50-54, 58, 60, 96, and 101, and a light chain variable domain of SEQ ID NO: 302; A light chain variable domain of SEQ ID NO: 301 and a light chain variable domain of SEQ ID NO: 302, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 302 selected from the group 25, 30-33, 35, 55-57, 91, 94-96 and 98; or A heavy chain variable domain of SEQ ID NO: 301, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 301 selected from the group 29, 30, 32, 50-54, 58, 60, 96, and 101; and a light chain variable domain of SEQ ID NO: 302, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 302 selected from the group 25, 30-33, 35, 55-57, 91, 94-96, and 98. (i) A heavy chain variable domain of Sequence ID No. 375, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 375 selected from the group consisting of 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108, and a light chain variable domain of Sequence ID No. 376; A heavy chain variable domain of SEQ ID NO: 375 and a light chain variable domain of SEQ ID NO: 376, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 376 selected from the group of 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102; or A heavy chain variable domain of Sequence ID No. 375, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in Sequence ID No. 375 selected from the group 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108; and a light chain variable domain of Sequence ID No. 376, wherein the light chain variable domain contains a histidine substitution at one or more positions in Sequence ID No. 376 selected from the group 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102. (j) A heavy chain variable domain of Sequence ID No. 459, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 459 selected from the group consisting of 32, 99, 101, 102, 106, and 111, and a light chain variable domain of Sequence ID No. 460; A light chain variable domain of SEQ ID NO: 459 and a light chain variable domain of SEQ ID NO: 460, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 460 selected from the group 30, 31, 33, 51, 92, and 95; or A heavy chain variable domain of SEQ ID NO: 459, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 459 selected from the group 32, 99, 101, 102, 106, and 111; and a light chain variable domain of SEQ ID NO: 460, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 460 selected from the group 30, 31, 33, 51, 92, and 95. (k) A heavy chain variable domain of Sequence ID No. 542, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 542 selected from the group consisting of 27, 29, 30, 31, 32, 53, 55, 58, 102, 104, and 105, and a light chain variable domain of Sequence ID No. 543; A light chain variable domain of SEQ ID NO: 542 and a light chain variable domain of SEQ ID NO: 543, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 543 selected from the group 25, 29, 30, 31, 32, 89, 92, and 98; or A heavy chain variable domain of sequence number 542, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in sequence number 542 selected from the group 27, 29, 30, 31, 32, 53, 55, 58, 102, 104, and 105, and a light chain variable domain of sequence number 543, wherein the light chain variable domain includes a histidine substitution at one or more positions in sequence number 543 selected from the group 25, 29, 30, 31, 32, 89, 92, and 98, (l) A heavy chain variable domain of Sequence ID No. 628, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 628 selected from the group consisting of 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102, and 103, and a light chain variable domain of Sequence ID No. 629; A light chain variable domain of SEQ ID NO: 628 and a light chain variable domain of SEQ ID NO: 629, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 629 selected from the group 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99, and 100; or A heavy chain variable domain of sequence number 628, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in sequence number 628 selected from the group 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102, and 103, and a light chain variable domain of sequence number 629, wherein the light chain variable domain contains a histidine substitution at one or more positions in sequence number 629 selected from the group 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99, and 100, (m) A heavy chain variable domain of Sequence ID No. 710, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 710 selected from the group consisting of 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110, and 113, and a light chain variable domain of Sequence ID No. 711; A heavy chain variable domain of SEQ ID NO: 710 and a light chain variable domain of SEQ ID NO: 711, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 711 selected from the group of 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95, 98, and 99; or A heavy chain variable domain of SEQ ID NO: 710, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 710 selected from the group 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110, and 113, and a light chain variable domain of SEQ ID NO: 711, wherein the light chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 711 selected from the group 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95, 98, and 99, (n) A heavy chain variable domain of Sequence ID No. 803, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 803 selected from the group consisting of 33, 50, 53, 55-58, 64, 100, and 107, and a light chain variable domain of Sequence ID No. 804; A light chain variable domain of SEQ ID NO: 803 and a light chain variable domain of SEQ ID NO: 804, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 804 selected from the group 31, 33-35, 52, 54, 98, and 99; or A heavy chain variable domain of SEQ ID NO: 803, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 803 selected from the group 33, 50, 53, 55-58, 64, 100, and 107; and a light chain variable domain of SEQ ID NO: 804, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 804 selected from the group 31, 33-35, 52, 54, 98, and 99. (o) A heavy chain variable domain of Sequence ID No. 1, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107, and a light chain variable domain of Sequence ID No. 2; A light chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 2 selected from the group 25, 29, 31, 35, 60, 93, and 94; or A heavy chain variable domain of SEQ ID NO: 1, wherein the heavy chain variable domain contains histidine substitutions at one or more positions in SEQ ID NO: 1 selected from the group 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107; and a light chain variable domain of SEQ ID NO: 2, wherein the light chain variable domain contains histidine substitutions at one or more positions in SEQ ID NO: 2 selected from the group 25, 29, 31, 35, 60, 93, and 94. (p) A heavy chain variable domain of Sequence ID No. 126, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 126 selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, and 111, and a light chain variable domain of Sequence ID No. 127; A heavy chain variable domain of SEQ ID NO: 126 and a light chain variable domain of SEQ ID NO: 127, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 127 selected from the group 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94; or A heavy chain variable domain of SEQ ID NO: 126, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 126 selected from the group 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, and 111; and a light chain variable domain of SEQ ID NO: 127, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 127 selected from the group 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94; and (q) A heavy chain variable domain of Sequence ID No. 229, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 229 selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100, and a light chain variable domain of Sequence ID No. 230; A heavy chain variable domain of SEQ ID NO: 229 and a light chain variable domain of SEQ ID NO: 230, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 230 selected from the group 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99; or A heavy chain variable domain of SEQ ID NO: 229, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 229 selected from the group 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100; and a light chain variable domain of SEQ ID NO: 230, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 230 selected from the group 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99. An antigen-binding protein construct (ABPC) containing one of the following.

2. The first ABD is (a) Heavy chain variable domains containing CDRs of sequence numbers 303 to 305, and light chain variable domains containing CDRs of sequence numbers 306 to 308, (b) Heavy chain variable domains containing CDRs of sequence numbers 377-379, and light chain variable domains containing CDRs of sequence numbers 380-382, (c) Heavy chain variable domains containing CDRs of sequence numbers 461 to 463, and light chain variable domains containing CDRs of sequence numbers 464 to 466, (d) Heavy chain variable domains containing CDRs of sequence numbers 544 to 546, and light chain variable domains containing CDRs of sequence numbers 547 to 549, (e) Heavy chain variable domains containing CDRs of sequence numbers 630 to 632, and light chain variable domains containing CDRs of sequence numbers 633 to 635, (f) Heavy chain variable domains containing CDRs of sequence numbers 712 to 714, and light chain variable domains containing CDRs of sequence numbers 715 to 717, or (g) Heavy chain variable domains containing CDRs of sequence numbers 805-807, and light chain variable domains containing CDRs of sequence numbers 808-810, The ABPC according to claim 1, including the following:

3. The first antigen-binding domain is (a) A heavy chain variable domain containing Sequence ID No. 301, and a light chain variable domain containing Sequence ID No. 302, (b) A heavy chain variable domain containing SEQ ID NO: 375, and a light chain variable domain containing SEQ ID NO: 376, (c) Heavy chain variable domain containing Sequence ID No. 459, and light chain variable domain containing Sequence ID No. 460, (d) Heavy chain variable domain containing Sequence ID No. 542, and light chain variable domain containing Sequence ID No. 543, (e) A heavy chain variable domain containing Sequence ID No. 628, and a light chain variable domain containing Sequence ID No. 629, (f) A heavy chain variable domain containing SEQ ID NO: 710, and a light chain variable domain containing SEQ ID NO: 711, or (g) A heavy chain variable domain containing sequence number 803, and a light chain variable domain containing sequence number 804, The ABPC according to claim 1, including the following:

4. The first antigen-binding domain is (a) A heavy chain variable domain of SEQ ID NO: 301, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 301 selected from the group consisting of 29, 30, 32, 50-54, 58, 60, 96, and 101, and a light chain variable domain of SEQ ID NO: 302; A light chain variable domain of SEQ ID NO: 301 and a light chain variable domain of SEQ ID NO: 302, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 302 selected from the group 25, 30-33, 35, 55-57, 91, 94-96 and 98; or A heavy chain variable domain of SEQ ID NO: 301, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 301 selected from the group 29, 30, 32, 50-54, 58, 60, 96, and 101; and a light chain variable domain of SEQ ID NO: 302, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 302 selected from the group 25, 30-33, 35, 55-57, 91, 94-96, and 98. (b) A heavy chain variable domain of Sequence ID No. 375, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 375 selected from the group consisting of 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108, and a light chain variable domain of Sequence ID No. 376; A heavy chain variable domain of SEQ ID NO: 375 and a light chain variable domain of SEQ ID NO: 376, wherein the light chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 376 selected from the group of 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102; or A heavy chain variable domain of Sequence ID No. 375, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in Sequence ID No. 375 selected from the group 26, 27, 30, 32, 34, 51, 52, 55, 58, 59, 63, 97, 99, and 108; and a light chain variable domain of Sequence ID No. 376, wherein the light chain variable domain contains a histidine substitution at one or more positions in Sequence ID No. 376 selected from the group 25, 29, 30, 31, 32, 33, 50, 51, 52, 53, 89, 91, 92, 93, 96, 97, 100, and 102. (c) A heavy chain variable domain of Sequence ID No. 459, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 459 selected from the group consisting of 32, 99, 101, 102, 106, and 111, and a light chain variable domain of Sequence ID No. 460; A light chain variable domain of SEQ ID NO: 459 and a light chain variable domain of SEQ ID NO: 460, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 460 selected from the group 30, 31, 33, 51, 92, and 95; or A heavy chain variable domain of SEQ ID NO: 459, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 459 selected from the group 32, 99, 101, 102, 106, and 111; and a light chain variable domain of SEQ ID NO: 460, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 460 selected from the group 30, 31, 33, 51, 92, and 95. (d) A heavy chain variable domain of SEQ ID NO: 542, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 542 selected from the group consisting of 27, 29, 30, 31, 32, 53, 55, 58, 102, 104, and 105, and a light chain variable domain of SEQ ID NO: 543; A light chain variable domain of SEQ ID NO: 542 and a light chain variable domain of SEQ ID NO: 543, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 543 selected from the group 25, 29, 30, 31, 32, 89, 92, and 98; or A heavy chain variable domain of sequence number 542, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in sequence number 542 selected from the group 27, 29, 30, 31, 32, 53, 55, 58, 102, 104, and 105, and a light chain variable domain of sequence number 543, wherein the light chain variable domain includes a histidine substitution at one or more positions in sequence number 543 selected from the group 25, 29, 30, 31, 32, 89, 92, and 98, (e) A heavy chain variable domain of Sequence ID No. 628, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 628 selected from the group consisting of 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102, and 103, and a light chain variable domain of Sequence ID No. 629; A heavy chain variable domain of SEQ ID NO: 628 and a light chain variable domain of SEQ ID NO: 629, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 629 selected from the group 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99, and 100; or A heavy chain variable domain of sequence number 628, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in sequence number 628 selected from the group 26, 28, 30, 50, 52, 53, 54, 55, 56, 57, 100, 101, 102, and 103, and a light chain variable domain of sequence number 629, wherein the light chain variable domain contains a histidine substitution at one or more positions in sequence number 629 selected from the group 25, 26, 28, 29, 33, 51, 55, 89, 91, 95, 96, 97, 98, 99, and 100, (f) A heavy chain variable domain of Sequence ID No. 710, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 710 selected from the group consisting of 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110, and 113, and a light chain variable domain of Sequence ID No. 711; A heavy chain variable domain of SEQ ID NO: 710 and a light chain variable domain of SEQ ID NO: 711, wherein the light chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 711 selected from the group of 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95, 98, and 99; or A heavy chain variable domain of SEQ ID NO: 710, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 710 selected from the group 29, 30, 31, 33, 35, 50, 53, 57, 58, 65, 96, 97, 98, 100, 101, 103, 105, 107, 108, 109, 110, and 113, and a light chain variable domain of SEQ ID NO: 711, wherein the light chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 711 selected from the group 25, 27, 29, 30, 35, 36, 56, 57, 91, 93, 94, 95, 98, and 99, (g) A heavy chain variable domain of SEQ ID NO: 803, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 803 selected from the group consisting of 33, 50, 53, 55-58, 64, 100, and 107, and a light chain variable domain of SEQ ID NO: 804; A light chain variable domain of SEQ ID NO: 803 and a light chain variable domain of SEQ ID NO: 804, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 804 selected from the group 31, 33-35, 52, 54, 98, and 99; or A heavy chain variable domain of SEQ ID NO: 803, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 803 selected from the group 33, 50, 53, 55-58, 64, 100, and 107; and a light chain variable domain of SEQ ID NO: 804, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 804 selected from the group 31, 33-35, 52, 54, 98, and 99. (h) A heavy chain variable domain of Sequence ID No. 1, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 1 selected from the group consisting of 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107, and a light chain variable domain of Sequence ID No. 2; A light chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 2 selected from the group 25, 29, 31, 35, 60, 93, and 94; or A heavy chain variable domain of SEQ ID NO: 1, wherein the heavy chain variable domain contains histidine substitutions at one or more positions in SEQ ID NO: 1 selected from the group 24, 27, 28, 29, 30, 31, 32, 34, 53, 54, 55, 57, 58, 64, 98, 100, 102, 103, and 107; and a light chain variable domain of SEQ ID NO: 2, wherein the light chain variable domain contains histidine substitutions at one or more positions in SEQ ID NO: 2 selected from the group 25, 29, 31, 35, 60, 93, and 94. (i) A heavy chain variable domain of SEQ ID NO: 126, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 126 selected from the group consisting of 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, and 111, and a light chain variable domain of SEQ ID NO: 127; A heavy chain variable domain of SEQ ID NO: 126 and a light chain variable domain of SEQ ID NO: 127, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 127 selected from the group 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94; or A heavy chain variable domain of SEQ ID NO: 126, wherein the heavy chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 126 selected from the group 53, 54, 56, 57, 60, 102, 103, 104, 105, 106, 108, 109, 110, and 111, and a light chain variable domain of SEQ ID NO: 127, wherein the light chain variable domain contains a histidine substitution at one or more positions in SEQ ID NO: 127 selected from the group 25, 26, 28, 29, 31, 32, 33, 50, 90, 92, and 94, or (j) A heavy chain variable domain of Sequence ID No. 229, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in Sequence ID No. 229 selected from the group consisting of 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100, and a light chain variable domain of Sequence ID No. 230; A light chain variable domain of SEQ ID NO: 229 and a light chain variable domain of SEQ ID NO: 230, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 230 selected from the group 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99; or A heavy chain variable domain of SEQ ID NO: 229, wherein the heavy chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 229 selected from the group 27, 32, 33, 34, 35, 51, 54, 56, 58, and 100; and a light chain variable domain of SEQ ID NO: 230, wherein the light chain variable domain includes a histidine substitution at one or more positions in SEQ ID NO: 230 selected from the group 30, 31, 33, 51, 53, 57, 91, 92, 94, and 99. The ABPC according to claim 1, including the following:

5. The first antigen-binding domain is (a) one heavy chain variable domain from sequence numbers 309 to 342, and the light chain variable domain of sequence number 302, The heavy chain variable domain of sequence number 301, and one of the light chain variable domains of sequence numbers 343 to 374, or One heavy chain variable domain from sequence numbers 309 to 342, and one light chain variable domain from sequence numbers 343 to 374, (b) one heavy chain variable domain from sequence numbers 383 to 423, and the light chain variable domain of sequence number 376, The heavy chain variable domain of sequence number 375, and one of the light chain variable domains of sequence numbers 424-458, or One heavy chain variable domain from sequence numbers 383 to 423, and one light chain variable domain from sequence numbers 424 to 458, (c) one heavy chain variable domain from sequence numbers 467 to 511, and the light chain variable domain of sequence number 460, The heavy chain variable domain of sequence number 459, and one of the light chain variable domains of sequence numbers 512 to 541, or One heavy chain variable domain from sequence numbers 467 to 511, and one light chain variable domain from sequence numbers 512 to 541, (d) one heavy chain variable domain from sequence numbers 550 to 592, and the light chain variable domain of sequence number 543, The heavy chain variable domain of sequence number 542, and one of the light chain variable domains of sequence numbers 593 to 627, or One heavy chain variable domain from sequence numbers 550 to 592, and one light chain variable domain from sequence numbers 593 to 627, (e) one heavy chain variable domain from sequence numbers 636 to 675, and the light chain variable domain of sequence number 629, The heavy chain variable domain of sequence number 628, and one of the light chain variable domains of sequence numbers 676 to 709, or One heavy chain variable domain from sequence numbers 636 to 675, and one light chain variable domain from sequence numbers 676 to 709, (f) One heavy chain variable domain from sequence numbers 718 to 767, and the light chain variable domain of sequence number 711, The heavy chain variable domain of sequence number 710, and one of the light chain variable domains from sequence numbers 768 to 802, or One heavy chain variable domain from sequence numbers 718-767, and one light chain variable domain from sequence numbers 768-802, (g) one heavy chain variable domain from sequence numbers 811 to 854, and the light chain variable domain of sequence number 804, The heavy chain variable domain of sequence number 803, and one of the light chain variable domains from sequence numbers 855 to 892, or One heavy chain variable domain from sequence numbers 811 to 854, and one light chain variable domain from sequence numbers 855 to 892, (h) Any one of the heavy chain variable domains of Sequence ID No. 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, and 105, and the light chain variable domain of Sequence ID No. 2, The heavy chain variable domain of SEQ ID NO: 1, and the light chain variable domain described in any one of SEQ ID NOs: 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122, 123, 124, or 125, or A heavy chain variable domain of any one of sequence numbers 14, 17, 18, 19, 20, 21, 22, 24, 25, 29, 30, 31, 33, 34, 40, 44, 46, 48, 49, 53, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, and 105, and a light chain variable domain of any one of sequence numbers 56, 60, 62, 66, 69, 76, 77, 78, 110, 113, 114, 119, 122, 123, 124, or 125, (i) Any one of the heavy chain variable domains of sequence numbers 147, 148, 150, 151, 154, 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, and 227, and the light chain variable domain of sequence number 127, The heavy chain variable domain of Sequence ID No. 126, and the light chain variable domain described in any one of Sequence ID Nos. 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, and 228, or One heavy chain variable domain of sequence numbers 147, 148, 150, 151, 154, 166, 167, 168, 169, 170, 172, 173, 174, 175, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 225, 226, and 227, and one light chain variable domain of sequence numbers 181, 182, 184, 185, 187, 188, 189, 191, 199, 201, 203, and 228, or (j) one heavy chain variable domain from sequence numbers 811 to 854, and the light chain variable domain of sequence number 804, The heavy chain variable domain of sequence number 803, and one of the light chain variable domains from sequence numbers 855 to 892, or One heavy chain variable domain from sequence numbers 811 to 854, and one light chain variable domain from sequence numbers 855 to 892, The ABPC according to claim 4, including the following:

6. The ABPC according to claim 1, wherein the ABPC is degraded in the target mammalian cell after internal translocation of the ABPC by the target mammalian cell.

7. The ABPC according to claim 1, further comprising a conjugated toxin, radioisotope, drug, or low molecule.

8. The ABPC according to claim 7, wherein the ABPC provides an increase in toxin release in the target mammalian cells compared to the same amount of control ABPC.

9. The ABPC according to claim 1, wherein the ABPC further comprises a second antigen-binding domain.

10. A pharmaceutical composition comprising an effective amount of ABPC according to any one of claims 1 to 9.

11. A kit comprising at least one dose of the pharmaceutical composition according to claim 10, or the ABPC according to any one of claims 1 to 9.

12. A pharmaceutical composition for treating cancer characterized by having a population of cancer cells having a predetermined level of PTK7 or PTK7 epitopes on their surface, wherein the composition comprises an effective amount of ABPC according to any one of claims 1 to 9.

13. A pharmaceutical composition for reducing the volume of a tumor in a subject, wherein the tumor is characterized by having PTK7-positive cancer cells, and the composition comprises an effective amount of ABPC according to any one of claims 1 to 9.

14. A pharmaceutical composition for inducing cell death in PTK7-positive cancer cells in a target, wherein the composition contains an effective amount of ABPC according to any one of claims 1 to 9.

15. A pharmaceutical composition for reducing the risk of metastasis or additional metastasis in a subject having PTK7-positive cancer, wherein the composition comprises an effective amount of ABPC according to any one of claims 1 to 9.

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