LRRC15-binding proteins, multispecific Anti-LRRC15 x Anti-tumor-associated antigen (TAA) antibodies, conjugation linkers, and methods of use and production thereof

Abstract

Provided herein are antigen-binding protein constructs (ABPCs) that bind LRRC15, bispecific ABPCs that bind both LRRC15 and an additional Tumor-Associated Antigen (TAA), conjugation linkers, and methods of production and uses therefor.

Description

Attorney Docket No: 45395-0070W01LRRC15-BINDING PROTEINS, MULTISPECIFIC ANTI-LRRC15 x ANTI-TUMOR- ASSOCIATED ANTIGEN (TAA) ANTIBODIES, CONJUGATION LINKERS, AND METHODS OF USE AND PRODUCTION THEREOFCROSS-REFERENCE TO RELATED APPLICATIONSUlis application claims the benefit of U. S. Provisional Application No. 63 / 724,409. filed November 24, 2024: U. S. Provisional Application No. 63 / 744.791. filed January 13. 2025; and U. S. Provisional Application No. 63 / 744,768, filed January 13, 2025, the disclosures of which are each incorporated herein by reference in their entireties.SEQUENCE LISTING

[0001] This application contains a Sequence Listing that has been submitted electronically as an XML file namedCLRRC15_4PCT_SL. XML”. The XML file, created on November 20, 2025. is 2,262,090 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to the field of biotechnology, and more specifically to monospecific antigen-binding molecules exhibiting pH-dependent, antigen specific binding, as well as multispecific (including multiparatopic) antigen-binding molecules including pH-dependent and / or non-pH-dependent antigen binding domains. The disclosure further relates to linkers and linker-payloads for conjugating payloads to antibodies to produce antibody-payload conjugates (APCs). including antibody-drug conjugates (ADCs), as well as to multispecific antibodies that include a component that specifically recognizes one, two, or more epitopes of LRRC15, and a component that specifically recognizes a tumor-associated antigen (TAA), in particular, a TAA expressed by cancer cells associated with LRRC 15 -positive cells.SUMMARY

[0003] Antibody-drug-conjugates (ADCs) have been designed to combat a variety of diseases. One particular advantage of this approach is the ability for ADCs to have cytostatic or cytotoxic effects. Despite years of development, improved ADCs are desired. In particular, while there is an increasing number of approved and late-stage clinical ADCs targeting antigen-positive tumor cells, such ADCs are largely effective only against tumor cells expressing the highest levels of target antigen. And even more elusive has been the development of an ADC capable of targeting antigen-positive non-tumor cells (e.g., stromal cells including cancer associated fibroblasts or CAFs).

[0004] LRRC 15 is a Leucine Rich Repeat Containing transmembrane protein that mediates cancer cell interactions with the ECM. LRRC 15 expression is upregulated by TGF in the tumor microenvironment, wherein LRRC 15+ fibroblasts play a role in immunosuppression. LRRC 15 is highly expressed on tumor cells of mesenchymal and neuronal origin (e.g., sarcoma, melanoma, glioblastoma), and on LRRC15+ fibroblasts in the tumor stroma of many other common cancers (e.g.. breast, lung, head and neck, pancreatic). ABBV-085Attorney Docket No: 45395-0070W01(AbbVie’s anti-LRRC15 vcMMAE ADC) showed some clinical efficacy against sarcoma, but it did not exhibit substantial efficacy against cancers associated with LRRC 15 -positive stromal cells.

[0005] This disclosure addresses serious unmet needs by providing novel anti-LRRC1 antigen binding protein constructs (ABPCs) that deliver more drug payload to LRRC 15 -positive tumors as well as to LRRC 15-negative tumors that are associated with LRRC 15-positive stroma. To Applicant’s knowledge, this disclosure presents the most compelling evidence to date supporting the development of an LRRC 15 -targeting ADC to address tumors associated with LRRC 15 -positive stroma.

[0006] In more detail, this disclosure provides monospecific and multispecific antigen-binding protein constructs (mspABPCs) comprising one or more antigen binding domain(s) (ABD(s)) recognizing either a single epitope or multiple epitopes on LRRC15. In some embodiments, the ABPC optionally includes one or more ABD(s) recognizing one or more antigen(s) other than LRRC 15. Unexpectedly, both monospecific ABDs comprising certain pH-dependent LRRC 15 -binding domains, and multispecific ABDs comprising certain combinations of pH-dependent and non-pH-dependent ABDs recognizing distinct epitopes on LRRC15 can display enhanced properties including enhanced efficacy. For example, when conjugated to a linker-cargo (e.g., a linker-toxin) to produce an LRRC 15 -directed antibody drug conjugate (ADC), the monospecific and multispecific LRRC 15 -binding protein constructs exhibit an increase in the depth of cell killing of LRRC 15-positive cells and an increase in endolysosomal delivery of said cargo, as compared with a corresponding control ABPC (c.g., any of the control ABPCs described herein).

[0007] Non-limiting examples of LRRC 15 -specific ABPCs and antibodies may include those comprising the variable domains and / or CDRs disclosed in WO 2022 / 216653 Al and WO 2024 / 081729 A2 (each to Mythic Therapeutics, and incorporated herein by reference in their entireties), including those ABPCs, antibodies, variable domains, and / or CDRs of the following constructs: MYT2737 (having an HCVD having the sequence of SEQ ID NO: 1 and an LCVD having the sequence of SEQ ID NO: 64), MYT3315 (having an HCVD having the sequence of SEQ ID NO: 84 and an LCVD having the sequence of SEQ ID NO: 154), MYT8391 (having an HCVD having the sequence of SEQ ID NO: 430 and an LCVD having the sequence of SEQ ID NO: 455), MYT8415 (having an HCVD having the sequence of SEQ ID NO: 382 and an LCVD having the sequence of SEQ ID NO: 489), MYT8417 (having an HCVD having the sequence of SEQ ID NO: 382 and an LCVD having the sequence of SEQ ID NO: 491), MYT8483 (having an HCVD having the sequence of SEQ ID NO: 516 and an LCVD having the sequence of SEQ ID NO: 522), MYT9776 (having an HCVD having the sequence of SEQ ID NO: 571 and an LCVD having the sequence of SEQ ID NO: 517), MYT8094 (having an HCVD having the sequence of SEQ ID NO: 576 and an LCVD having the sequence of SEQ ID NO: 581). MYT9521 (having an HCVD having the sequence of SEQ ID NO: 576 and an LCVD having the sequence of SEQ ID NO: 639), MYT9731 (having an HCVD having the sequence of SEQ ID NO: 576 and an LCVD having the sequence of SEQ ID NO: 700), MYT8416 (having an HCVD having the sequence of SEQ ID NO: 382 and an LCVD having the sequence of SEQ ID NO: 490), MYT8500 (having an HCVD having the sequence of SEQ ID NO: 570 andAttorney Docket No: 45395-0070W01an LCVD having the sequence of SEQ ID NO: 522), MYT9523 (having an HCVD having the sequence of SEQ ID NO: 576 and an LCVD having the sequence of SEQ ID NO: 641), MYT4174 (having an HCVD having the sequence of SEQ ID NO: 84 and an LCVD having the sequence of SEQ ID NO: 177), and MYT9507 (having an HCVD having the sequence of SEQ ID NO: 576 and an LCVD having the sequence of SEQ ID NO: 625).

[0008] In some embodiments, the LRRC 15 -specific ABPCs may comprise an HCVD having the sequence of SEQ ID NO: 1441 and an LCVD having the sequence of SEQ ID NO: 1442. In some embodiments, the LRRC-specific ABPCs may comprise an HCVD having the HCDR1,2,3 sequences of SEQ ID NOs: 1442, 1443, 1444, respectively, and an LCVD having the LCDR1,2,3 sequences SEQ ID NOs: 1445, 1446, and 1447, respectively. In some embodiments, the HCVD and LCVD may comprise sequences that are at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to, and comprise the same HCDRs and LCDRs as, the sequences of SEQ ID NO: 1441 and SEQ ID NO: 1442, respectively. In some embodiments, the HCDRs and / or LCDRs may include a histidine substitution.

[0009] In some embodiments, the LRRC15-specific ABPCs may comprise an HCVD having a single heavy chain only domain (“HCAb” or “VHH”) having the sequence of SEQ ID NO: 1557 (e.g., the LRRC15 epitope bin 6 HCAb called “168” having the HCDR1,2.3 sequences of SEQ ID NOs: 1558, 1559, and 1560, respectively. In some embodiments, the LRRC 15-specific ABPCs may comprise an HCVD having a single HCAb having the sequence of SEQ ID NO: 1561 (e.g., the LRRC15 epitope bin 7 HCAb called “523” having the HCDR1,2,3 sequences of SEQ ID NOs: 1562, 1563, and 1564, respectively. In particular embodiments, an HCAb may be linked via a dipeptide or polypeptide to the heavy chain of a second LRRC 15 -binding domain.

[0010] As disclosed herein, ABPCs recognizing specific and distinct epitopes of LRRC 15 may be combined to produce multispecific ABPCs (mspABPCs) having a variety of physicochemical properties, including superior and unexpected properties relative to suitable control ABPCs (e.g., ones recognizing only a single epitope of LRRC15). As the skilled person understands, the term “multiparatopic” may be used to describe a specific “multispecific” binding construct that recognizes two or more epitopes on the same antigen (e.g., LRRC15). An example of a multiparatopic ABPC is a biparatopic ABPC (e.g., an ABPC comprising a first antigen binding domain that recognizes a first epitope of a target antigen and a second antigen binding domain that recognizes a second epitope of the target antigen, optionally wherein the epitopes are substantially or entirely non -overlapping).

[0011] As disclosed herein, certain combinations of antigen binding proteins (ABP) recognizing different epitopes on LRRC 15 combine particularly well to produce effective mspABPCs. That said, even when a given ABD has been demonstrated to “pair with itself’ (i.e., to produce a functional, monospecific / monoparatopic, LRRC 15 -binding ABPC), the data disclosed herein indicate that it is initially unpredictable whether two ABDs recognizing distinct epitopes (“epitope bin members”) will combine to produce a functional mspABPC. For example, until this disclosure, it was not known that ABDs recognizing a LRRC15 epitope bin 2.1 would pair well with ABPs recognizing LRRC15 epitope bins 2.2, 2.3, and 5 (see, e.g., Example 13). It was also not knownAttorney Docket No: 45395-0070W01prior to this disclosure that combining pH-dependent and non-pH-dependent ABDs recognizing different LRRC15 epitopes can be combined to produce a biparatopic ABPC possessing superior properties and exhibiting superior in vitro and in vivo effects as compared with either of its corresponding monoparatopic parent ABPCs or its corresponding biparatopic ABPC having zero or two pH-dependent ABDs.

[0012] In some embodiments, tire ABPC comprises a biparatopic or multiparatopic binding protein comprising a first antigen-binding domain (ABD) that is capable of specifically binding a first epitope of LRRC 15 presented on the surface of a target mammalian cell, and a second ABD capable of specifically binding a second epitope of LRRC 15, optionally wherein (a) the dissociation rate of the first ABD from the first epitope at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0: and / or (b) the dissociation constant (KD) of the first ABD with respect to the first epitope at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0; and / or optionally wherein (c) the dissociation rate of the second ABD from the first epitope at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; and / or (d) the dissociation constant (KD) of the second ABD with respect to the second epitope at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0.

[0013] In some embodiments, the biparatopic or multiparatopic antigen binding protein constructs described herein may comprise zero, one, two, or more antigen binding domains (or “arms”) that may bind well to LRRC15 at a pH of about 7.0 to about 8.0 (e.g., approximately physiological conditions), but not bind well to LRRC 15 at a pH of about pH 4.0 to about 6.5 (e.g., conditions in the cndolysosomal to lysosomal intracellular compartments). Such amis are referred to herein as “pH-dependent amis” or interchangeably as “pH-amis”.

[0014] In some embodiments, the monospecific, biparatopic, or multiparatopic ABPC is a biparatopic ABPC (bpABPC).

[0015] In some embodiments, the APBC comprises a biparatopic ABPC (a bpABPC) comprising no pH-dependent amis.

[0016] In some embodiments, APBC comprises a bpABPC comprising only one pH-dependent arm.

[0017] In some embodiments, the APBC comprises a bpABPC comprising two pH-dependent arms.

[0018] In some embodiments, the APBC comprises a “monospecific ABPC” (one comprising arms that bind to the same epitope of LRRC 15), optionally wherein one arm is pH-dependent and the other is not.

[0019] In some embodiments, the APBC comprises a monospecific ABPC, wherein both arms are pH-dependent.

[0020] In some embodiments, the first ABD includes a heavy chain variable domain (HCVD) of HC Ab- 168, HCAb-523, 66H2, 54F1, 56F3, 15G7, 24D9, or 29F1, each HCVD optionally with at least one total histidine substitution in the CDRs.

[0021] In some embodiments, the first ABD includes a light chain variable domain (LCVD) of HC Ab- 168, HCAb-523, 66H2, 54F1, 56F3, 15G7, 24D9, or 29F1, each LCVD optionally with at least one histidine substitution in a CDR.Attorney Docket No: 45395-0070W01

[0022] In some embodiments, the second ABD includes a heavy chain variable domain (HCVD) of HCAb-168, HCAb-523, 66H2, 54F1, 56F3, 15G7, 24D9, or 29F1, each HCVD optionally comprising at least one total histidine substitution in the CD Rs.

[0023] In some embodiments, the second ABD includes a light chain variable domain (LCVD) of HCAb-168, HCAb-523, 66H2, 54F1, 56F3, 15G7, 24D9, or 29F1, each LCVD optionally comprising at least one total histidine substitution in the CD Rs.

[0024] In some embodiments, the first ABD includes a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD) of HCAb-168. HCAb-523. 66H2, 54F1, 56F3, 15G7. 24D9, or 29F1. optionally wherein the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0025] In some embodiments, the second ABD includes a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD) of HCAb-168, HCAb-523, 66H2, 54F1, 56F3, 15G7, 24D9, or 29F1, optionally wherein the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0026] In some embodiments, the first ABD includes one of (a) to (f): (a) an HCVD and LCVD of 66H2; (b) an HCVD and LCVD of 54F1; (c) an HCVD and LCVD of 56F3; (d) an HCVD and LCVD of 15G7; (e) an HCVD and LCVD of 24D9; and (f) an HCVD and LCVD of 29F1. The first ABD may also include an HCVD of HCAb-168 or HCAb-523. In some embodiments, the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0027] In some embodiments, the second ABD includes one of (a) to (f): (a) an HCVD and LCVD of 66H2; (b) an HCVD and LCVD of 54F1; (c) an HCVD and LCVD of 56F3; (d) an HCVD and LCVD of 15G7; (e) an HCVD and LCVD of 24D9; and (f) an HCVD and LCVD of 29F1. The first ABD may also include an HCVD of HCAb-168 or HCAb-523. In some embodiments, the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0028] In some embodiments, the first ABD includes a heavy chain variable domain (HCVD) of SEQ ID NO: 741, SEQ ID NO: 749, SEQ ID NO: 382, SEQ ID NO: 516, SEQ ID NO: 576, SEQ ID NO: 1375, SEQ ID NO: 1383, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO: 1423, SEQ ID NO: 1431, SEQ ID NO: 1441, SEQ ID NO: 1557, or SEQ ID NO: 1561, each HCVD optionally comprising at least one total histidine substitution in the CDRs.

[0029] In some embodiments, the first ABD includes a light chain variable domain (LCVD) of SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 700, SEQ ID NO: 1376, SEQ ID NO: 1384, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, SEQ ID NO: 1432, or SEQ ID NO: 1442, each LCVD optionally comprising at least one total histidine substitution in the CDRs.

[0030] In some embodiments, the second ABD includes a heavy chain variable domain (HCVD) of SEQ ID NO: 741, SEQ ID NO: 749. SEQ ID NO: 382, SEQ ID NO: 516. SEQ ID NO: 576, SEQ ID NO: 1375, SEQ ID NO: 1383, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO:Attorney Docket No: 45395-0070W011423, SEQ ID NO: 1431, SEQ ID NO: 1441, SEQ ID NO: 1557, or SEQ ID NO: 1561, each HCVD optionally comprising at least one total histidine substitution in tire CDRs.

[0031] In some embodiments, the second ABD includes a light chain variable domain (LCVD) of SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 700, SEQ ID NO: 1376, SEQ ID NO: 1384, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, SEQ ID NO: 1432, or SEQ ID NO: 1442, each LCVD optionally comprising at least one total histidine substitution in tire CDRs.

[0032] In some embodiments, the first ABD includes a heavy chain variable domain (HCVD) and a light chain vanable domain (LCVD) of SEQ ID NOs: 741 & 742, SEQ ID NOs: 749 & 750, SEQ ID NOs: 382 & 455, SEQ ID NOs: 516 & 522, SEQ ID NOs: 576 & 581, SEQ ID NOs: 576 & 700, SEQ ID NOs: 1375 & 1376, SEQ ID NOs: 1383 & 1384, SEQ ID NOs: 1391 & 1392, SEQ ID NOs: 1399 & 1400, SEQ ID NOs: 1407 & 1408, SEQ ID NOs: 1415 & 1416, SEQ ID NOs: 1423 & 1424, SEQ ID NOs: 1431 & 1432, or SEQ ID NOs: 1441 & 1442, respectively, optionally wherein the HCVD and / or tire LCVD comprise at least one total histidine substitution in the CDRs.

[0033] In some embodiments, the first ABD includes a heavy chain variable domain (HCVD) of SEQ ID NO: 1557 or SEQ ID NO: 1561.

[0034] In some embodiments, the second ABD includes a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD) of SEQ ID NOs: 741 & 742, SEQ ID NOs: 749 & 750, SEQ ID NOs: 382 & 455. SEQ ID NOs: 516 & 522, SEQ ID NOs: 576 & 581, SEQ ID NOs: 576 & 700, SEQ ID NOs: 1375 & 1376, SEQ ID NOs: 1383 & 1384, SEQ ID NOs: 1391 & 1392, SEQ ID NOs: 1399 & 1400, SEQ ID NOs: 1407 & 1408, SEQ ID NOs: 1415 & 1416, SEQ ID NOs: 1423 & 1424, SEQ ID NOs: 1431 & 1432, or SEQ ID NOs: 1441 & 1442, respectively, optionally wherein the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0035] In some embodiments, the first ABD includes one of (a) to (f): (a) an HCVD and LCVD of SEQ ID NOs: 741 & 742, respectively; (b) an HCVD and LCVD of SEQ ID NOs: 749 & 750, respectively; (c) an HCVD and LCVD of SEQ ID NOs: 382 & 455, respectively, or an HCVD and LCVD of SEQ ID NOs: 382 & 489, respectively; (d) an HCVD and LCVD of SEQ ID NOs: 516 & 522, respectively; (e) an HCVD and LCVD of SEQ ID NOs: 576 & 581; and (f) an HCVD and LCVD of SEQ ID NOs: 1441 & 1442, respectively. In some embodiments, the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0036] In some embodiments, the second ABD includes one of (a) to (f): (a) an HCVD and LCVD of SEQ ID NOs: 741 & 742, respectively; (b) an HCVD and LCVD of SEQ ID NOs: 749 & 750, respectively; (c) an HCVD and LCVD of SEQ ID NOs: 382 & 455, respectively, or an HCVD and LCVD of SEQ ID NOs: 382 & 489, respectively; (d) an HCVD and LCVD of SEQ ID NOs: 516 & 522, respectively; (e) an HCVD and LCVD of SEQ ID NOs: 576 & 581; and (f) an HCVD and LCVD of SEQ ID NOs: 1441 & 1442, respectively. In some embodiments, the HCVD and / or the LCVD comprise at least one total histidine substitution in tire CDRs.Attorney Docket No: 45395-0070W01

[0037] In some embodiments, the first HCVD includes one of (a) to (f): (a) an HCVD of 54F1 including the sequence of SEQ ID NO: 741; (b) an HCVD of 56F3 including the sequence of SEQ ID NO: 749; (c) an HCVD of 15G7 including the sequence of SEQ ID NO: 382; (d) an HCVD of 24D9 including the sequence of SEQ ID NO: 516; (e) an HCVD of 29F1 including the sequence of SEQ ID NO: 576; and (f) an HCVD of 66H2 including the sequence of SEQ ID NO: 1441.

[0038] In some embodiments, the first LCVD includes one of (a) to (f): (a) an LCVD of 54F1 including the sequence of SEQ ID NO: 742; (b) an LCVD of 56F3 including the sequence of SEQ ID NO: 750; (c) an LCVD of 15G7 including the sequence of SEQ ID NO: 455 or SEQ ID NO: 489; (d) an LCVD of 24D9 including the sequence of SEQ ID NO: 522; (e) an LCVD of 29F1 including the sequence of SEQ ID NO: 581; and (f) an LCVD of 66H2 including the sequence of SEQ ID NO: 1442.

[0039] In some embodiments, the second HCVD includes one of (a) to (e): (a) an HCVD of 54F1 including the sequence of SEQ ID NO: 741; (b) an HCVD of 56F3 including the sequence of SEQ ID NO: 749; (c) an HCVD of 15G7 including the sequence of SEQ ID NO: 382; (d) an HCVD of 24D9 including the sequence of SEQ ID NO: 516; (e) an HCVD of 29F1 including the sequence of SEQ ID NO: 576: and (f) an HCVD of 66H2 including the sequence of SEQ ID NO: 1441.

[0040] In some embodiments, the second LCVD includes one of (a) to (f): (a) an LCVD of 54F1 including the sequence of SEQ ID NO: 742; (b) an LCVD of 56F3 including the sequence of SEQ ID NO: 750; (c) an LCVD of 15G7 including the sequence of SEQ ID NO: 455 or SEQ ID NO: 489; (d) an LCVD of 24D9 including the sequence of SEQ ID NO: 522; (e) an LCVD of 29F1 including the sequence of SEQ ID NO: 581; and (f) an LCVD of 66H2 including the sequence of SEQ ID NO: 1442.

[0041] In some embodiments, the first or second antigen-binding domain (ABD) includes an HCVD of one of (a) to (f): (a) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine; (b) an HCVD including an HCDRL an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 751, 752, and 753, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine; (c) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having tire sequences set forth in SEQ ID NOs: 379, 380, and 381, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 379. 380, and 381 substituted with a histidine; (d) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 513, 514, and 515, respectively, optionally with collectively a total of one ormore total amino acid positions in the sequences of SEQ ID NOs: 513, 514, and 515 substituted with a histidine; (e) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 573, 574, and 575, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 573, 574, and 575 substituted with a histidine; and (f) an HCVDAttorney Docket No: 45395-0070W01including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 1443, 1444, and 1445, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1443, 1444, and 1445 substituted with a histidine.

[0042] In some embodiments, the first or second antigen-binding domain (ABD) includes an LCVD of one of (a) to (f): (a) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine; (b) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 754, 755, and 756. respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine; (c) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 452, 453, and 454, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 452, 453, and 454 substituted with a histidine; (d) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 519, 520, and 521, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 519, 520, and 521 substituted with a histidine: (e) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 578, 579, and 580, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 578, 579, and 580 substituted with a histidine; and (f) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 1446, 1447, and 1448, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1446, 1447, and 1448 substituted with a histidine.

[0043] In some embodiments, the first or second antigen-binding domain (ABD) includes an HCVD of one of (a) to (f):

[0044] (a) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 743, 744. and 745, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine;

[0045] (b) an HCVD including an HCDR1. an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 751, 752. and 753, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having tire sequences set forth in SEQ ID NOs: 754, 755, and 756, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 754, 755. and 756 substituted with a histidine;Attorney Docket No: 45395-0070W01

[0046] (c) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 379, 380, and 381, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 379, 380, and 381 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 452, 453, and 454, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 452, 453, and 454 substituted with a histidine;

[0047] (d) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 513, 514. and 515, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 513, 514, and 515 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 519, 520, and 521, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 519, 520, and 521 substituted with ahistidine; and

[0048] (e) an HCVD including an HCDR1. an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 573, 574. and 575, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 573, 574, and 575 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having tire sequences set forth in SEQ ID NOs: 578, 579, and 580, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 578, 579. and 580 substituted with ahistidine; and

[0049] (f) an HCVD including an HCDR1. an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 1443, 1444, and 1445, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1443, 1444, and 1445 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 1446, 1447, and 1448, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1446, 1447, and 1448 substituted with ahistidine.

[0050] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of tire sequence of SEQ ID NO: 1557.

[0051] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 1561.

[0052] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of tire sequence of SEQ ID NO: 741.

[0053] In some embodiments, tire first or second ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprisesAttorney Docket No: 45395-0070W01the CDRs of the sequence of SEQ ID NO: 742.

[0054] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%. 91%. 92%. 93%. 94%. 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 741, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 742.

[0055] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 749.

[0056] In some embodiments, the first or second ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of tire sequence of SEQ ID NO: 750.

[0057] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 749, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 750.

[0058] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 382.

[0059] In some embodiments, the first or second ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 455.

[0060] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 382, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 455.

[0061] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 382, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 489.

[0062] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprisesAttorney Docket No: 45395-0070W01the CDRs of the sequence of SEQ ID NO: 516.

[0063] In some embodiments, the first or second ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%. 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 522.

[0064] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 516, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%. 95%. 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 522.

[0065] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of tire sequence of SEQ ID NO: 576.

[0066] In some embodiments, tire first or second ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 581.

[0067] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 576, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%. 95%. 96%. 97%. 98%. 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 581.

[0068] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 1441.

[0069] In some embodiments, the first or second ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of tire sequence of SEQ ID NO: 1442.

[0070] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%. 98%, or 99% identical to, and comprises the CDRs of the sequence of S EQ ID NO: 1557.

[0071] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 1561.

[0072] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 1441, and the first or second ABD includes an LCVD comprising a sequenceAttorney Docket No: 45395-0070W01that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0073] In some embodiments, the ABPC is degraded in the target mammalian cell following internalization of the ABPC by the target mammalian cell. In some embodiments, the ABPC includes a conjugated toxin, radioisotope, drug, or small molecule.

[0074] In some embodiments, a composition including the ABPC provides for an increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 20% increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 50% increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 2-fold increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 5 -fold increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0075] In some embodiments, the composition provides for an increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 20% or 50% increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 2- or 5-fold increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including tire same amount of a control ABPC.

[0076] In some embodiments, the composition provides for an increase in endolysosomal delivery in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 20% or 50% increase in endolysosomal delivery in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 2- or 5-fold increase in endolysosomal delivery' in the target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0077] In some embodiments, the composition results in a less of a reduction in the level of LRRC15 presented on the surface of the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition does not result in a detectable reduction in the level of the LRRC15 presented on the surface of the target mammalian cell.

[0078] In some embodiments, the composition is a pharmaceutical composition including an effective amount of an antigen-binding protein construct (ABPC) including: a first ABD that is capable of specifically binding LRRC 15 or an epitope of LRRC 15 presented on the surface of a target mammalian cell; and a conjugated toxin,Attorney Docket No: 45395-0070W01radioisotope, drug, or small molecule, where the composition provides for one or more of an increase in the depth of killing of a target mammalian cell killing, as compared to a composition including the same amount of a control ABPC.

[0079] In some embodiments, the composition is a pharmaceutical composition including an effective amount of an antigen-binding protein construct (ABPC) including: a first ABD that is capable of specifically binding to a first epitope of LRRC 15 presented on the surface of a target mammalian cell and a second ABD that is capable of specifically binding to a second epitope of LRRC 15 presented on the surface of a target mammalian cell; and a conjugated toxin, radioisotope, drug, or small molecule, optionally where the composition provides for one or more of an increase in the depth of killing of a target mammalian cell killing, as compared to a composition including the same amount of a control ABPC.

[0080] In some embodiments of the composition, the first ABD includes a heavy chain variable domain (HCVD) of SEQ ID NO: 741, SEQ ID NO: 749, SEQ ID NO: 382, SEQ ID NO: 516, SEQ ID NO: 576, SEQ ID NO: 1375, SEQ ID NO: 1383, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO: 1423, SEQ ID NO: 1431. SEQ ID NO: 1441, SEQ ID NO: 1557, or SEQ ID NO: 1561, each HCVD optionally comprising at least one total histidine substitution in the CDRs.

[0081] In some embodiments of the composition, the first ABD includes a light chain variable domain (LCVD) of SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 700, SEQ ID NO: 1376, SEQ ID NO: 1384, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, SEQ ID NO: 1432. or SEQ ID NO: 1442. each LCVD optionally comprising at least one total histidine substitution in the CDRs.

[0082] In some embodiments of tire composition, the second ABD includes a heavy chain variable domain (HCVD) of SEQ ID NO: 741, SEQ ID NO: 749, SEQ ID NO: 382, SEQ ID NO: 516, SEQ ID NO: 576, SEQ ID NO: 1375, SEQ ID NO: 1383, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO: 1423, SEQ ID NO: 1431. SEQ ID NO: 1441, SEQ ID NO: 1557, or SEQ ID NO: 1561, each HCVD optionally comprising at least one total histidine substitution in the CDRs.

[0083] In some embodiments of the composition, the second ABD includes a light chain variable domain (LCVD) of SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 700, SEQ ID NO: 1376, SEQ ID NO: 1384, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, SEQ ID NO: 1432, or SEQ ID NO: 1442. each LCVD optionally comprising at least one total histidine substitution in the CDRs.

[0084] In some embodiments of the composition, the first ABD includes a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD) of SEQ ID NOs: 741 & 742, SEQ ID NOs: 749 & 750, SEQ ID NOs: 382 & 455, SEQ ID NOs: 516 & 522, SEQ ID NOs: 576 & 581, SEQ ID NOs: 576 & 700, SEQ ID NOs: 1375 & 1376, SEQ ID NOs: 1383 & 1384, SEQ ID NOs: 1391 & 1392, SEQ ID NOs: 1399 & 1400, SEQ ID NOs: 1407 & 1408, SEQ ID NOs: 1415 & 1416. SEQ ID NOs: 1423 & 1424, SEQ ID NOs: 1431 &Attorney Docket No: 45395-0070W011432, or SEQ ID NOs: 1441 & 1442, respectively, optionally wherein the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0085] In some embodiments of the composition, the second ABD includes a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD) of SEQ ID NOs: 741 & 742, SEQ ID NOs: 749 & 750, SEQ ID NOs: 382 & 455, SEQ ID NOs: 516 & 522, SEQ ID NOs: 576 & 581, SEQ ID NOs: 576 & 700, SEQ ID NOs: 1375 & 1376, SEQ ID NOs: 1383 & 1384, SEQ ID NOs: 1391 & 1392, SEQ ID NOs: 1399 & 1400, SEQ ID NOs: 1407 & 1408, SEQ ID NOs: 1415 & 1416, SEQ ID NOs: 1423 & 1424, SEQ ID NOs: 1431 & 1432, or SEQ ID NOs: 1441 & 1442, respectively, optionally wherein the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0086] In some embodiments of the composition, the first ABD includes one of (a) to (f): (a) an HCVD and LCVD of SEQ ID NOs: 741 & 742, respectively; (b) an HCVD and LCVD of SEQ ID NOs: 749 & 750, respectively; (c) an HCVD and LCVD of SEQ ID NOs: 382 & 455, respectively, or an HCVD and LCVD of SEQ ID NOs: 382 & 489, respectively; (d) an HCVD and LCVD of SEQ ID NOs: 516 & 522, respectively; (e) an HCVD and LCVD of SEQ ID NOs: 576 & 581; and (f) an HCVD and LCVD of SEQ ID NOs: 1441 & 1442, respectively. In some embodiments of the composition, the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0087] In some embodiments of the composition, the second ABD includes one of (a) to (f): (a) an HCVD and LCVD of SEQ ID NOs: 741 & 742, respectively: (b) an HCVD and LCVD of SEQ ID NOs: 749 & 750, respectively; (c) an HCVD and LCVD of SEQ ID NOs: 382 & 455, respectively, or an HCVD and LCVD of SEQ ID NOs: 382 & 489, respectively; (d) an HCVD and LCVD of SEQ ID NOs: 516 & 522, respectively; (e) an HCVD and LCVD of SEQ ID NOs: 576 & 581; and (f) an HCVD and LCVD of SEQ ID NOs: 1441 & 1442, respectively. In some embodiments of the composition, the HCVD and / or the LCVD comprise at least one total histidine substitution in the CDRs.

[0088] In some embodiments of the composition, the first HCVD includes one of (a) to (f): (a) an HCVD of 54F1 including the sequence of SEQ ID NO: 741; (b) an HCVD of 56F3 including the sequence of SEQ ID NO: 749: (c) an HCVD of 15G7 including the sequence of SEQ ID NO: 382; (d) an HCVD of 24D9 including the sequence of SEQ ID NO: 516; (e) an HCVD of 29F1 including the sequence of SEQ ID NO: 576; and (f) an HCVD of 66H2 including the sequence of SEQ ID NO: 1441.

[0089] In some embodiments of the composition, the first LCVD includes one of (a) to (f): (a) an LCVD of 54F1 including the sequence of SEQ ID NO: 742; (b) an LCVD of 56F3 including the sequence of SEQ ID NO: 750; (c) an LCVD of 15G7 including the sequence of SEQ ID NO: 455; (d) an LCVD of 24D9 including the sequence of SEQ ID NO: 522; (e) an LCVD of 29F1 including the sequence of SEQ ID NO: 581; and (f) an LCVD of 66H2 including the sequence of SEQ ID NO: 1442.

[0090] In some embodiments of the composition, the second HCVD includes one of (a) to (f): (a) an HCVD of 54F1 including the sequence of SEQ ID NO: 741; (b) an HCVD of 56F3 including the sequence of SEQ IDAttorney Docket No: 45395-0070W01NO: 749; (c) an HCVD of 15G7 including the sequence of SEQ ID NO: 382; (d) an HCVD of 24D9 including the sequence of SEQ ID NO: 516; (e) an HCVD of 29F1 including the sequence of SEQ ID NO: 576; and (f) an HCVD of 66H2 including the sequence of SEQ ID NO: 1441.

[0091] In some embodiments of the composition, the second LCVD includes one of (a) to (f): (a) an LCVD of 54F1 including the sequence of SEQ ID NO: 742; (b) an LCVD of 56F3 including the sequence of SEQ ID NO: 750; (c) an LCVD of 15G7 including the sequence of SEQ ID NO: 455; (d) an LCVD of 24D9 including the sequence of SEQ ID NO: 522; (e) an LCVD of 29F1 including the sequence of SEQ ID NO: 581; and (f) an LCVD of 66H2 including the sequence of SEQ ID NO: 1442.

[0092] In some embodiments of the composition, the first or second antigen-binding domain (ABD) includes an HCVD of one of (a) to (f): (a) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine; (b) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 751, 752. and 753, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine; (c) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 379, 380, and 381, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 379, 380, and 381 substituted with a histidine; (d) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 513, 514, and 515, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 513, 514, and 515 substituted with a histidine; (e) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 573, 574, and 575, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 573, 574, and 575 substituted with a histidine; and (f) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 1443, 1444, and 1445, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1443. 1444, and 1445 substituted with a histidine.

[0093] In some embodiments of the composition, the first or second antigen-binding domain (ABD) includes an LCVD of one of (a) to (f): (a) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine; (b) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 754, 755, and 756, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine; (c) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having tire sequences set forth in SEQ ID NOs: 452, 453, and 454, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequencesAttorney Docket No: 45395-0070W01of SEQ ID NOs: 452, 453, and 454 substituted with a histidine; (d) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 519, 520, and 521, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 519, 520, and 521 substituted with a histidine; (e) an LCVD including an LCDR1. an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 578, 579, and 580, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 578, 579, and 580 substituted with a histidine; and (f) an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 1446, 1447, and 1448, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1446. 1447, and 1448 substituted with a histidine.

[0094] In some embodiments of the composition, the first or second antigen-binding domain (ABD) includes an HCVD of one of (a) to (f):

[0095] (a) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having tire sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine;

[0096] (b) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 751, 752. and 753, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having tire sequences set forth in SEQ ID NOs: 754, 755, and 756, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine;

[0097] (c) an HCVD including an HCDR1. an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 379, 380. and 381, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 379, 380, and 381 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having tire sequences set forth in SEQ ID NOs: 452, 453, and 454, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 452, 453. and 454 substituted with a histidine;

[0098] (d) an HCVD including an HCDR1. an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 513, 514, and 15, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 513, 514, and 515 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having tire sequences set forth in SEQ ID NOs: 519, 520, and 521, respectively, optionally with collectively a total of one or more total amino acid positions in tire sequences of SEQ ID NOs: 519, 520, and 521 substituted with a histidine;Attorney Docket No: 45395-0070W01

[0099] (c) an HCVD including an HCDR1, an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 573, 574, and 575, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 573, 574, and 575 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 578, 579, and 580, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 578, 579, and 580 substituted with a histidine; and

[0100] (f) an HCVD including an HCDR1. an HCDR2, and an HCDR3 having the sequences set forth in SEQ ID NOs: 1443, 1444, and 1445, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1443, 1444, and 1445 substituted with a histidine, and an LCVD including an LCDR1, an LCDR2, and an LCDR3 having the sequences set forth in SEQ ID NOs: 1446, 1447, and 1448, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 1446, 1447, and 1448 substituted with a histidine.

[0101] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is identical to. or is at least 90%, 91%, 92%. 93%. 94%. 95%. 96%. 97%, 98%, or 99% identical to, and comprises the CD Rs of the sequence of SEQ ID NO: 741.

[0102] In some embodiments of tire composition, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to. and comprises the CD Rs of the sequence of SEQ ID NO: 742.

[0103] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 741, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 742.

[0104] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 749.

[0105] In some embodiments of the composition, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%. 93%. 94%, 95%, 96%, 97%, 98%, or 99% identical to. and comprises the CDRs of the sequence of SEQ ID NO: 750.

[0106] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 749, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 750.

[0107] In some embodiments of the composition, the first or second ABD includes an HCVD comprising aAttorney Docket No: 45395-0070W01sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 1441.

[0108] In some embodiments of the composition, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0109] In some embodiments of tire composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 1441, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0110] In some embodiments of tire composition, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to. and comprises the CDRs of the sequence of SEQ ID NO: 382.

[0111] In some embodiments of the composition, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 455.

[0112] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 382, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 455.

[0113] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 382. and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 489.

[0114] In some embodiments of tire composition, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%. 93%. 94%, 95%, 96%, 97%, 98%, or 99% identical to. and comprises the CDRs of the sequence of SEQ ID NO: 516.

[0115] In some embodiments of the composition, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 522.

[0116] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 516, and the first or second ABD includes an LCVDAttorney Docket No: 45395-0070W01comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 522.

[0117] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the CDRs of the sequence of SEQ ID NO: 576.

[0118] In some embodiments of tire composition, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to. and comprises the CDRs of the sequence of SEQ ID NO: 581.

[0119] In some embodiments of the composition, the first or second ABD includes an HCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 576, and the first or second ABD includes an LCVD comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to and comprises the CDRs of the sequence of SEQ ID NO: 581.

[0120] In some embodiments, the sequence variations in the framework regions comprise conservative amino acid substitutions. In some embodiments, the sequence variations maintain the structural stability of the variable domains while permitting the CDRs to maintain their spatial orientation for antigen binding.

[0121] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 741 and SEQ ID NO: 742, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 741 and SEQ ID NO: 742, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0122] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%. 96%, 97%, 98%, 99%. or 100% identity to the corresponding CDRs of SEQ ID NO: 741 and SEQ ID NO: 742, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0123] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 749 and SEQ ID NO: 750, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 749 and SEQ ID NO: 750, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0124] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%. 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 749 and SEQ ID NO: 750, except for any histidine substitutions; and (c)Attorney Docket No: 45395-0070W01optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0125] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 388 and SEQ ID NO: 455, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 388 and SEQ ID NO: 455, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0126] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 388 and SEQ ID NO: 455, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0127] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 516 and SEQ ID NO: 522, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 516 and SEQ ID NO: 522, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0128] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%. 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 516 and SEQ ID NO: 522, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0129] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 516 and SEQ ID NO: 522, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 516 and SEQ ID NO: 522, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0130] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 516 and SEQ ID NO: 522, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0131] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 576 and SEQ ID NO: 581, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 576 and SEQ ID NO: 581, respectively, except for any histidine substitutions: and (c) any variations in framework regions maintain orAttorney Docket No: 45395-0070W01enhance the stability of the variable domains.

[0132] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 576 and SEQ ID NO: 581, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0133] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 576 and SEQ ID NO: 700, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 576 and SEQ ID NO: 700, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0134] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%. 96%, 97%, 98%, 99%. or 100% identity to the corresponding CDRs of SEQ ID NO: 576 and SEQ ID NO: 700, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0135] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 382 and SEQ ID NO: 489, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 382 and SEQ ID NO: 489, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0136] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%. 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 382 and SEQ ID NO: 489, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0137] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1441 and SEQ ID NO: 1442, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1441 and SEQ ID NO: 1442, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0138] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1441 and SEQ ID NO: 1442. except for any histidine substitutions; andAttorney Docket No: 45395-0070W01(c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0139] In some embodiments, the first or second ABD comprises an HCVD wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1557, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1557, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0140] In some embodiments, the first or second ABD comprises an HCVD wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1561. respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1557, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0141] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1375 and SEQ ID NO: 1376, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1375 and SEQ ID NO: 1376, respectively, except for any histidine substitutions: and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0142] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1375 and SEQ ID NO: 1376, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0143] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1383 and SEQ ID NO: 1384, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1383 and SEQ ID NO: 1384, respectively, except for any histidine substitutions; and (c) any variations in framew'ork regions maintain or enhance the stability of the variable domains.

[0144] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1383 and SEQ ID NO: 1384, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0145] In some embodiments, tire first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1391 and SEQ ID NO: 1392, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1391 and SEQ ID NO: 1392,Attorney Docket No: 45395-0070W01respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance tire stability of the variable domains.

[0146] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains: (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1391 and SEQ ID NO: 1392, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0147] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1399 and SEQ ID NO: 1400, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1399 and SEQ ID NO: 1400, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of tire variable domains.

[0148] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1399 and SEQ ID NO: 1400, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0149] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1407 and SEQ ID NO: 1408, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1407 and SEQ ID NO: 1408, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0150] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1407 and SEQ ID NO: 1408, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0151] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1415 and SEQ ID NO: 1416, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1415 and SEQ ID NO: 1416, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.Attorney Docket No: 45395-0070W01

[0152] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1415 and SEQ ID NO: 1416, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0153] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1423 and SEQ ID NO: 1424, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1423 and SEQ ID NO: 1424, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0154] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%. 96%, 97%, 98%, 99%. or 100% identity to the corresponding CDRs of SEQ ID NO: 1423 and SEQ ID NO: 1424, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0155] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1431 and SEQ ID NO: 1432, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1431 and SEQ ID NO: 1432, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0156] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of either or both variable domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1431 and SEQ ID NO: 1432, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0157] In some embodiments, the first or second ABD comprises an HCVD and LCVD pair wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1441 and SEQ ID NO: 1442, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1441 and SEQ ID NO: 1442, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance tire stability of the variable domains.

[0158] In some embodiments, the first or second ABD comprises variable domains wherein: (a) sequence variations occur only in framework regions selected from FR1. FR2, FR3, and FR4 of either or both variableAttorney Docket No: 45395-0070W01domains; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1441 and SEQ ID NO: 1442, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0159] In some embodiments, the first or second ABD comprises an HCVD wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1557, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1557, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0160] In some embodiments, the first or second ABD comprises a variable domain wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3, and FR4 of the variable domain; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1557, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0161] In some embodiments, the first or second ABD comprises an HCVD wherein: (a) at least 90% of the framework region positions are identical to SEQ ID NO: 1561, respectively; (b) 100% of the CDR positions are identical to SEQ ID NO: 1561, respectively, except for any histidine substitutions; and (c) any variations in framework regions maintain or enhance the stability of the variable domains.

[0162] In some embodiments, the first or second ABD comprises a variable domain wherein: (a) sequence variations occur only in framework regions selected from FR1, FR2, FR3. and FR4 of the variable domain; (b) the CDR regions maintain at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding CDRs of SEQ ID NO: 1561, except for any histidine substitutions; and (c) optionally wherein any framework variations comprise substitutions that maintain or enhance domain stability.

[0163] In some embodiments, composition comprising the ABPC provides for an increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 20% or 50% increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 2- or 5-fold increase in toxin liberation in tire target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0164] In some embodiments, tire composition provides for an increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 20% or 50% increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 2- or 5-fold increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC.Attorney Docket No: 45395-0070W01

[0165] In some embodiments, the composition provides for an increase in cndolysosomal delivery, including at least a 20% or 50% increase in cndolysosomal delivery as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition provides for at least a 2- or 5 -fold increase in cndolysosomal delivery in the target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0166] In some embodiments, the composition results in a less of a reduction in the level of LRRC15 presented on the surface of the target mammalian cell as compared to a composition including the same amount of a control ABPC. In some embodiments, the composition does not result in a detectable reduction in the level of the LRRC15 presented on the surface of the target mammalian cell. In some embodiments, the target mammalian cell is a cancer cell.

[0167] In some embodiments, the dissociation rate of the first and / or second ABD at a pH of ~4.0 to ~6.5 is at least 10% faster than the dissociation rate of the first and / or second ABD at a pH of ~7.0 to ~8.0. In some embodiments, the dissociation rate of the first and / or second ABD at a pH of ~4.0 to ~6.5 is at least 3-fold faster than the dissociation rate of the first and / or second ABD at a pH of ~7.0 to ~8.0. In some embodiments, the dissociation rate of the first and / or second ABD at a pH of ~4.0 to ~6.5 is at least 10-fold faster than the dissociation rate of the first and / or second ABD at a pH of ~7.0 to ~8.0. In some embodiments, the KDof the first and / or second ABD at a pH of ~4.0 to ~6.5 is at least 10% greater than the KDof the first and / or second ABD at a pH of ~7.0 to ~8.0. In some embodiments, the KDof the first and / or second ABD at a pH of ~4.0 to ~6.5 is at least 3-fold greater than the KD of the first and / or second ABD at a pH of ~7.0 to ~8.0. In some embodiments, the KD of the first and / or second ABD at a pH of ~4.0 to ~6.5 is at least 10-fold greater than the KD of the first and / or second ABD at a pH of ~7.0 to ~8.0.

[0168] In some embodiments of an ABPC having a first and a second ABD, recognizing a first and second epitope of LRRC15, respectively, the dissociation rate of the first ABD from the first epitope at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or the dissociation constant (KD) of the first ABD with respect to the first epitope at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0 and / or (b) the dissociation rate of the second ABD from the second epitope at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or the dissociation constant (KD) of the second ABD with respect to the second epitope at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0; and (c) the composition provides for one or more of: an increase in toxin liberation in the target mammalian cell as compared to a composition including the same amount of a control ABPC; an increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC; and an increase in cndolysosomal delivery in the target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0169] In some embodiments, the ABPC is cytotoxic or cytostatic to the target mammalian cell.Attorney Docket No: 45395-0070W01

[0170] In some embodiments, the ABPC is cross-reactive with a non-human primate LRRC15 and human LRRC15. In some embodiments, the ABPC is cross-reactive with a non-human primate LRRC15, a human LRRC15, and one or both of rat LRRC15 and a mouse LRRC15. In some embodiments, the ABPC is cross-reactive with a non-human primate LRRC15, a human LRRC15, a rat LRRC15, and a mouse LRRC15. In some embodiments, the first and / or second ABD binds to an epitope of LRRC15 that is present on the surface of cells from an Old World Monkey.

[0171] In some embodiments, the ABPC includes a single polypeptide. In some embodiments, the first and / or second ABD is selected from a VH domain, a VHH domain, a VNAR domain, and a scFv. In some embodiments, the ABPC is a BiTe, a (scFvh, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, aHSAbody, scDiabody-HSA, or atandem-scFv.

[0172] In some embodiments, the ABPC includes two or more polypeptides. In some embodiments, the ABPC is selected from the group of 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 assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a KZ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L, H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2. a scFv-KIH, a Fab-scFv-Fc, atetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc. a VHH-Fc, a tandem VHH-Fc, a VHH-Fc KiH, a Fab-VHH-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, a scFvl-PEG-scFv2, an Adnectin, a DARPin, a fibronectin, a DEP conjugate, and a PROTAB.

[0173] In some embodiments, the ABPC or first and / or second ABD includes a proteolysis-targeting antibody (PROTAB) (as described, e.g., in Marei et al, “Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature.6 October 2022). In some embodiments, the PROTAB may tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo.

[0174] “Knob-into-hole” mutations could be incorporated into the Fc: Fc binding interfaces. In some embodiments, knob-into-holes ensure appropriate pairing of two distinct heavy chains during manufacturing. In an embodiment, tire first heavy chain constant domain (“HCCD”) or the first Fc of the multispecific antibodies herein comprises the sequence of 762, and the second HCCD or the second Fc of the multispecific antibodies herein comprises the sequence of 763. In another embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises the sequence of 763, and the second HCCD or the second Fc of the multispecific antibodies herein comprises the sequence of 762. In an embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises the sequence of 761, and the second HCCD or the second Fc of the multispecific antibodies herein comprises tire sequence of 764. In another embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises the sequence of 761, and the second HCCD orAttorney Docket No: 45395-0070W01the second Fc of the multispecific antibodies herein comprises the sequence of 764. In an embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises the sequence of 818, and the second HCCD or the second Fc of tire multispecific antibodies herein comprises the sequence of 819. In another embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises the sequence of 819, and the second HCCD or the second Fc of the multispecific antibodies herein comprises the sequence of 818.

[0175] In another embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises a variant of a human IgGl constant domain comprising T366W, and second HCCD or the second Fc of the multispecific antibodies herein comprises a variant of a human IgGl constant domain comprising T366S, L368A, and Y407V (EU Numbering).

[0176] In another embodiment, the first HCCD or the first Fc of the multispecific antibodies herein comprises a variant of the human IgGl constant domain comprising T366S, L368A, and Y407V, and second HCCD or the second Fc of the multispecific antibodies herein comprises a variant of the human IgGl constant domain comprising T366W (EU Numbering).

[0177] In some embodiments, at least one polypeptide of the ABPC is conjugated to the toxin, the radioisotope, the drug, or the small molecule via a cleavable linker. In some embodiments, the cleavable linker is cleavable by specific enzymes located primarily and / or exclusively inside of mammalian cells. In some embodiments, at least one polypeptide of the ABPC is conjugated to the toxin, the radioisotope, the drug, or the small molecule via a non-cleavable linker.

[0178] In some embodiments, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo. In some embodiments, the half-life of the ABPC in vivo is increased about 5% to about 95% as compared to the half-life of a control ABPC in vivo. In some embodiments, the half-life of the ABPC in vivo is increased about 10% to about 95% as compared to the half-life of a control ABPC in vivo. In some embodiments, the half-life of the ABPC in vivo is increased about 30% to about 95% as compared to the half-life of a control ABPC in vivo. In some embodiments, the half-life of the ABPC in vivo is increased about 50% to about 95% as compared to the half-life of a control ABPC in vivo. In some embodiments, the half-life of the ABPC in vivo is increased about 70% to about 95% as compared to the half-life of a control ABPC in vivo. In other embodiments, the in vivo half-life may be decreased.

[0179] In some embodiments, the control ABPC is capable of specifically binding to LRRC15 or an epitope of LRRC15 presented on the surface of a target mammalian cell, where: (a) the control ABPC includes a first ABD: (b) the dissociation rate of the first ABD of the control ABPC at a pH of ~4.0 to ~6.5 is no more than 3-fold faster than the dissociation rate at a pH of ~7.0 to ~8.0; and (c) the dissociation constant (KD) of the first ABD of the control ABPC at a pH of ~4.0 to ~6.5 is no more than 3-fold greater than the KDat a pH of ~7.0 to ~8.0.

[0180] In some embodiments, the control ABPC is capable of specifically binding to LRRC15 or an epitopeAttorney Docket No: 45395-0070W01of LRRC15 presented on the surface of a target mammalian cell, where: (a) tire control ABPC includes a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of ~4.0 to ~6.5 is no more than 2-fold faster than the dissociation rate at a pH of ~7.0 to ~8.0; and (c) tire dissociation constant (KD) of the first ABD of the control ABPC at a pH of ~4.0 to ~6.5 is no more than 2-fold greater than the KD at a pH of ~7.0 to ~8.0.

[0181] In some embodiments, the control ABPC is capable of specifically binding to LRRC 15 or an epitope of LRRC15 presented on the surface of a target mammalian cell, where: (a) tire control ABPC includes a first ABD; (b) the dissociation rate of the first ABD of the control ABPC at a pH of ~4.0 to ~6.5 is no more than 1-fold faster than the dissociation rate at a pH of ~7.0 to ~8.0; and (c) tire dissociation constant (KD) of the first ABD of the control ABPC at a pH of ~4.0 to ~6.5 is no more than 1-fold greater than the KD at a pH of ~7.0 to ~8.0.

[0182] In some embodiments, the control ABPC is selected from one of tire following (1) to (3):

[0183] (1) a full-length control antibody of (a) 54F1, (b) 56F3, (c) 15G7, (d) 24D9, (e) 29F1, or (f) 66H2;

[0184] (2) a full-length control antibody comprising the VH and VL domains of (a) 54F1, (b) 56F3, (c) 15G7, (d) 24D9, (e) 29F1, or (f) 66H2; and

[0185] (3) a full-length control antibody comprising the HCDRs and LCDRs of (a) 54F1, (b) 56F3, (c) 15G7, (d) 24D9, (e) 29F1, or (f) 66H2.

[0186] In some embodiments, the ABPC includes a second ABD.

[0187] As detailed in Example 13, clone 54F1 binds to epitope 2.2 of human LRRC15, clone 56F3 binds to epitope 5 of human LRRC 15, and clones 15G7, 24D9, and 29F1 bind to epitope 2.1 of human LRRC 15.

[0188] As detailed in Example 14, antigen binding domains (ABDs) of clones, hu54Fl, hu56F3, hul5G7, hu24D9, and hu29Fl may be combined with one another and with ABDs of clones belonging to other human LRRC 15 epitope bins to produce functional anti-LRRC15 biparatopic antibodies.

[0189] As detailed in Example 15, ABDs of clones, hu54Fl, hu56F3, hul5G7, hu24D9, and hu29Fl may be combined with ABDs from clones belonging to specific human LRRC 15 epitope bins to produce functional anti -LRRC 15 biparatopic antibodies that exhibit superior internalization into LRRC -positive cells as compared to the internalization exhibited by a control anti-LRRC15 antibody.

[0190] In some embodiments, the ABPC comprises a first and second ABD, wherein the first ABD specifically binds to Epitope 2.1 of human LRRC 15 and tire second ABD binds to Epitope 2.1.Table 1A. Presents particular anti-LRRC15 biparatopic ABPCs and their constituent elements Antigen Binding Domain 1 Antigen Binding Domain 2 ID bpABPC VH1 HC1 VL1 LC1 VH2 HC2 VL2 LC2 Description158- hu15G7-v hu15G7 SwapK- hu15G7-v VL Ck-Swap hu54Fl H hu54Fl Ck- V Swap VH V98C VH VL98 V98C Knob / hu54F SQN: 382 SQN: 818 SQN: 489 SQN: 765 SQN: 741 SQN: SQN: 742 SQN: C1 Hole 763 770Attorney Docket No: 45395-0070W01hu54Fl hu54Fl HC-Knob hu54Fl Ck-V98C hu15G7 Swap hul5G7-v Ck- VH VL SEQ ID VH VL159- Knob / hul5G Hole- Swap 7-v Swap SQN: 741 SQN: 762 SQN: 742 NO: 770 SQN: 382 V98C SQN: 489 SQN:V98Hole SQN: 765 C819hu54Fl hu54Fl HC-Knob hu54Fl Ck-S14C hul5G7 Swap hul5G7-v Ck- 159- Knob / hul5G VH VL SQN: VH Hole- VL Swap S14 7-v Swap SQN: 741 SQN: 762 SQN: 742 1622 SQN: 382 S14C SQN: 489 SQN:C Hole SQN: 7651623hul5G7-v hul5G7 SwapK- 160- hul5G7-v VL Ck-Swap hu56F3 H hu56F3 Ck- VH SQN:V Swap V98C 489 SQN: 765 VH SQN: VL98 V98C Knob / hu56F SQN: 382 SQN: 818 SQN: 749 763 SQN: 750 SQN:C3 Hole 770 hu56F3 hu56F3 HC-K hu56F3 Ck-V98C hul5G7 Swap H- hul5G7-v Ck- 161- Knob / hul5G VH VL VH V98C VL Swap V98 7-v Swap SQN: 749 SQN: 762 SQN: 750 SQN: 770 SQN: 382 SQN: SQN: 489 SQN:C Hole 819 765 hu56F3 hu56F3 HC-K hu56F3 Ck-S14C hul5G7 Swap hul5G7-v Ck- 161- Knob / liul5G VH VL SQN: VH Hole- VL Swap S14 7-v Swap SQN: 749 SQN: 762 SQN: 750 1622 SQN: 382 S14C SQN: 489 SQN:C Hole SQN: 7651623hul5G7 hu15G7 SwapK- hu15G7 Ck-Swap hu54Fl H hu54Fl Ck- 162- Swap VH V98C VL VH VL V98C V98 Knob / hu54F SQN: 382 SQN: 455 SQN: 765 SQN: 741 SQN: SQN: 742 C 1 Hole SQN: 818 763 SQN:770 hu54Fl hu54Fl HC-K hu54Fl Ck-V98C hul5G7 Swap H- hul5G7 Ck- 163- Knob / hul5G VH VL SQN: 770 VH V98C VL Swap V98 7 Swap Hole SQN: 741 SQN: 762 SQN: 742 SQN: 382 SQN: SQN: 455 SQN:C 819 765 hu54Fl hu54Fl HC-K hu54Fl Ck-S14C hul5G7 Swap hul5G7 Ck- 163- Knob / hul5G VH SEQ ID VL SQN: VH Holc- VL Swap S14 7 Swap Hole SQN: 741 SQN: 742 1622 SQN: 382 S14C SQN: 455 SQN:C NO: 762 SQN: 7651623hul5G7 hul5G7 SwapK- hul5G7 hu56F3 H hu56F3 Ck- 164- Ck-SwapVH VL SQN: 765 VH SQN: VLV98 Swap V98C V98C Knob / hu56F SQN: 382 SQN: 818 SQN: 455 SQN: 749 763 SQN: 750 SQN:C3 Hole 770HC-K hu56F3 Ck-V98C hul5G7 Swap H- hul5G7 Ck- 165- hu56F3 hu56F3Knob / hul5G VH VL SQN: 770 VH V98C VL Swap V987 Swap Hole SQN: 749 SQN: 762 SQN: 750 SQN: 382 SQN: SQN: 455 SQN:C819 765 hu56F3 hu56F3 HC-K hu56F3 Ck-S14C hul5G7 Swap hul5G7 Ck- 165- Knob / hul5G VH VL SQN: VH Hole- VL Swap S14 7 Swap Hole SQN: 749 SQN: 762 SQN: 750 1441 SQN: 382 S14C SQN: 455 SQN:C SQN: 765144266H2 66H2 HC-K 66H2 Ck-V hu54Fl hu54Fl Ck- 200- 98C Swap H- K / liu54Fl SQN: SQN: 762 SQN: 1442 SQN: 770 VH V98C VL Swap V98Swap Hole 1441 SQN: 741 SQN: SQN: 742 SQN:C819 765Attorney Docket No: 45395-0070W01hu54Fl hu54Fl SwapK- hu54Fl Ck-Swap 66H2 H 66H2 Ck- 201- S VH VL SQN: SQN: SQN: 1442 V98 wap V98C V98C K / 66H2 Hole SQN: 741 SQN: 818 SQN: 742 SQN: 765 1441 763 SQN:C 770 hu29Fl hu29Fl HC-K 66H2 66H2 Ck- 217- hu29Fl Ck-V98C Swap H- V98 K / 66H2 SQN: 576 SQN: 762 SQN: 700 SQN: 770 SQN: V98C SQN: 1442 Swap Swap Hole 1441 SQN: SQN:C 819 765 66H2 Swap 66H2 VH SwapK- 66H2 Ck-Swap hu29Fl H hu29Fl Ck- 218- K / hu29Fl SQN: V98C SQN: 1442 SQN: 765 SQN: 576 SQN: SQN: 700 V98C V98Hole 1441 SQN: 818 763 SQN:C770 244- hu54Fl hu54Fl HC-K hu54Fl Ck-S14C hu15G7 Swap hu15G7-v Ck- S14 Knob / hul5G VH SQN: 762 SQN: 742 SQN: VH Hole- VL Swap C 7-v Swap SQN: 741 1441 SQN: 382 S14C SQN: 489 SQN:Hole SQN: 7651442hul5G7-v hul5G7 SwapK-V98 hu15G7-var Ck-Swap hu54Fl H hu54Fl Ck-V98 Swap VH SQN: 761 VL SQN: 765 VH VL158- Knob / liu54F SQN: 382 SQN: 489 SQN: 741 SQN: SQN: 742 SQN:V981 Hole 763 353 hu54Fl hu54Fl HC-K hu54Fl Ck-V98 hul5G7 Swap H- hul5G7-v Ck- VH VL VH V98 VL159- Knob / hul5G Swap 7-v Swap SQN: 741 SQN: 762 SQN: 742 SQN: 353 SQN: 382 SQN: SQN: 489 SQN:V98Hole 764 765 hu15G7-v hu15G7 SwapK-V98 hu15G7-v VL Ck-Swap hu56F3 H hu56F3 Ck-V98 160- Swap VH SQN: 761 SQN: 489 SQN: 765 VH VLV98 Knob / hu56F SQN: 382 SQN: 749 SQN: SQN: 750 SQN:3 Hole 763 353 hu56F3 hu56F3 HC-K hu56F3 Ck-V98 hul5G7 Swap H- hul5G7-v Ck- 161- Knob / hul5G VH VL VH V98 VL Swap V98 7-v Swap SQN: 749 SQN: 762 SQN: 750 SQN: 353 SQN: 382 SQN: SQN: 489 SQN:Hole 764 765 hul5G7 hu15G7 SwapK-V98 hu15G7 Ck-Swap hu54Fl H hu54Fl Ck-V98 162- Swap VH SQN: 761 VL SQN: 765 VH VLV98 Knob / hu54F SQN: 382 SQN: 455 SQN: 741 SQN: SQN: 742 SQN:1 Hole 763 353 hu54Fl hu54Fl HC-K hu54Fl Ck-V98 hu15G7 Swap H- hul5G7 Ck- 163- Knob / hul5G VH VL VH V98 VL Swap V98 7 Swap Hole SQN: 741 SQN: 762 SQN: 742 SQN: 353 SQN: 382 SQN: SQN: 455 SQN:764 765 hul5G7 hul5G7 SwapK-V98 hul5G7 Ck-Swap hu56F3 H liu56F3 Ck-V98 164- Swap VH SQN: 761 VL SQN: 765 VH SQN: VL SQN:V98 Knob / hu56F SQN: 382 SQN: 455 SQN: 749 763 SQN: 750 353 3 Holehu56F3 hu56F3 HC-K hu56F3 Ck-V98 hu15G7 Swap H- hu15G7 Ck- 165- Knob / hul5G VH SQN: 762 VL SQN: 353 VH V98 VL Swap V98 7 Swap Hole SQN: 749 SQN: 750 SQN: 382 SQN: SQN: 455 SQN:764 765 66H2 66H2 HC-K 66H2 Ck-V98 hu54Fl Swap H- hu54Fl Ck- 200- K / liu54Fl SQN: SQN: 762 SQN: 1442 SQN: 353 VH V98 VL Swap V98 Swap Hole 1441 SQN: 741 SQN: SQN: 742 SQN:764 765 hu54Fl hu54Fl SwapK-V98 hu54Fl Ck-Swap 66H2 H 66H2 Ck-V98 201- VH SQN: 761 VL SQN: SQN: SQN: 1442 SQN:V98 SwapK / 66H2 Hole SQN: 741 SQN: 742 SQN: 765 1441 763 353Attorney Docket No: 45395-0070W01hu29Fl hu29Fl HC-K hu29Fl Ck-V98 66H2 Swap H- 66H2 Ck- 217- K / 66H2 SQN: 576 SQN: 762 SQN: 700 SQN: 353 SQN: V98 SQN: 1442 Swap V98 Swap Hole 1441 SQN: SQN:764 765 66H2 Swap 66H2 VH SwapK-V98 66H2 hu29Fl H hu29Fl Ck-V98 218- Ck-SwapV98 K / hu29Fl SQN: SQN: 761 SQN: 1442 SQN: 765 SQN: 576 SQN: SQN: 700 SQN:Hole 1441 763 353 244- hu54Fl hu54Fl HC-Knob hu54Fl Ck-S14 hul5G7 Swap hul5G7-v Ck- S14 Knob / hul5G VH SQN: 762 SQN: 742 SQN: VH Hole VL Swap 7-v Swap SQN: 741 1444 SQN: 382 SQN: SQN: 489 SQN: Hole 1445 765 “V98” means this version of the biparatopic antibody includes two of HC1, LC1, HC2, and LC2 comprising an amino acid sequence having a valine at a position corresponding to the valine at position 98 in the sequence of SQN: 353 (wildtype kappa light chain). For example. SQN: 353 contains a valine at amino acid position 98 and SQN: 761 contains a valine at amino acid position 98.“V98C” means this version of the biparatopic antibody includes two of HC1. LC1, HC2, and LC2 comprising an amino acid sequence having a cysteine at a position corresponding to the cysteine at position 98 in the sequence of SQN: 770 (“V98C” kappa light chain).“S14” means this version of the biparatopic antibody includes two of HC1, LC1. HC2. and LC2 comprising an amino acid sequence having a serine at a position corresponding to the serine at position 14 in the sequence of SQN: 353 (wildtype kappa light chain).“S14C” means this version of the biparatopic antibody includes two of HC1, LC1, HC2, and LC2 comprising an amino acid sequence having a cysteine at a position corresponding to the cysteine at position 14 in the sequence of SQN: 1622 (“S14C” kappa light chain).Table IB. Presents particular bispecific ABPCs, each including an anti-LRRC15 biparatopic ABPC component and an anti-tumor-associated antigen (anti-TAA) componentTAA Binding Domain LRRC15 ABDI Linker LRRC15 (TAABD) ABD2 ID ABPC VH1 HC1 VL1 LC1 VH1 HC1 VL1 LC1 HCAb 250- hu29Fl MYTX Swap MYTX Swap hu29F knob hu29F Ck- G4AG4S 168 VH V98 knob -011 hole- -011 LC 1 VH 1 VL V98C 168VH / MAB V98 MAB C45 Swap VH C VL SQNhole SQN: SQN: SQN: SQN SQN:: 762 SQN: SQN: SQN: SQN:1597 819 1598: 765 576 700 770 1556 1557 251- 45 Swap MYTX Swap MYTX Swap hu29F hole hu29F Ck- G4AG4S 168 VH V98 knob / -011 knob -011 LC 1 VH 1 VL V98C hu29Fl MAB MAB Chole VH V98 VL168VH SQN: C SQN: SQN SQN: SQN SQN: SQN: SQN: SQN:1597 SQN: 1598: 765 576: 763 700 770 1556 1557818Attorney Docket No: 45395-0070W01252- 66H2 MYTX Swap MYTX Swap 66H2 knob 66H2 Ck- (G4A)2G4523 VH V98 knob -Oil hole- -011 LC VH VL V98 sC 523 VH / MAB V98 MAB C045 VH C VL SQNSwap SQN: SQN: SQN: SQN SQN:: 762 SQN: SQN: SQN: SQN: hole 1597 819 1598: 765 1441 1442 770 774 1561 253- 045 MYTX Swap MYTX Swap 66H2 hole 66H2 Ck- (G4A)2G4523 VH V98 Swap -011 knob -011 LC VH VL V98 sC knob / MAb MAb C66H2 VH V98 VLhole SQN: C SQN: SQN SQN: SQN SQN: SQN: SQN: SQN: 523VH 1597 SQN: 1598: 765 1441: 763 1442 770 774 1561818“SQN” = “SEQ ID NO”

[0191] For tire headers of Table 1A, VH1, HC1, VL1, and LC1 are the heavy chain variable, heavy chain constant, light chain variable, and light chain constant domains of the first antibody binding domains (ABD), respectively, and VH2, HC2, VL2, and LC2 are the heavy chain variable, heavy chain constant, light chain variable, and light chain constant domains of the second ABD, respectively, of the indicated biparatopic antibody (BP). Each cell beneath these table headers provides a brief description of the indicated first or second ABD component followed by the SEQ ID NO (" SQN") setting forth the amino acid sequence of each such component.

[0192] For the headers of Table IB, the first / left-most set of VH1, HC1, VL1, and LC1 are the heavy chain variable, heavy chain constant, light chain variable, and light chain constant domains of the anti-TAA antibody, respectively, and the second set of VH1, HC 1, VL1, and LC 1 are the heavy chain variable, heavy chain constant, light chain variable, and light chain constant domains of the first antigen-binding domain (ABD) of the anti-LRRC 15 antibody. The first ABD and the second ABD (here, the heavy-chain only or HCAb LRRC 15-binding protein) are linked by the indicated "‘Linker”. Each cell beneath these table headers provides a brief description of the indicated component followed by the SEQ ID NO (“SQN”) setting forth the amino acid sequence of each such component.

[0193] In some embodiments, the biparatopic antibodies arc produced using a process as disclosed in Example 17.

[0194] In some embodiments, the biparatopic antibodies are selected from one of the V98 biparatopic antibodies recited in Table 1A: 158-V98, 159-V98, 160-V98, 161-V98, 162-V98, 163-V98, 164-V98, 165-V98, 200-V98, 201-V98, 217-V98, and 218-V98. Such V98 antibodies may serve as usefill surrogates for their corresponding V98C versions, which tend to be characterized by uncontrolled conjugation leading to technical challenges including antibody aggregation.

[0195] In some embodiments, the biparatopic antibodies are selected from one of the V98C or S14C biparatopic antibodies recited in Table 1A: 158-V98C, 159-V98C, 159-S14C, 160-V98C, 161-V98C, 161-S14C, 162-V98C, 163-V98C, 163-S14C, 164-V98C, 165-V98C, 165-S14C, 200-V98C, 201-V98C, 217-V98C,Attorney Docket No: 45395-0070W01218-V98C, 244-S14C. In some embodiments, the biparatopic antibodies are selected from one of the bispecific antibodies recited in Table IB: 250-V98C, 251-V98C, 252-V98C, and 253-V98C. Such antibodies may be used directly for conjugation to. for example, linkers, which may be conjugated to cargoes including drugs, including anti -cancer drugs. Such antibodies may also be conjugated via the cysteine of the V98C substitution to a neutral cap to prevent the aforementioned uncontrolled conjugation. Suitable caps are known in art, e.g., as discussed in Marion H. Emmert et al., “Build Your Own” ADC Mimics”; Organic Process R& D; Vol 28, Issue 8, July 17, 2024.

[0196] In still other embodiments, “half V98C” or “V98 x V98C” or “V98C x V98” versions of any of the biparatopic antibodies described in Table 1A may be produced by combining corresponding V98 antigen binding domains (ABDs) with V98C ABDs. For example, the half V98C biparatopic antibody may comprise the ABDI of 1 8-V98 and the ABD2 of 158-V98C.

[0197] In still other embodiments, the S 14C sequences may replace tire V98C sequences to produce a different conjugation site (i.e., other than the V98C conjugation site) for the production, for example, of DAR2 antibody drug conjugates (ADCs). Any or all the of the antibodies and / or antibody drug conjugates as disclosed herein may be produced as S14C, V98C. and / or combinations thereof.Anti-LRRC15 biparatopic antibody VH and VL pairing embodiments

[0198] In some embodiments, the first antigen binding domain (ABD) comprises a VH1 domain comprising the sequence of SEQ ID NO: 382 and a VL1 domain comprising the sequence of SEQ ID NO: 489, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 741 and a VL2 domain comprising the sequence of SEQ ID NO: 742.

[0199] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 741 and a VL1 domain comprising the sequence of SEQ ID NO: 742, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382 and a VL2 domain comprising the sequence of SEQ ID NO: 489.

[0200] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382 and a VL1 domain comprising the sequence of SEQ ID NO: 489, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 749 and a VL2 domain comprising the sequence of SEQ ID NO: 750.

[0201] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 749 and a VL1 domain comprising tire sequence of SEQ ID NO: 750. and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, and a VL2 domain comprising the sequence of SEQ ID NO: 489.

[0202] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382 and a VL1 domain comprising the sequence of SEQ ID NO: 455, and the second ABD comprises a VH2 domain comprising tire sequence of SEQ ID NO: 741 and a VL2 domain comprising the sequence of SEQAttorney Docket No: 45395-0070W01ID NO: 742.

[0203] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 741 and a VL1 domain comprising tire sequence of SEQ ID NO: 742. and the second ABD comprises a VH2 domain comprising tire sequence of SEQ ID NO: 382 and a VL2 domain comprising the sequence of SEQ ID NO: 455.

[0204] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382 and a VL1 domain comprising tire sequence of SEQ ID NO: 455, and the second ABD comprises a VH2 domain comprising tire sequence of SEQ ID NO: 749 and a VL2 domain comprising the sequence of SEQ ID NO: 750.

[0205] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 749 and a VL1 domain comprising the sequence of SEQ ID NO: 750, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382 and a VL2 domain comprising the sequence of SEQ ID NO: 455.

[0206] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 489. wherein any amino acid sequence variations relative to SEQ ID NO: 489 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 741, wherein any amino acid sequence variations relative to SEQ ID NO: 741 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 742, wherein any amino acid sequence variations relative to SEQ ID NO: 742 occur only in framework regions.

[0207] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 741, wherein any amino acid sequence variations relative to SEQ ID NO: 741 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 742. wherein any amino acid sequence variations relative to SEQ ID NO: 742 occur only in framework regions; and tire second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 489, wherein any amino acid sequence variations relative to SEQ ID NO: 489 occur only in framework regions.Attorney Docket No: 45395-0070W01

[0208] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 489, wherein any amino acid sequence variations relative to SEQ ID NO: 489 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 749, wherein any amino acid sequence variations relative to SEQ ID NO: 749 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 750, wherein any amino acid sequence variations relative to SEQ ID NO: 750 occur only in framework regions.

[0209] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 749, wherein any amino acid sequence variations relative to SEQ ID NO: 749 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 750, wherein any amino acid sequence variations relative to SEQ ID NO: 750 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 489, wherein any amino acid sequence variations relative to SEQ ID NO: 489 occur only in framework regions.

[0210] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 455, wherein any amino acid sequence variations relative to SEQ ID NO: 455 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 741, wherein any amino acid sequence variations relative to SEQ ID NO: 741 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 742, wherein any amino acid sequence variations relative to SEQ ID NO: 742 occur only in framework regions.

[0211] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 741,Attorney Docket No: 45395-0070W01wherein any amino acid sequence variations relative to SEQ ID NO: 741 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 742. wherein any amino acid sequence variations relative to SEQ ID NO: 742 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 455, wherein any amino acid sequence variations relative to SEQ ID NO: 455 occur only in framework regions.

[0212] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 455. wherein any amino acid sequence variations relative to SEQ ID NO: 455 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 749, wherein any amino acid sequence variations relative to SEQ ID NO: 749 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 750, wherein any amino acid sequence variations relative to SEQ ID NO: 750 occur only in framework regions.

[0213] In some embodiments, the first ABD comprises: (a) a VH1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 749, wherein any amino acid sequence variations relative to SEQ ID NO: 749 occur only in framework regions, and (b) a VL1 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 750. wherein any amino acid sequence variations relative to SEQ ID NO: 750 occur only in framework regions; and the second ABD comprises: (c) a VH2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 382, wherein any amino acid sequence variations relative to SEQ ID NO: 382 occur only in framework regions, and (d) a VL2 domain comprising a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 455, wherein any amino acid sequence variations relative to SEQ ID NO: 455 occur only in framework regions.Anti-LRRC15 V98 biparatopic antibody embodiments

[0214] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, an HC1 domain comprising the sequence of SEQ ID NO: 761, a VL1 domain comprising the sequence of SEQ ID NO: 489, and an LC1 domain comprising the sequence of SEQ ID NO: 765, and the second ABDAttorney Docket No: 45395-0070W01comprises a VH2 domain comprising the sequence of SEQ ID NO: 741, an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising the sequence of SEQ ID NO: 742, and an LC2 domain comprising the sequence of SEQ ID NO: 353.

[0215] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 741, an HC1 domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 742, and an LC1 domain comprising the sequence of SEQ ID NO: 353, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 764, a VL2 domain comprising the sequence of SEQ ID NO: 489, and an LC2 domain comprising the sequence of SEQ ID NO: 765.

[0216] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, an HC1 domain comprising the sequence of SEQ ID NO: 761, a VL1 domain comprising the sequence of SEQ ID NO: 489, and an LC1 domain comprising the sequence of SEQ ID NO: 765, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 749, an HC2 domain comprising tire sequence of SEQ ID NO: 763, a VL2 domain comprising the sequence of SEQ ID NO: 750, and an LC2 domain comprising the sequence of SEQ ID NO: 353.

[0217] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 749, anHCl domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 750, and an LC1 domain comprising the sequence of SEQ ID NO: 353, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 764, a VL2 domain comprising the sequence of SEQ ID NO: 489, and an LC2 domain comprising the sequence of SEQ ID NO: 765.

[0218] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, anHCl domain comprising the sequence of SEQ ID NO: 761, a VL1 domain comprising the sequence of SEQ ID NO: 455, and an LC1 domain comprising the sequence of SEQ ID NO: 765, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 741, an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising the sequence of SEQ ID NO: 742, and an LC2 domain comprising the sequence of SEQ ID NO: 353.

[0219] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 741, anHCl domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 742, and an LC1 domain comprising the sequence of SEQ ID NO: 353, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 764, a VL2 domain comprising tire sequence of SEQ ID NO: 455, and an LC2 domain comprising the sequence of SEQ ID NO: 765.

[0220] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, an HC1 domain comprising tire sequence of SEQ ID NO: 761, a VL1 domain comprising the sequenceAttorney Docket No: 45395-0070W01of SEQ ID NO: 455, and an LC1 domain comprising the sequence of SEQ ID NO: 765, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 749, an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising the sequence of SEQ ID NO: 750, and an LC2 domain comprising the sequence of SEQ ID NO: 353.

[0221] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 749, an HC1 domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 750, and an LC1 domain comprising the sequence of SEQ ID NO: 353, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 764, a VL2 domain comprising the sequence of SEQ ID NO: 455, and an LC2 domain comprising the sequence of SEQ ID NO: 765.Anti-LRRC15 V98C biparatopic anti-LRRC15 antibody embodiments

[0222] In some embodiments, the first antigen binding domain (ABD) comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, anHCl domain comprising the sequence ofSEQ ID NO: 818, aVLl domain comprising the sequence of SEQ ID NO: 489, and an LC1 domain comprising the sequence of SEQ ID NO: 765. and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 741. an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising the sequence of SEQ ID NO: 742, and an LC2 domain comprising the sequence of SEQ ID NO: 770.

[0223] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 741, anHCl domain comprising the sequence ofSEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 742, and an LC1 domain comprising the sequence of SEQ ID NO: 770, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 819, a VL2 domain comprising tire sequence of SEQ ID NO: 489, and an LC2 domain comprising the sequence ofSEQ ID NO: 765.

[0224] In some embodiments, the first antigen binding domain (ABD) comprises a VH1 domain comprising the sequence ofSEQ IDNO: 382, anHCl domain comprising the sequence ofSEQ ID NO: 818, aVLl domain comprising the sequence of SEQ ID NO: 489, and an LC1 domain comprising the sequence of SEQ ID NO: 765, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 749, an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising the sequence of SEQ ID NO: 750, and an LC2 domain comprising the sequence of SEQ ID NO: 770.

[0225] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 749, an HC1 domain comprising the sequence ofSEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 750, and an LC 1 domain comprising the sequence of SEQ ID NO: 770, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence ofSEQ IDNO: 819, a VL2 domain comprising tire sequence ofSEQ IDNO: 489, and an LC2 domain comprising the sequence ofSEQ IDNO: 765.Attorney Docket No: 45395-0070W01

[0226] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, anHCl domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 455, and an LC1 domain comprising the sequence of SEQ ID NO: 765, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 741, an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising tire sequence of SEQ ID NO: 742, and an LC2 domain comprising the sequence of SEQ ID NO: 770.

[0227] In some embodiments, the first antigen binding domain (ABD) comprises a VH1 domain comprising the sequence of SEQ IDNO: 741, anHCl domain comprising the sequence ofSEQ ID NO: 762, aVLl domain comprising the sequence of SEQ ID NO: 742, and an LC1 domain comprising the sequence of SEQ ID NO: 770, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 819, a VL2 domain comprising the sequence of SEQ ID NO: 455, and an LC2 domain comprising the sequence of SEQ ID NO: 765.

[0228] In some embodiments, the first ABD comprises a VH1 domain comprising the sequence of SEQ ID NO: 382, anHCl domain comprising the sequence ofSEQ IDNO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 455, and an LC 1 domain comprising the sequence of SEQ ID NO: 765, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 749, an HC2 domain comprising the sequence of SEQ ID NO: 763, a VL2 domain comprising tire sequence of SEQ ID NO: 750, and an LC2 domain comprising the sequence ofSEQ IDNO: 770.

[0229] In some embodiments, the first antigen binding domain (ABD) comprises a VH1 domain comprising the sequence ofSEQ ID NO: 749, anHCl domain comprising the sequence ofSEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 750, and an LC1 domain comprising the sequence of SEQ ID NO: 770, and the second ABD comprises a VH2 domain comprising the sequence of SEQ ID NO: 382, an HC2 domain comprising the sequence of SEQ ID NO: 819, a VL2 domain comprising the sequence of SEQ ID NO: 455, and an LC2 domain comprising the sequence ofSEQ ID NO: 765.

[0230] In addition, the LRRC 15 -specific ABPCs disclosed herein may be used to construct multispecific antibodies comprising other modalities, including but not limited to a second tumor associated antigen (TAA), immune checkpoints or immune stimulators, or to form fusion proteins or ADCs.

[0231] In another aspect, the ABPC comprises a monoparatopic or biparatopic LRRC 15 -binding protein construct and a monoparatopic or biparatopic tumor-associated antigen-binding (TAA-binding) protein construct. In some embodiments, the LRRC 15 -binding protein is selected from a monoparatopic LRRC15-binding protein construct as disclosed herein. In some embodiments, the LRRC15-binding protein construct is selected from a biparatopic LRRC 15 -binding protein as disclosed herein. In some embodiments, the LRRC15-binding protein construct is selected from any LRRC 15 -binding protein construct that specifically recognizes substantially the same epitope(s) as any one of the LRRC 15 -binding protein constructs as disclosed herein. In some embodiments, the TAA-binding protein construct is selected from a TAA-binding protein construct asAttorney Docket No: 45395-0070W01disclosed herein. In some embodiments, the TAA-binding protein construct is selected from any TAA-binding protein construct that specifically recognizes substantially the same epitope(s) as any one of the TAA-binding protein constructs as disclosed herein.

[0232] In some embodiments, the ABPC comprises a monoparatopic LRRC 15 -binding protein construct as disclosed herein and a TAA-binding protein construct (TAABPC) as disclosed herein. In some embodiments, the TAABPC specifically recognizes an antigen that recognizes a TAA expressed in tumor cells associated with LRRC 15 -positive cancer associated fibroblasts (CAFs).

[0233] In some embodiments, the TAABPC specifically recognizes an antigen selected from: EGFR, MUC1, Nectin-4, B7H4. MET, TROP2. and ITGB6.

[0234] In some embodiments, the ABPC comprises a bispecific ABPC comprising a biparatopic LRRC15-binding protein construct as disclosed herein and a TAA-binding protein construct (TAABPC) as disclosed herein. In some embodiments, the TAABPC specifically recognizes an antigen that recognizes a TAA expressed in tumor cells associated with LRRC 15 -positive cancer associated fibroblasts (CAFs). In some embodiments, the bispecific anti -Tumor-Associated Antigen (TAA) x anti-LRRC15 antibody comprising a TAA binding domain (TAABD) and an LRRC 15 binding domain, optionally wherein the TAABD is selected from a B7H3 TAABD, a B7H4 TAABD, a CEACAM5 TAABD, a MET TAABD, a DLL3 TAABD, an EGFR TAABD, a FOLR1 TAABD, a HER2 TAABD, a HER3 TAABD, an IGF1R TAABD, an ITGB6 TAABD, a MUC1 TAABD, a NECTIN4 TAABD, a PTK7 TAABD, an RNF43 TAABD, a TROP2 TAABD, and a ZNRF3 TAABD. In some particular embodiments, the TAABD is selected from an EGFR TAABD, a MUC1 TAABD, a Nectin-4 TAABD. a B7H4 TAABD, a MET TAABD. a TROP2 TAABD. and an ITGB6 TAABD.Non-limiting examples of the anti-TAA component of the Anti-TAA x anti-LRRC15 antibodies

[0235] In an aspect, the disclosure provides bispecific anti -Tumor-Associated Antigen (TAA) x anti-LRRC15 antibodies, each comprising a TAA binding domain (TAABD) and an LRRC 15 -binding domain, optionally wherein the TAABD is selected from a B7H3 TAABD, a B7H4 TAABD, a CEACAM5 TAABD, a MET TAABD, a DLL3 TAABD, an EGFR TAABD, a FOLR1 TAABD, a HER2 TAABD. a HER3 TAABD, an IGF1R TAABD, an ITGB6 TAABD. a MUC1 TAABD, a NECTIN4 TAABD, a PTK7 TAABD, an RNF43 TAABD, a TROP2 TAABD, and a ZNRF3 TAABD.

[0236] In some embodiment, the TAABD specifically recognizes any TTA recited in Sections 1 to 17 below. In some embodiments, the TAABD comprises a B7H4 TAABD described in Section 2, a MET TAABD described in Section 4, an EGFR TAABD described in Section 6. a TROP2 TAABD described in Section 16, an ITGB6 TAABD described in Section 11, a NECTIN4 TAABD described in Section 13, or a MUC1 TAABD described in Section 12.Section 1 - B7H3-binding proteins

[0237] In cases where the TAA is B7H3, the TAABD may be any B7H3-bining protein capable of pairingAttorney Docket No: 45395-0070W01with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC15 x anti-B7H3 antibody. As used in this and the following Sections, "functional anti-LRRC15 x anti-TAA antibody” means that the anti-LRRC 15 antibody and anti-TAA antibody components continue to be capable of specifically recognizing their respective antigens when combined to form the multispecific antibody. In some embodiments, the TAABD may comprise enoblituzumab, ifinatamab, mirzotamab, vobramitamab, or a pH-dependent, a half-pH-dependent, or a non-pH-dependent B7H3-binding variant or B7H3-binding fragment of any one of them. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 2 - B7H4-binding proteins

[0238] In cases where the TAA is B7H4, the TAABD may be any B7H4-bining protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC 15 x anti-B7H4 antibody. B7H4-binding proteins may include but not solely any of the B7H4-binding proteins disclosed in US2023 / 0117205 Al (to Seagen), the content of which is incorporated herein by reference in its entirety. B7H4-binding proteins may also include alsevalimab, emiltatug, puxitatug, and pH-dependent, half-pH-dependent, or non-pH-dependent B7H4-binding variants or fragments of any one of them. In an embodiment, the TAABD comprises felmetatug or a B7H4-binding fragment thereof. In an embodiment, the TAABD comprises an ABPC comprising an HCVD having the HCDRs of the HCVD sequence set forth in SEQ ID NO: 1589 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1590. In some embodiments, the TAABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the HCDRs of the sequence of SEQ ID NO: 1589, and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1590. In some embodiments, the TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1591, 1592, and 1593, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1594, 1595, and 1596, respectively. In some other embodiments, the TAABD may be modified to render it pH-dependent, such that it binds well to its target antigen at higher pH (e.g., about physiologic pH), but not as well at lower pH (e g., about tire pH typical of the endolysosomal space inside cells).Section 3 - CEACAM5-binding proteins

[0239] In cases where the TAA is CEACAM5, the TAABD may be any CEACAM5-bining protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC 15 x anti-CEACAM5 antibody. In some embodiments, the TAABD may comprise tusamitamab, cibisatamab, labctuzumab, or a pH-dcpcndcnt, a half-pH-dependent, or a non-pH-dependent CEACAM5-binding variant or CEACAM5-binding fragment of any one of them. Tire TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 4 - MET-binding proteinsAttorney Docket No: 45395-0070W01

[0240] In cases where tire TAA is MET, the TAABD may be any MET-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-MET antibody. MET-binding proteins may include but not solely any of the MET-binding proteins disclosed in US2022 / 0281984A1, US2024 / 0101688A1, and US2024 / 0197906 Al (to Mythic Therapeutics), the contents of which are incorporated herein by reference in their entireties. In some embodiments, the TAABD may comprise emibetuzumab, onartuzumab, telisotuzumab, or a pH-dependent, a half-pH-dependent, or a non-pH-dependent MET-binding variant or MET-binding fragment of any one of them. In an embodiment, the TAABD comprises the MYTX-011 mAb or a MET-binding variant or fragment thereof. In an embodiment, the TAABD comprises an ABPC comprising an HCVD having the HCDRs of tire HCVD sequence set forth in SEQ ID NO: 1597 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1598. In some embodiments, the TAABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the HCDRs of the sequence of SEQ ID NO: 1597, and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1598. In some embodiments, the TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1599, 1600, and 1601, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1602, 1603, and 1604, respectively. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 5 - DLL3-binding proteins

[0241] In cases where the TAA is DLL3, the TAABD may be any DLL3 -binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-DLL3 antibody. DLL3-binding proteins may include but not solely any of the DLL3 -binding proteins disclosed in US2022 / 0281984A1, US2024 / 0101688A1, and US2024 / 0197906A1 (to Mythic Therapeutics, Inc. (" Mythic")), the contents of which are incorporated herein by reference in their entireties. In some embodiments, the TAABD may comprise rovalpituzumab. SC16.4, SC16.13, SC16.15, SC16.25, SC16.34, SC16.67, or a pH-dependent (e.g., a pH-dependent DLL3-binding protein as recited in any one of the Mythic patents or patent applications), a half-pH-dependent, or a non-pH-dependent DLL3 -binding variant or DLL3-binding fragment of any one of them. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 6 - EGFR-binding proteins

[0242] In cases where the TAA is EGFR, the TAABD may be any EGFR-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-EGFR antibody. EGFR-binding proteins may include any known or yet to be made EGFR-binding protein. In some embodiments, the TAABD may comprise EGFR-binding components of cetuximab, becotatug, demupitamab, depatuxizumab, ficerafiisp, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab,Attorney Docket No: 45395-0070W01modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomuzotuximab, alutumumab, or pH-dependent, half-pH-dependent, or non-pH-dependent EGFR-binding variants or fragments of any one of them. In an embodiment, the TAABD comprises an ABPC comprising an HCVD having the HCDRs of the HCVD sequence set forth in SEQ ID NO: 1565 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1566. In some embodiments, the TAABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the HCDRs of the sequence of SEQ ID NO: 1565, and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1565. In some embodiments, the TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1567. 1568, and 1569, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1570, 1571, and 1572, respectively. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 7 - FOLR1 -binding proteins

[0243] In cases where the TAA is FOLR1, the TAABD may be any FOLRl-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-FOLR1 antibody. FOLRl-binding proteins may include any known or yet to be made FOLRl-binding protein, including any disclosed in WO2020247827A1 (to Mythic Therapeutics), which is herein incorporated by reference in its entirety. In some embodiments, the TAABD may comprise mirvetuximab, STRO-002, farletuzumab, or pH-dependent, half-pH-dependent, or non-pH-dependent FOLRl-binding variants or fragments of any one of them. Tire TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 8 - HER2-binding proteins

[0244] In cases where the TAA is HER2, the TAABD may be any HER2-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC15 x anti-HER2 antibody. HER2 -binding proteins may include any known or yet to be made HER2 -binding protein, including trastuzumab (HERCEPTIN®), pertuzumab (PERJETA®), margetuximab, or pH-dependent, half-pH-dependent, or non-pH-dependent HER2-binding variants or fragments of any one of them. Hie TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 9 - HER3-binding proteins

[0245] In cases where the TAA is HER3, the TAABD may be any HER3-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC 15 x anti-HER3 antibody. HER3 -binding proteins may include any known or yet to be made HER3 -binding protein, including patritumab (U3-1287), seribantumab (MM-121). lumretuzumab (RO5479599), or pH-dependent, half-pH-dependent, or non-pH-dependent HER2-binding variants or fragments of any one of them. TheAttorney Docket No: 45395-0070W01TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 10 - IGFIR-binding proteins

[0246] In cases where the TAA is IGF1R, the TAABD may be any IGFIR-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-IGF1R antibody. IGFIR-binding proteins may include any known or yet to be made IGFIR-binding protein, including ganitumab, hl0H5.vX, lonigutamab, robatumumab, or pH-dependent, half-pH-dependent, or non-pH-dependent HER2 -binding variants or fragments of any one of them. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 11 - ITGp6-binding proteins

[0247] In cases where the TAA is ITG[36, the TAABD may be any ITGp6-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-ITGP6 antibody. ITGp6-binding proteins may include but not solely any of the ITGp6-binding proteins disclosed in WO2024 / 263932A2 (to Mythic Therapeutics), the content of which is incorporated herein by reference in its entirety. In some embodiments, the TAABD may comprise sigvotatug, hu2A2 (SGN-P6A antibody, Seagen, US 20210198367A1), h!5H3 (Seagen, US20160009806A1), 6.3G9, STX-100 / BG00011, or a pH-dependent. a half-pH-dependent, or a non-pH-dependent ITGp6-binding variant or fragment of any one of them. In an embodiment, the TAABD comprises sigvotatug or an ITGp6-binding variant or fragment thereof. In an embodiment, the TAABD comprises an ABPC comprising an HCVD having the HCDRs of the HCVD sequence set forth in SEQ ID NO: 1613 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1614. In some embodiments, the TAABD includes an HCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to, and comprises the HCDRs of the sequence of SEQ ID NO: 1613, and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1614. In some embodiments, the TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1615, 1616, and 1617, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1618, 1619, and 1620, respectively. Tire TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 12 - MUCl-binding proteins

[0248] In cases where the TAA is MUC1, the TAABD may be any MUCl-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC15 x anti-MUC1 antibody. In some embodiments, the TAABD may comprise DS-3939, cantuzumab, clivatuzumab, gatipotuzumab, or a pH-dependent, a half-pH-dependent, or a non-pH-dependent MUCl-binding variant or fragment of any one of them. In an embodiment, the TAABD comprises DS-3939 or an MUCl-binding variant or fragment thereof. In an embodiment, the TAABD comprises an ABPC comprising an HCVD having theAttorney Docket No: 45395-0070W01HCDRs of the HCVD sequence set forth in SEQ ID NO: 1573 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1574. In some embodiments, tire TAABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%. 93%. 94%, 95%, 96%, 97%, 98%, or 99% identical to. and comprises the HCDRs of the sequence of SEQ ID NO: 1573. and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1574. In some embodiments, the TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1575, 1576, and 1577, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1578, 1579, and 1580, respectively. Tire TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 13 - NECTIN4-binding proteins

[0249] In cases where the TAA is NECTIN4, the TAABD may be any NECTIN4-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC 15 x anti-NECTIN4 antibody. In an embodiment, tire TAABD comprises an ABPC comprising an HCVD having the HCDRs of the HCVD sequence set forth in SEQ ID NO: 1581 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1582. In some embodiments, the TAABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, or 99% identical to, and comprises the HCDRs of the sequence of SEQ ID NO: 1581, and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1582. In some embodiments, tire TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1583, 1584, and 1585, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1586, 1587, and 1588, respectively. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 14 - PTK7-binding proteins

[0250] In cases where the TAA is PTK7, the TAABD may be any PTK7 -binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC 15 x anti-PTK7 antibody. Tire TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof. PTK7 -binding proteins may include any known or yet to be made PTK7 -binding protein, including any disclosed in WO2023225639A1 (to Mythic Therapeutics), which is herein incorporated by reference in its entirety. In some embodiments, the TAABD may comprise cofetuzumab, 7C8, and 12C6, or a pH-dependent, a half-pH-dependent, or a non-pH-dependent ITGB6-binding variant or fragment of any one of them. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 15 - RNF43-binding proteins

[0251] In cases where the TAA is RNF43, the TAABD may be any RNF43-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC 15 x antiAttorney Docket No: 45395-0070W01RNF43 antibody. The TAABD may include any known or yet to be made RNF43-binding protein, and may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 16 - TROP2-binding proteins

[0252] In cases where the TAA is TROP2, the TAABD may be any TROP2-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC15 antibody to produce a functional anti-LRRC15 x anti-TROP2 antibody. TROP2-binding proteins may include any known or yet to be made TROP2 -binding protein, including but not solely any of the pH-dependent or non-pH-dependent TROP2-binding proteins disclosed in WO2024 / 206815 (to Mythic Therapeutics), the content of which is incorporated herein by reference in its entirety.

[0253] In some embodiments, the TAABD may comprise sacituzumab, datopotamab, tizetatug, hu7E6SVG, or Al, 2X4, or a pH-dependent, a half-pH-dependent, or a non-pH-dependent ITGB6-binding variant or fragment of any one of them. In an embodiment, the TAABD comprises an ABPC comprising an HCVD having the HCDRs of the HCVD sequence set forth in SEQ ID NO: 1605 and an LCVD having the LCDRs of the LCVD sequence set forth in SEQ ID NO: 1606. In some embodiments, the TAABD includes an HCVD comprising a sequence that is identical to. or is at least 90%, 91%, 92%. 93%. 94%. 95%. 96%, 97%, 98%, or 99% identical to, and comprises the HCDRs of the sequence of SEQ ID NO: 1605, and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, and comprises the LCDRs of the sequence of SEQ ID NO: 1606. In some embodiments, the TAABD HCVD comprises the HCDR1,2,3 sequences of SEQ ID NOs: 1607, 1608, and 1609, respectively, and the TAABD LCVD comprises the LCDR1,2,3 sequences of SEQ ID NOs: 1610, 1611, and 1612, respectively. The TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Section 17 - ZNRF3-binding proteins

[0254] In cases where the TAA is ZNRF3, the TAABD may be any ZNRF3-binding protein capable of pairing with the selected mono- or multiparatopic anti-LRRC 15 antibody to produce a functional anti-LRRC15 x anti-TAA antibody. Hie TAABD may be pH-dependent, half-pH-dependent, non-pH-dependent or any variation thereof.Bispecific anti-LRRC15 x anti-Tumor-Associated Antigen (TAA) antibodies

[0255] In some embodiments, the disclosure provides a bispecific anti-LRRC 15 x anti-Tumor-Associated Antigen (TAA) antibody comprising:

[0256] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, anHCl domain, aVLl domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain:

[0257] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain;Attorney Docket No: 45395-0070W01

[0258] (c) a second LRRC15-binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and

[0259] (d) a linker connecting the first and second LRRC 15 -binding domains.

[0260] In some embodiments, the disclosure provides a bispecific anti-LRRC15 x anti -Tumor-Associated Antigen (TAA) antibody comprising:

[0261] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC 1 domain;

[0262] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain;

[0263] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and

[0264] (d) a linker connecting the first and second LRRC 15 -binding domains.

[0265] In some embodiments, the disclosure provides a bispecific anti-LRRC15 x anti -Tumor-Associated Antigen (TAA) antibody comprising:

[0266] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HCl domain, aVLl domain comprising the sequence of SEQ ID NO: 1598, and an LC 1 domain;

[0267] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC1 domain;

[0268] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and

[0269] (d) a linker connecting the first and second LRRC 15 -binding domains.

[0270] In some embodiments, the disclosure provides a bispecific anti-LRRC15 x anti-Tumor-Associated Antigen (TAA) antibody comprising:

[0271] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765;

[0272] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain comprising the sequence of SEQ ID NO: 763, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC 1 domain comprising the sequence of SEQ ID NO: 770;

[0273] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and

[0274] (d) a linker connecting the first and second LRRC 15 -binding domains.Attorney Docket No: 45395-0070W01

[0275] In some embodiments, the disclosure provides a bispccific anti-LRRC15 x anti-Tumor-Associatcd Antigen (TAA) antibody comprising:

[0276] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 819, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC 1 domain comprising the sequence of SEQ ID NO: 765;

[0277] (b) a first LRRC 1 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain comprising the sequence of SEQ ID NO: 770;

[0278] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and

[0279] (d) a linker connecting the first and second LRRC 15 -binding domains; optionally wherein the linker is selected from an amino acid sequence set forth in one of the following SEQ ID NOs: 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 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, 1556, and 1624.

[0280] In some embodiments, the disclosure provides a bispecific anti-LRRC15 x anti-Tumor-Associated Antigen (TAA) antibody comprising:

[0281] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765;

[0282] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain comprising the sequence of SEQ ID NO: 763, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC 1 domain comprising the sequence of SEQ ID NO: 770;

[0283] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and

[0284] (d) a linker connecting the first and second LRRC 15 -binding domains: optionally wherein the linker is selected from an amino acid sequence set forth in one of the following SEQ ID NOs: 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 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, 1556, and 1624.

[0285] In some embodiments, the disclosure provides a bispecific anti-LRRC15 x anti -Tumor-Associated Antigen (TAA) antibody comprising:

[0286] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising theAttorney Docket No: 45395-0070W01sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 819, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765;

[0287] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC 1 domain comprising the sequence of SEQ ID NO: 770;

[0288] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and

[0289] (d) a linker connecting the first and second LRRC 15 -binding domains: optionally wherein the linker is selected from an amino acid sequence set forth in one of the following SEQ ID NOs: 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 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, 1556, and 1624.

[0290] In some embodiments, the disclosure provides a bispecific anti-LRRC15 x anti -Tumor-Associated Antigen (TAA) antibody comprising:

[0291] (a) a tumor-associate antigen (TAA) binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765:

[0292] (b) a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain comprising the sequence of SEQ ID NO: 763, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC 1 domain comprising the sequence of SEQ ID NO: 770;

[0293] (c) a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and

[0294] (d) a linker connecting the first and second LRRC 15 -binding domains; optionally wherein the linker is selected from an amino acid sequence set forth in one of the following SEQ ID NOs: 771, 772, 773, 774, 775, 776, 777, 778, 779. 780, 781, 782, 783, 784, 785, 786, 787, 788, 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, 1556, and 1624.

[0295] In an embodiment, the anti-LRRC15 x anti-TAA antibody comprises:

[0296] (a) a TAABD comprising a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 819, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765;

[0297] (b) a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 576, an HC1 domain having the sequence of SEQ ID NO: 762, a VL1 domain having the sequence of SEQ ID NO: 700, andAttorney Docket No: 45395-0070W01an LC1 domain having the sequence of SEQ ID NO: 770;

[0298] (c) a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and

[0299] (d) a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 1556.

[0300] In an embodiment, the anti-LRRC15 x anti-TAA antibody comprises:

[0301] (a) a TAABD comprising a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 818, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765;

[0302] (b) a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 576, an HC1 domain having the sequence of SEQ ID NO: 763, a VL1 domain having the sequence of SEQ ID NO: 700, and an LC1 domain having the sequence of SEQ ID NO: 770;

[0303] (c) a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and

[0304] (d) a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 1556.

[0305] In an embodiment, the anti-LRRC15 x anti-TAA antibody comprises:

[0306] (a) a TAABD comprising a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 819, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765;

[0307] (b) a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 1441, an HC1 domain having the sequence of SEQ ID NO: 762, a VL1 domain having the sequence of SEQ ID NO: 1442, and an LC1 domain having the sequence of SEQ ID NO: 770;

[0308] (c) a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and

[0309] (d) a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 774.

[0310] In an embodiment, the anti-LRRC15 x anti-TAA antibody comprises:

[0311] (a) a TAABD comprising a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 818, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765;

[0312] (b) a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 1441, an HC1 domain having the sequence of SEQ ID NO: 763, a VL1 domain having the sequence of SEQ ID NO: 1442, and an LC1 domain having tire sequence of SEQ ID NO: 770;

[0313] (c) a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and

[0314] (d) a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 774.

[0315] Also provided herein are methods of treating a cancer characterized by having a population of cancer cells that have LRRC15 or an epitope of LRRC15 presented on their surface, the method including: 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 and / or cancer-associated cells.Attorney Docket No: 45395-0070W01

[0316] Also provided herein are methods of reducing the volume of a tumor in a subject, where the tumor is characterized by having a population of cancer cells that have LRRC15 or an epitope of LRRC15 presented on their surface, the method including: 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 and / or cancer-associated cells.

[0317] Also provided herein are methods of inducing cell death in a cancer cell in a subject, where the cancer cell has LRRC15 or an epitope of LRRC15 presented on its surface, where the method includes: 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 a population of the cancer cells.

[0318] Also provided herein are methods of inducing cell death in a cancer-associated cell in a subject, where the cancer-associated cell has LRRC15 or an epitope of LRRC15 presented on its surface, where the method includes: 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 a population of the cancer-associated cells.

[0319] Also provided herein are methods of treating a cancer characterized by having a population of cancer cells, cancer associated fibroblasts (CAFs), and / or stromal cells that have LRRC15 or an epitope of LRRC15 presented on their surface, the method including: 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, CAFs, and / or stromal cells.

[0320] Also provided herein are methods of reducing the volume of a tumor in a subject, where the tumor is characterized by having a population of cancer cells, CAFs, and / or stromal cells that have LRRC15 or an epitope of LRRC15 presented on their surface, the method including: 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, CAFs, and / or stromal cells.

[0321] Also provided herein are methods of inducing cell death in a cancer cell, CAF, and / or stromal cell in a subject, where the cancer cell, CAF, and / or stromal cell has LRRC15 or an epitope ofLRRC15 presented on its surface, where the method includes: administering a therapeutically effective amount of any of the pharmacal compositions described herein or any of the ABPCs described herein to a subject identified as having a cancer characterized by having a population of the cancer cells, CAFs, and / or stromal cells.

[0322] Also provided herein are methods of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, where tire cancer is characterized by having a population of cancer cells, CAFs, and / or stromal cells that have LRRC15 or an epitope of LRRC15 presented on their surface the method including: administering a therapeutically effective amount of any one of the pharmacal compositions described herein or any of the ABPCs described herein to a subject identifiedAttorney Docket No: 45395-0070W01as having a cancer characterized by having the population of cancer cells, CAFs, and / or stromal cells.

[0323] In some embodiments, the cancer is a primary tumor. In some embodiments, tire cancer is a metastasis.

[0324] in some embodiments, the cancer is a non-T-cell-infiltrating tumor. In some embodiments, the cancer is a T-cell infiltrating tumor.

[0325] Also provided herein are methods of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, where the cancer is characterized by having a population of cancer cells that have LRRC15 or an epitope of LRRC 15 presented on their surface the method including: 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 the population of cancer cells and / or cancer-associated cells.Definitions

[0326] As used herein, the term “stromal cell" means a cell that is not cancerous but is part of and / or associated with a tumor (e.g., a cancer-associated fibroblast or CAF).

[0327] As used herein, the term “LRRC 15-positive stromal cell" (also, “LRRC 15 -positive CAF") refers to a stromal cell (including a CAF) that expresses LRRC 15 and / or an immunologically equivalent portion thereof on its cellular surface. LRRC 15 -positive stromal cells may be detected using techniques known in the art (e.g., tumor biopsy followed by immunohistochemistry using reagents capable of detecting LRRC 15 -positivity; e.g., an LRRC 15 -specific IHC assay). Such detection methods may be performed prior to, during, and after treatment of a subject or patient.

[0328] As used herein, the term “antigen-binding protein construct" is (i) a single polypeptide that includes at least one ABD or (ii) a complex of two or more polypeptides (e.g., the same or different polypeptides) that together form at least one ABD. Non-limiting examples and aspects of antigen-binding protein constructs are described herein. Additional examples and aspects of antigen-binding protein constructs are known in the art.

[0329] A “multispecific ABPC" is an ABPC that includes two or more different ABDs that collectively specifically bind two or more different epitopes. The two or more different epitopes may 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 present on the surface of different cells). In some aspects, the antigen is present on the surface of the cell. In some aspects, a multi-specific ABPC binds two different epitopes (i.e.. a “bispecific ABPC"). In some aspects, a multi-specific ABPC binds three different epitopes (i.e., a “trispecific ABPC"). In some aspects, a multi-specific ABPC binds four different epitopes (i.e., a “quadspecific ABPC”). In some aspects, a multi -specific ABPC binds five different epitopes (i.e., a “quintspecific ABPC”). Each binding specificity may be present in any suitable valency. Non-limiting examples of multi-specific ABPC s are described herein.

[0330] An “Antigen-Binding Domain” (also “ABD”) is one or more protein domain(s) (e.g., formed from amino acids from a single polypeptide or formed from amino acids from two or more polypeptides (e.g., theAttorney Docket No: 45395-0070W01same or different polypeptides)) that is capable of specifically binding to one or more different antigen(s). In some examples, an ABD can bind to an antigen or epitope with specificity and affinity similar to that of naturally-occurring antibodies. In some embodiments, the first and / or second ABD can be an antibody or a fragment thereof. In some embodiments, an ABD can include an alternative scaffold. In other embodiments, the ABD is an ABD formed by a VH-VL dimer. In still other embodiments, the ABD can bind to a single antigen. Non-limiting examples of ABDs are described herein and additional examples of ABDs are known in the art.

[0331] Hie tenn “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules that include one or more ABDs that specifically bind to an antigen or epitope. An antibody specifically includes, e.g., intact antibodies (e.g., intact immunoglobulins, e.g., human IgG (e.g., human IgGl, human IgG2, human IgG3, human IgG4)), antibody fragments, and multi-specific antibodies. Additional examples of an antibody are described herein. Additional examples of an antibody are known in the art.

[0332] As used herein, “framework regions” or “FRs” refer to the non-CDR portions of the variable domains of the heavy and light chains. Specifically, each variable domain comprises four framework regions (FR1, FR2, FR3, and FR4) which are the more conserved portions of the variable domain that serve to position and align the CDRs for proper antigen interaction. In the heavy chain variable domain, FR1 includes amino acid positions 1-30, FR2 includes positions 36-49, FR3 includes positions 66-94, and FR4 includes positions 103-113, based on Kabat numbering. In the light chain variable domain, FR1 includes amino acid positions 1-23, FR2 includes positions 35-49, FR3 includes positions 57-88, and FR4 includes positions 98-107, based on Kabat numbering. Framework regions provide the scaffold that positions the CDRs (which are interspersed between the FRs) in the correct spatial orientation for antigen binding.

[0333] The phrase “endosomal / lysosomal pathway” refers to a network of endosomes (early endosomes, multi-vesicular bodies, late endosomes, and lysosomes) in the cytoplasm of a mammalian cell, wherein molecules are internalized through cell-mediated internalization processes, e.g., pinocytosis, micropinocytosis, receptor-mediated endocytosis, and / or phagocytosis, are sorted.

[0334] Once the endosomes in the endosomal / lysosomal pathway are purified or isolated, assays for a target protein (e.g., an antigen-binding protein construct described herein) can be performed using methods known in the art (ELISA, Western blot, immunofluorescence, and immunoprecipitation followed by an assay for protein concentration), and can be used to determine the concentration or relative level of the target protein in the endosomes. Alternatively, endosomes in the endosomal / lysosomal pathway can be imaged using immunofluorescence microscopy using a detectably-labelled antibody (e.g., a fluorophore-labelled, a dye-labelled, or a GFP-labelled antibody, e.g., CellLight™ Early Endosome-GFP) that specifically binds to a characteristic protein present in the endosomes (e.g., EEA1 for early endosomes) and a fluorophore-labelled antibody that specifically binds to the protein of interest (e.g., an ABPC), and the level of the target protein in the endosomes can be determined by quantitation of the overlap in the fluorescence emissions of the twoAttorney Docket No: 45395-0070W01different antibodies.

[0335] Tire phrase “endolysosomal delivery" refers to rate of accumulation over time or the total accumulation at a specific timepoint of an ABPC (e.g., any of the ABPCs described herein) in the endosomal / lysosomal pathway in a mammalian cell (e.g., any of the exemplary target mammalian cells described herein).

[0336] An exemplary method to calculate the increase in endolysosomal delivery of a pH engineered ABPC variant as compared to its corresponding starting ABPC from cellular fluorescence data is to measure the ratio of the variant’s mean fluorescence intensity minus the mean fluorescence intensity of a non-binding IgG control, then all divided by the variant's corresponding starting ABPC’s mean fluorescence intensity minus the mean fluorescence intensity of the IgG control.

[0337] An exemplary assay for measuring endolysosomal delivery of any of the ABPCs described herein include those which involve labeling of an ABPC with a fluorescent dye, followed by incubation of the labeled ABPC with cells and measurement of cellular fluorescence as an indicator of endolysosomal delivery of the ABPC (e.g., as described generally in Wustner, Traffic 7(6):699-715. 2006). Alternatively, pH-sensitive dyes which preferentially fluoresce at acidic pH but not neutral pH can be used to label any of the ABPCs described herein, which can then be incubated with cells and the cellular fluorescence measured as an indicator of delivery of the ABPC into acidic endolysosomal compartments.

[0338] As used herein, unless otherwise indicated by the context, “the CDRs of’ mean the amino acid residues of a given antigen binding domain (e g., a heavy chain variable domain (HCVD) or a light chain variable domain (LCVD)). Unless otherwise stated or otherwise expressly indicated by the context, CDRs of a given heavy chain variable domain or light chain variable domain are determined by including the amino acid residues falling under either or both the Kabat and IMGT CDR definitions (hereafter “Kabat-IMGT"). Where a specific system for determining CDR residues is intended, such system may be included parenthetically, e.g., “the CDRs (Kabat-IMGT) of...”, “the CDRs (Kabat) of...”, “the CDRs (IMGT) of...”, “the CDRs (Chothia) of...”, and the like. Accordingly, as used herein and unless otherwise specified “the CDRs of’ means “the CDRs (Kabat-IMGT) of’.

[0339] For example, the CDRs of (or the CDRs (Kabat-IMGT) of) the heavy chain variable domain sequence having the sequence of SEQ ID NO: 741 are as set forth in the sequences of SEQ ID NOs: 743, 744, and 745, respectively; the CDRs of the light chain variable domain sequence having the sequence of SEQ ID NO: 742 are as set forth in the sequences of SEQ ID NOs: 746, 747, and 748; the CDRs of the sequence of SEQ ID NO: 749 are as set forth in the sequences of SEQ ID NOs: 751, 752, and 753: and the CDRs of the sequence of SEQ ID NO: 750 are as set forth in the sequences of SEQ ID NOs: 754, 755, and 756. Likewise, “the HCDRs of’ means the CDRs of the HCVD and “the LCDRs of’ means the CDRs of the LCVD.

[0340] The term “population” when used before a noun means two or more of the specific 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.Attorney Docket No: 45395-0070W01

[0341] The phrase “cytostatic to a cell” refers to a direct or indirect decrease in the proliferation (cell division) of the cell (e.g., a cancer cell) in vivo or in vitro. When an agent is cytostatic to a cell, the agent can, e.g., directly or indirectly result in cell cycle arrest of the cell (e.g.. a cancer cell). In some examples, an agent that is cytostatic to a cell can reduce the number of cells in a population of the cells that are in S phase (as compared to the number of cells in a population of the cells that are in S phase prior to contact with the agent). In some examples, an agent that is cytostatic to a cell can reduce the percentage of the cells in S phase by at least 20%, at least 40%, at least 60%, or at least 80% (e.g., as compared to the percentage of cells in a population of the cells that are in S phase prior to contact with the agent).

[0342] The phrase "cytotoxic to a cell” refers to the inducement, directly or indirectly, in the death (e.g., necrosis or apoptosis) of the cell (e.g., a mammalian cell, e g., a cancer cell).

[0343] “Affinity” refers to the strength of the sum total of non-covalent interactions between an antigenbinding site and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1: 1 interaction between members of an ABD and an antigen or epitope. The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity? can be determined, e.g., using surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®). Additional methods for determining the affinity' for an ABD and its corresponding antigen or epitope are known in the art.

[0344] The term “epitope” means a portion of an antigen that is specifically bound by an ABD through a set of physical interactions between: (i) all monomers (e.g. individual amino acid residues, sugar side chains, and post-translationally modified amino acid residues) on the portion of the ABD that specifically binds 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, e.g., consist of surface-accessible amino acid residues, sugar side chains, phosphorylated amino acid residues, methylated amino acid residues, and / or acetylated amino acid residues and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that binding to the former, but not the latter, may be lost in the presence of denaturing solvents. In some embodiments, an epitope is defined by a linear amino acid sequence of at least about 3 to 6 amino acids, or about 10 to 15 amino acids. In some embodiments, an epitope refers to a portion 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 discontinuous amino acid sequence that is brought together via protein folding. In some embodiments, an epitope is defined by a discontinuous amino acid sequence that is brought together by? quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequences between the residues that define the epitope may not be critical to three-dimensional structure of the epitope. A conformational epitope may be determined and screened using assaysAttorney Docket No: 45395-0070W01that compare binding of antigen-binding protein construct to a denatured version of the antigen, such that a linear epitope is generated. An epitope may include amino acid residues that are directly involved in tire binding, and others, which are not directly involved in the binding.

[0345] “Epitope binning” is known in the art. Briefly here, antibodies against a target antigen are tested against other antibodies in a pairwise fashion to determine whether antibodies specifically block one another's binding to the epitope of an antigen. As discussed herein, an antibody is deemed to be a member of the same bin (or epitope bin) when it can substantially, including completely, prevent the binding of a reference member of the bin. According, “bin member” means one of the binders that recognizes a given “epitope bin” (or simply “bin”) of a given antigen (e.g., LRRC15).

[0346] Methods for identifying an epitope to which an ABD specifically binds are known in the art, e.g., structure-based analysis (e.g. X-ray crystallography, NMR, and / or electron microscopy) (e.g. on the antigen and / or the antigen-ABD complex) and / or mutagenesis-based analysis (e.g. alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis) wherein mutants are measured in a binding assay with a binding partner, many of which are known in the art.

[0347] The phrase “present on the surface of a mammalian cell” means (1) an antigen that physically attached to or at least partially embedded in the plasma membrane of a mammalian cell (e.g., a transmembrane protein, a peripheral membrane protein, a lipid-anchored protein (e.g., a GPI -anchor), an N-myristoylated protein, or a S-palmitoylated protein) or (2) an antigen that is stably bound to its cognate receptor, where the cognate receptor is physically attached to the plasma membrane of a cell (e.g., a ligand bound to its cognate receptor, where the cognate receptor is physically attached to the plasma membrane). Non-limiting methods for determining the presence of antigen on the surface of a mammalian cell include fluorescence-activated cell sorting (FACS), immunohistochemistry, cell-fractionation assays and Western blotting.

[0348] When used in the context of pH-engineered antigen binding protein constructs, the phrase “control ABPC” or “control antigen-binding protein construct” means (i) an ABPC that is capable of specifically binding to LRRC15 or an epitope of LRRC15 presented on the surface of a mammalian cell (e.g.. a target mammalian cell), where one or both of the following is true: (a) the dissociation rate of the first ABD at a pH of ~4.0 to ~6.5 (e.g., any of the subranges of this range described herein) is no more than 3-fold (e.g., no more than 2.8-fold, no more than 2.6-fold, no more than 2.5-fold, no more than 2.4-fold, no more than 2.2-fold, no more than 2.0-fold, no more than 1.8-fold, no more than 1.6-fold, no more than 1.5-fold, no more than 1.4-fold, no more than 1.2-fold, no more than 1.0-fold, no more than 0.8-fold, no more than 0.6-fold, no more than 0.5-fold, no more than 0.4-fold, no more than 0.3-fold no more than 0.2-fold, or no more than 0.1-fold) faster than the dissociation rate at a pH of ~7.0 to ~8.0 (e.g., any of the subranges of this range described herein); or (b) the dissociation constant (KD) of the first ABD at a pH of ~4.0 to ~6.5 (e.g., any of the subranges of this range described herein) is no more than 3-fold (e.g., no more than 2.8-fold, no more than 2.6-fold, no more than 2.5-fold, no more than 2.4-fold, no more than 2.2-fold, no more than 2.0-fold, no more than 1.8-fold, no more thanAttorney Docket No: 45395-0070W011.6-fold, no more than 1.5-fold, no more than 1.4-fold, no more than 1.2-fold, no more than 1.0-fold, no more than 0.8-fold, no more than 0.6-fold, no more than 0.5-fold, no more than 0.4-fold, no more than 0.3-fold no more than 0.2-fold, or no more than 0.1-fold) greater than the KD at a pH of ~7.0 to ~8.0 (e.g., any of the subranges of this range described herein): (ii) a 54F1 ABPC having the VH and VL domains set forth in SEQ ID NOs: 741 and 742, respectively; (iii) a 56F3 ABPC having the VH and VL domains set forth in SEQ ID NOs: 749 and 750, respectively; (iv) a 15G7 ABPC having the VH and VL domains set forth in SEQ ID NOs: 382 and 455, respectively; and / or (v) a 24D9 ABPC having the VH and VL domains set forth in SEQ ID NOs: 516 and 522, respectively.

[0349] The term “extracellular space” means the liquid exterior to the plasma membrane of a mammalian cell. When a mammalian cell is in vitro, the extracellular space can be a liquid culture medium. When a mammalian cell is in vivo, the extracellular space can be, e.g., plasma, serum, blood, interstitial fluid, or lymph.

[0350] The term “endolysosomal space” means the fluid encapsulated by the vesicles and organelles that make-up the endosomal / lysosomal pathway in a mammalian cell.

[0351] The phrase “a reduced level” or “a decreased level” can be a reduction or decrease of at least a 1% (e.g., at least a 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least a 99%) reduction as compared to a reference level or value.

[0352] The tenn “cell killing potency” refers to the ability of an agent (e.g., any of the ABPCs described herein) to induce, directly or indirectly, the apoptosis and / or necrosis of a mammalian cell (e.g.. a cancer cell), measured as a rate over time or at a relevant timepoint. Methods for determining the cell killing potency of a cell are known in the art (e g., trypan blue staining, microscopy, fluorescence-assisted cell sorting, and assays to detect markers of apoptosis (e.g., Annexin V)). In non-limiting examples, cell killing potency can be measured, e.g., by cell killing at a single concentration of an agent, by the IC50 of the agent (i.e., the concentration of tire agent whereby half the maximal cell killing potency is achieved), or by the ratio of an agent’s dissociation constant KD on mammalian cells divided by its IC50. In some non-limiting examples, the IC50s and / or the KD ratios described herein are compared to those of a control ABPC (as defined herein), and, optionally, demonstrate that the ABPCs described herein have a higher cell killing potency as compared to the control ABPC.

[0353] Hie term “toxin liberation” 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 ABPCs or control ABPCs described herein) that are conjugated to a toxin, and subsequently release the toxin conjugated to the ABPC, measured as a rate over time or at a specific timepoint. Toxin liberation can be assessed using a variety of different exemplary assays, e.g., ELISA, immunofluorescence, cell killing assays, cell cycle arrest assays, DNA damage assays, mass spectrometry, HPLC, and / or an isotope-labeled toxin.Attorney Docket No: 45395-0070W01

[0354] The phrase “target cell” or “target mammalian cell” or “mammalian target cell” means a mammalian cell that has at least one LRRC15 present on its surface. In some examples, a mammalian target cell can be a cancer cell. In some embodiments of a target mammalian cell can have a total of about the following (each ± about 10%): 1 to 10E6, 1 to 9E6, 1 to 8E6, 1 to 7E6, 1 to 6E6, 1 to 5E6, 1 to 4E6, 1 to 3E6, 1 to 2E6, 1 to 1E6, 1 to 800,000, 1 to 600,000, 1 to 400,000, 1 to 200,000, 1 to 100,000, 1 to 80,000, 1 to 80,000, 1 to 75,000, 1 to 70,000, 1 to 65,000, 1 to 60,000, 1 to 55,000, 1 to 50,000, 1 to 45,000, 1 to 40,000, 1 to 35,000, 1 to 30,000, 1 to 25,000, 1 to 20,000, 1 to 15,000, 1 to 10,000, 1 to 7,500, 1 to 5,000, 1 to 4,000, 1 to 3,000, 1 to 2,000, 1 to 1,000, 1 to 500, 1 to 100, 1 to 50, or 1 to 10, or any of the ranges of numbers recited in paragraph

[0065] of US 2022 / 0281984, of the LRRC15 present on the plasma membrane of the target mammalian cell.

[0355] The phrase “antigen density ” means the number of LRRC15 present on the surface of a target mammalian cell or the average number of LRRC 15 on the surface of a population of particular type of target mammalian cells. It can be measured, e.g., using the Quantibright bead kit or radiolabel (e.g., BD Biosciences PE Phycoerythrin Fluorescence Quantitation Kit, catalog #340495).

[0356] The phrase “amino acid substituted with a histidine” means the substitution of an amino acid residue that is not histidine in a reference polypeptide sequence with a histidine. Non-limiting methods for substituting an amino acid residue in a reference polypeptide with a histidine are described herein. Additional methods for substituting an amino acid residue in a reference polypeptide with a histidine are known in the art.

[0357] The phrase “amino acid substituted with an alanine” means 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.

[0358] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention: other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0359] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.BRIEF DESCRIPTION OF DRAWINGS

[0360] FIGs. 1A to 1C are schematic diagrams of anti-LRRC15 antibodies having 0, 1, or 2 pH-dependent antigen binding domains (ABDs).

[0361] FIG. 1A depicts a biparatopic anti-LRRC15 antibody having 2 pH-dependent arms.

[0362] FIG. IB depicts a biparatopic anti-LRRC15 antibody having 0 pH-dependent arms.Attorney Docket No: 45395-0070W01

[0363] FIG. 1C depicts a biparatopic anti-LRRC15 antibody having 1 pH-dependent arm.

[0364] FIG. ID depicts a biparatopic anti-LRRC15 antibody having a 54F1 ABD and a 15G7-var ABD.

[0365] FIG. IE depicts a bispecific antibody comprising an anti-GP120 IgG component (left of vertical dashed line) and a biparatopic anti-LRRC15 component.

[0366] FIG. IF depicts a bispecific antibody comprising an anti-Tumor-associated antigen (TAA) IgG component (left of vertical dashed line) and a biparatopic anti-LRRC15 component.

[0367] FIG. 1G depicts a monospecific and monoparatopic anti-TAA IgG-formatted antibody.

[0368] FIGs.2A & 2B are octet plots forhu54Fl (MYT8150) and hu56F3 (MYT8159). 2A: Yaxes are fixed; 2B: Y axes are automatically applied to maximize vertical separation; Y-Axis Minor Tick = 0.1 nM; Y-Axis Major Tick = 0.4 nM; X-Axis Minor Ticks = 20 seconds; X-Axis Major Ticks = 100 seconds. Grey and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0369] FIG. 3A is a graph showing the binding of the indicated control or ADC test article as a function of mean fluorescent intensity (MFI) vs. concentration.

[0370] FIG. 3B is a graph showing bystander killing efficacy of tire indicated control or ADC test article expressed as fold over samrotamab-vedotin (hinge conjugated, HIC-purified DAR2).

[0371] FIG. 3C is a graph showing bystander killing efficacy of tire indicated control or ADC test article expressed as fold over samrotamab-vedotin (hinge conjugated, HIC-purified DAR2).

[0372] FIG. 4A is a graph of median SA3851 tumor volume (TV) in mouse-LRRC15 (i.e., wildtype for the LRRC15 gene) mice at days post a single administration of the indicated controls (vehicle, NTC-MMAE mpADC (0 pH-arms), and samrotamab-vedotin mpADC (0 pH-arms, hinge conjugated, HIC-purified DAR2) and test articles (hu15G7 parent-MMAE mpADC (DAR2, 0 pH-arms), hu15G7 pH-Engineered-MMAE mpADC (DAR2, 2 pH-arms), and hu29F1-pH-dep-MMAE mpADC (DAR2, 2 pH-arms).

[0373] FIG. 4B is a graph of median EBC-1 tumor volume in huLRRC15 mice at days post a single administration of the indicated controls (vehicle, NTC-MMAE mpADC (DAR2, 0 pH-arms), and samrotamab-vedotin mpADC (0 pH-arms, hinge conjugated, HIC-purified DAR2)) and test articles (hu15G7 parent-MMAE mpADC (DAR2, 0 pH-dep arms), hu15G7 pH-Engineered-MMAE mpADC (DAR2, 2 pH-arms), and hu29F1 pH-dependent-mpADC (DAR2, 2 pH-arms).

[0374] FIG. 4C is a graph of median EBC-1 tumor volume in huLRRC15 mice at days post a single administration of the indicated controls: vehicle, NTC-MMAE mpADC (DART, 0 pH-arms), and test articles: hu15G7 parent-MMAE mpADC (DAR2, 0 pH-arms), hu15G7 pH-Engineered-MMAE mpADC (DAR2, 2 pH-arms), 159-MMAE bpADC (DAR2, 1 pH-arm), 162-MMAE bpADC (DAR2, 0 pH-arms), and 164-MMAE bpADC (DAR2, 0 pH-arms).

[0375] FIG. 5A depicts immunohistochemistry’ (IHC) micrographs showing LRRC15 expression in HCC 1806, JIMT-1, and HCC 1954 human breast cancer tumors.

[0376] FIG. 5B is a graph of median HCC 1806 (TNBC) tumor volume in huLRRC15 mice at days post aAttorney Docket No: 45395-0070W01single administration (and selective redosing) of the indicated controls: vehicle, NTC-MMAE mpADC (DAR2, 0 pH-arms), and test articles: Samrotamab monoparatopic ADC (DAR2, 0 pH-arms), 159-MMAE bpADC (DAR2, 1 pH-arm), and 162-MMAE bpADC (DAR2, 0 pH-anns). The samrotamab-vedotin mpADC group was redosed as indicated by the arrow below the x-axis.

[0377] FIG. 5C is a graph of median JIMT-1 (HR- / HER2+) tumor volume in huLRRC15 mice at days post a single administration (and selective redosing) of the indicated controls: vehicle, NTC-MMAE mpADC (DART, 0 pH-arms). and samrotamab-vedotin mpADC (0 pEI-anns, hinge conjugated, HIC-purified DAR2), and test articles: 159-MMAE bpADC (DAR2, 1 pH-arm), and 162-MMAE bpADC (DART, 0 pH-arms).

[0378] FIG. 5D is a graph of median HCC 1954 (HR- / HER2+) tumor volume in huLRRC15 mice at days post a single administration (and selective redosing) of the indicated controls: vehicle, NTC-MMAE mpADC (0 pH-arms), and samrotamab-vedotin mpADC (0 pH-arms, hinge conjugated, HIC-purified DART), and test articles: 159-MMAE bpADC (DAR2, 1 pH-arm) and 162-MMAE bpADC (DAR2, 0 pH-arms).

[0379] FIG.6A depicts IHC micrographs showing LRRC15 expression in NCI -Hl 650 cells (lung tissue from a bronchoalveolar carcinoma patient) and EBC-1 (squamous cell carcinoma of the lung. Met-amplified).

[0380] FIG. 6B is a graph of median NCI-H1650 tumor volume at days post a single administration (and selective redosing) of the indicated controls and test articles to huLRRC 15 mice: vehicle, NTC-MMAE mpADC (DART, 6 mg / kg, 0 pH-arms), samrotamab-vedotin mpADC (6 mg / kg, 0 pH-arms, hinge conjugated, HIC-purified DAR2). 159-MMAE bpADC (DART, 6 mg / kg, 1 pH-ami), 159-MMAE bpADC (3 mg / kg, DART, 1 pH-arm), 162-MMAE bpADC (DAR2, 6 mg / kg. 0 pH-arms), and 162-MMAE bpADC (3 mg / kg, DAR2, 0 pH-arms). The 162-MMAE bpADC and 159-MMAE bpADC 6 mg / kg groups were redosed on the days indicated by the first and second arrows, respectively.

[0381] FIG.6C is a graph of median EBC- 1 tumor volume at days post a single administration (and selective redosing) of the indicated controls and test articles to huLRRC15 mice: vehicle, NTC-MMAE mpADC (0 pH-arms). samrotamab-vedotin mpADC (0 pH-arms, hinge conjugated, HIC-purified DART), 159-MMAE bpADC (DAR2, 6 mg / kg, 1 pH-arm), 159-MMAE bpADC (DAR2, 3 mg / kg, 1 pH-arm), 162-MMAE bpADC (DAR2, 6 mg / kg, 0 pH-arms), and 162-MMAE bpADC (DAR2, 3 mg / kg, 0 pH-arms). The 162-MMAE bpADC and 159-MMAE bpADC 6 mg / kg groups were redosed on the days indicated by the top and bottom arrows.

[0382] FIG. 6D is a graph of median EBC-1 tumor volume at days post a single administration (Q2Wx6 dosing) of the indicated controls and test articles to huLRRC15 mice: vehicle, NTC-MMAE mpADC (0 pH-arms), samrotamab-vedotin mpADC (0 pH-arms, hinge conjugated, HIC-purified DART), 159-MMAE bpADC (DAR2, 6 mg / kg, 1 pH-arm), and 162-MMAE bpADC(DAR2, 6 mg / kg, 0 pH-arms). Each group was redosed every 2 weeks (arrows).

[0383] FIG. 6E is a graph of median EBC-1 tumor volume in huLRRC 15 mice at days post a single administration of the indicated controls and test articles to huLRRC 15 mice: vehicle, NTC-MMAE mpADC (DART, cell membrane permeable toxin, 0 pH-arms), samrotamab-MMAE mpADC (DART, cell membraneAttomey Docket No: 45395-0070W01permeable toxin, 0 pH-arms), samrotamab-MMAF mpADC (DAR2, cell membrane impermeable toxin, 0 pH-anns), 162-MMAE bpADC (DAR2, cell membrane permeable toxin, 6 mg / kg, 0 pH-arms), and 162-MMAF bpADC (DAR2. cell membrane impenneable toxin, 6 mg / kg, 0 pH-arms).

[0384] FIG. 6F is a graph of median EBC-1 tumor volume in huLRRC 15 mice at the indicated time points post a single administration of the indicated controls (except for samrotamab-vedotin, which was dosed as indicated by the arrows beneath the x-axis) and test articles to huLRRC 15 mice: vehicle, NTC-MMAE mpADC (DAR2, 0 pH-arms, single dose), samrotamab-vedotin mpADC (0 pH-arms, Q2Wx3 dosing, hinge conjugated, HIC-purified DAR2), 162-MMAE bpADC (DAR2, 6 mg / kg, 0 pH-arms, single dose), and 162-MMAE bpADC (DAR2, 6 mg / kg, 0 pH-arms, single dose).

[0385] FIG. 7A is a graph of median JIMT-1 tumor volume at the indicated time points post a single administration (with Q2Wx3 dosing thereafter) of the indicated controls and test articles to huLRRC 15 mice: vehicle, NTC-MMAE bpADC (DART, 6 mg / kg, 0 pH-arms), samrotamab-vedotin mpADC (6 mg / kg, 0 pH-arms, hinge conjugated, HIC-purified DART), 159-MMAE bpADC (DART, 6 mg / kg. 1 pH-ami), and 162-MMAE bpADC (DART, 6 mg / kg. 0 pH-arms). Each group was redosed every 2 weeks (arrows).

[0386] FIG. 7B is a graph showing the tumor volume for each in huLRRC15 mouse in the 159-MMAE bpADC (DAR2, 6 mg / kg, 1 pH-arm) group.

[0387] FIG. 8A is a graph showing total ADC concentration at the indicated time points post administration of the following ADCs to non-tumor bearing huLRRC15 mice: NTC-MMAE mpADC (DART, 0 pH-anns), samrotamab-vedotin mpADC (0 pH-anns, hinge conjugated, HIC-purified DART). hul5G7-parent-MMAE mpADC (DART, 0 pH-arms), hul5G7-pH-engineered-MMAE mpADC (DART, 2 pH-arms), and hu29Fl-naturally-pH-dependent-MMAE mpADC (DART, 2 pH-arms). Total ADC was measured using an anti-MMAE capture antibody to pull down conjugated antibodies.

[0388] FIG.8B is a graph showing total IgG concentration at the indicated time points post administration of the following ADCs to non-tumor bearing huLRRC 15 mice: 1) NTC-MMAE mpADC (DART, 0 pH-arms). 2) hul5G7-pH-engineered-MMAE mpADC (DART, 2 pH-arms), 159-MMAE bpADC (DART, 1 pH-arm) and 162-MMAE bpADC (DAR2, 0 pH-arms).

[0389] FIG. 9A is a graph showing total ADC concentration at the indicated time points post administration of the following ADCs to cynomolgus monkeys: 1) NTC-MMAE mpADC (DART, 0 pH-anns), 2) samrotamab-vedotin mpADC (0 pH-arms, hinge conjugated, HIC-purified DART), 3) hul5G7 parental-MMAE mpADC (DART, 0 pH-anns), 4) hul5G7 pH-engineered-MMAE mpADC (DART, 2 pH-arms), and 5) hu29Fl naturally-pH-dependent-MMAE mpADC (DAR2, 2 pH-arms).

[0390] FIG. 9B is a graph showing total human IgG concentration at the indicated time points post administration of the following ADCs to cynomolgus monkeys: 1) NTC-MMAE mpADC (DAR2, 0 pH-arms), 2) hul5G7 pH-engineered-MMAE mpADC (DART, 2 pH-arms), 3) 159-MMAE bpADC (DAR2. 1 pH-arm = “half-pH-dependent”), 4) 162-MMAE bpADC (DAR2, 0 pH-arms), and 5) 164-MMAE bpADC (DAR2, 0 pH-Attorney Docket No: 45395-0070W01arms).

[0391] FIGs. 10A & 10B are octet plots for 66H2 (MYT13620) heavy chain variable domain (HCVD) variants (MYT16007 to MYT16044). 2A: Y axes are fixed; 2B: Y axes are automatically applied to maximize vertical separation; Y-Axis Minor Tick = O.lnM Y-Axis Major Tick = 0.5nM; X-Axis Minor Ticks = 20 seconds; X-Axis Major Ticks = 100 seconds. Grey and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0392] FIGs. 11A & 11B are octet plots for 66H2 (MYT13620) light chain variable domain (LCVD) pairing variants (MYT16045 to MYT16071). 3A: Y axes are fixed; 3B: Y axes are automatically applied to maximize vertical separation; Y-Axis Minor Tick = O.lnM Y-Axis Major Tick = 0.5nM; X-Axis Minor Ticks = 20 seconds; X-Axis Major Ticks = 100 seconds. Grey and black lines correspond to pH 5.4 and pH 7.4, respectively.

[0393] FIGs. 12A & 12B are octet plots for 66H2 (MYT13620) heavy chain variable domain combination (HCC) variants (MYT17069 to MYT17088). 4A: Y axes are fixed; 4B: Y axes are automatically applied to maximize vertical separation; Y-Axis Minor Tick = O.lnM: Y-Axis Major Tick = 0.4 nM; X-Axis Minor Ticks = 20 seconds; X-Axis Major Ticks = 100 seconds. Grey and black lines correspond to pH 5.4 and pH 7.4, respectively.DETAILED DESCRIPTION

[0394] Antibody-drug-conjugates (ADCs) have been designed to combat a variety of diseases. One particular advantage of this approach is the ability for ADCs to have cytostatic or cytotoxic effects. Despite years of development, improved ADCs are desired. In particular, while there is an increasing number of approved and late-stage clinical ADCs targeting antigen-positive tumor cells, such ADCs are largely effective only against tumor cells expressing the highest levels of target antigen. And even more elusive has been the development of an ADC capable of targeting antigen-positive non-tumor cells (e.g., “stroma” including cancer associated fibroblasts or CAFs).

[0395] In an aspect, the disclosure is based in part on the unexpected finding that certain biparatopic antibody drug-conjugates (ADCs) specific for at least two epitopes of human LRRC15 are effective against LRRC15-tumor-positive cancer indications as well as LRRC 15 -stroma-positive / LRRC 15 -tumor-negative cancer indications.

[0396] In another aspect, the disclosure provides unexpected results indicating that biparatopic anti-LRRC15 ADCs containing 0 or 1 pH-dependent antigen binding domains (“pH-ABD”; “pH-arm”) exhibit increased killing of LRRC 15 -positive cells in vitro and increased efficacy against LRRC 15 -stroma-positive cancer cells in mouse models of various cancers as compared to corresponding monoparatopic anti-LRRC15 ADCs containing 2 pH-arms. As used herein, unless otherwise indicated by the context, “pH-dependent binding” and “pH-sensitive binding” mean that a given antigen-binding protein construct (ABPC) or ABD binds well to LRRC 15 at about physiological pH (e.g., a pH of about 7.4) but not well at about late endolysosomal / lysosomalAttorney Docket No: 45395-0070W01pH (e.g., a pH of about 5.4).

[0397] In another aspect, the disclosure provides evidence that biparatopic anti-LRRC15 antibodies having 1 pH-arm. but not 0 or 2 pH-arms, exhibit more favorable pharmacokinetic properties (e.g., longer half-life) in non-human primates.

[0398] In another aspect, the disclosure provides antigen-binding protein constructs (ABPCs) that include: a first and / or a second ABD each capable of specifically binding a first and / or second epitope of LRRC15 presented on the surface of a target mammalian cell, where: (a) the dissociation rate of the first ABD at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; and / or (b) the dissociation constant (KD) of the first ABD at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0.

[0399] In some embodiments of any aspect of this disclosure, the ABPC is degraded in the target mammalian cell following internalization of the ABPC by the target mammalian cell.

[0400] In some embodiments, the ABPCs described herein further include a conjugated “cargo”, including but not limited to a toxin, radioisotope, drug, other small molecule (e.g., a fluorophore or dye), nucleic acid, immune modulator, optionally wherein the cargo is conjugated to the ABPC via a linker.

[0401] In some embodiments, tire first and second epitopes of LRRC15 are distinct epitopes or substantially non-overlapping epitopes.

[0402] In yet another aspect, the disclosure provides antigen-binding protein constructs (ABPCs) that include: a first and / or a second ABD that is capable of specifically binding a first and / or second epitope of LRRC15 presented on the surface of a target mammalian cell; and a conjugated cargo including but not limited to a toxin, radioisotope, drug, or small molecule, where the ABPC provides for an increase (e.g., a detectable increase) in the depth of target mammalian cell killing as compared to a composition comprising the same amount of a control ABPC. In some embodiments, the cargo is conjugated to the cargo via a linker.

[0403] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 54F1, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 54F1, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, tire first ABD includes an HCVD of 54F1, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 54F1, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 54F 1 comprises the sequence of SEQ ID NO: 741. In some embodiments, the LCVD of 54F1 comprises the sequence of SEQ ID NO: 742. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 741 comprise a total of one or more amino acid positions in SEQ ID NO: 741 substituted with a histidine selected from SEQ ID NO: 741 positions 34, 35, 54, 55, 58, 97, 103, 110, and 111, such substitution reflecting a “pH-dependent binding substitution”, and the LCVD of SEQ ID NO: 742 comprises the CDRs in SEQ ID NO: 742. In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 741 comprise a total of one or more amino acid positionsAttorney Docket No: 45395-0070W01in SEQ ID NO: 741 substituted with a histidine selected from SEQ ID NO: 741 positions 26, 27, 28, 29, 30, 31, 33, 52, 53, 60, 61, 62, 63, 64, 96, 98, 99, 101, 106, 109, and 112, and / or the CDRs of tire LCVD of SEQ ID NO: 742 comprise a total of one or more positions in SEQ ID NO: 742 substituted with a histidine selected from SEQ ID NO: 742 positions 24, 30, 31, 32, 33, 34, 50, 51, 52, 53, 54, 55, 56, and 92, such substitution reflecting a ‘'tolerated substitution’’.

[0404] Antigen binding domains (ABDs) described herein containing “pH-dependent binding substitutions” exhibit pH-dependent binding for LRRC15 as compared to control ABDs. In some embodiments, the control ABDs only differ from the substituted ABD by the pH-dependent binding substitution.

[0405] Antigen binding domains (ABDs) described herein containing ‘"tolerated substitutions” exhibit substantially similar binding for LRRCI5 as compared to control ABDs. In some embodiments, the control ABDs only differ from the substituted ABD by the tolerated substitution.

[0406] In some embodiments, the first ABD includes an HCVD of 66H2 with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 66H2 with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 66H2 with one or more total amino acids substituted in the CDRs with a histidine; and an LCVD of 66H2 with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 66H2 comprises SEQ ID NO: 1441. In some Embodiments, the LCVD of 66H2 comprises SEQ ID NO: 1442.

[0407] In some embodiments, the first ABD comprises an HCVD comprising a CDR1, a CDR2. and a CDR3 having the sequences as set forth in SEQ ID NOs: 1443, 1444, and 1445, respectively, optionally with collectively a total of one or more amino acid positions in the sequences of SEQ ID NOs: 1443, 1444, and 1445 substituted with a histidine. In some embodiments, the first ABD comprises an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences as set forth in SEQ ID NOs: 1446, 1447, and 1448, respectively, optionally with collectively a total of one or more amino acid positions in the sequences of SEQ ID NOs: 1446, 1447, and 1448 substituted with a histidine. In some embodiments, the first ABD includes: an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences as set forth in SEQ ID NOs: 1443, 1444, and 1445, respectively, optionally with collectively a total of one or more amino acid positions in the sequences of SEQ ID NOs: 1443, 1444, and 1445 substituted with a histidine; and an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences as set forth in SEQ ID NOs: 1446, 1447, and 1448, respectively, optionally with collectively a total of one or more amino acid positions in the sequences of SEQ ID NOs: 1446. 1447, and 1448 substituted with a histidine.

[0408] In some embodiments, the first ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1441, where tire HCVD includes a histidine at one or more amino acid positions in SEQ ID NO: 1441 selected from: 27, 28, 29, 30, 31. 32. 33, 34, 50, 51, 52, 53, 54, 55, 56, 59. 99. 100, 101. 102, 103, 105, 106, 107, 108,Attorney Docket No: 45395-0070W01and 109, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the CDRs of SEQ ID NO: 1441. In some embodiments, tire first ABD includes an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical to. the sequence of SEQ ID NO: 1442, where the LCVD includes a histidine at one or more amino acid positions in SEQ ID NO: 1442 selected from: 29, 32, 34, 50, 52, 53, 54, 55, 90, 91, 92, 94, 96, and 97, optionally wherein apart from the histidine at the one or more amino acids, the LCVD comprises the CDRs of SEQ ID NO: 1442. In some embodiments, the first ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1441, where the HCVD includes a histidine at one or more amino acid positions in SEQ ID NO: 1441 selected from: 27, 28, 29, 30, 31, 32. 33. 34. 50. 51. 52. 53, 54, 55, 56, 59, 99, 100. 101, 102, 103. 105, 106. 107, 108, and 109, optionally wherein apart from the histidine at the one or more positions, the HCVD comprises the CDRs of SEQ ID NO: 1441; and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1442, where the LCVD includes a histidine at one or more amino acid positions in SEQ ID NO: 1442 selected from: 29, 32, 34, 50, 52, 53, 54, 55, 90, 91, 92, 94, 96, and 97, optionally wherein apart from the histidine at the one or more amino acids, the LCVD comprises the CDRs of SEQ ID NO: 1442.

[0409] In some embodiments, an HCVD includes an HCVD comprising a sequence that is at least 90% (e.g., > 92%, > 94%, > 96%, > 98%, > 99%, or 100%) identical to SEQ ID NO: 1441, where the HCVD includes a histidine at any of the specific combinations of two or more amino acid positions in SEQ ID NO: 1441 listed in Table 2. optionally wherein apart from tire two or more amino acid positions, the HCVD comprises the CDRs of SEQ ID NO: 1441.

[0410] In some embodiments, the first ABD includes: an HCVD that is > 90% (e.g., > 92%, > 94%, > 96%, > 98%, > 99%, or 100%) identical to SEQ ID NO: 1441, where the HCVD includes a histidine at one or more amino acid positions in SEQ ID NO: 1441 selected from: [27, 28, 29, 30, 31, 32, 33, 34, 50, 51, 52, 53, 54, 55, 56, 59, 99, 100, 101, 102, 103, 105, 106, 107, 108, and 109], optionally wherein apart from the histidine at the one or more positions, the HCVD comprises the CDRs of SEQ ID NO: 1441; and an LCVD that is > 90% (e.g., > 92%, > 94%, > 96%, > 98%, > 99%, or 100%) identical to SEQ ID NO: 1442, where the LCVD includes a histidine at one or more amino acid positions in SEQ ID NO: 1442 selected from: [29, 32, 34, 50, 52, 53, 54, 55, 90, 91, 92, 94, 96, and 97], optionally wherein apart from the histidine at the one or more amino acids, the LCVD comprises the CDRs of SEQ ID NO: 1442.

[0411] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1441, where the HCVD includes a histidine at one or more amino acid positions in the sequence of SEQ ID NO: 1441 selected from: 27, 28, 29, 30, 31, 32, 33, 34, 50, 51, 52, 53, 54, 55, 56, 59, 99, 100, 101, 102, 103, 105, 106, 107, 108, and 109, optionally wherein apart from the histidine at the one or more aminoAttorney Docket No: 45395-0070W01acid positions, the HCVD comprises “the CDRs of’ (as defined below) the sequence of SEQ ID NO: 1441.

[0412] In some embodiments, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1442, where the LCVD includes a histidine at one or more amino acid positions in the sequence of SEQ ID NO: 1442 selected from: 29, 32, 34, 50, 52, 53, 54, 55, 90, 91, 92, 94, 96, and 97, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0413] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to. or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1441, where the HCVD includes a histidine at two or more amino acid positions in the sequence of SEQ ID NO: 1441 selected from: 27, 28, 29, 30, 31, 32, 33, 34, 50, 51, 52, 53, 54, 55, 56, 59, 99, 100, 101, 102, 103, 105, 106, 107, 108, and 109, optionally wherein apart from the histidine at the two or more amino acid positions, the HCVD comprises the CDRs of the sequence of SEQ ID NO: 1441.

[0414] In some embodiments, the first or second ABD includes an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1442, where the LCVD includes a histidine at two or more amino acid positions in the sequence of SEQ ID NO: 1442 selected from: 29, 32, 34, 50, 52, 53, 54, 55, 90, 91, 92, 94, 96, and 97, optionally wherein apart from the histidine at the two or more amino acid positions, the LCVD comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0415] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1441, where the HCVD includes a histidine at one or more amino acid positions in the sequence of SEQ ID NO: 1441 selected from: 27, 28, 29, 30, 31, 32, 33, 34, 50, 51, 52, 53, 54, 55, 56, 59, 99, 100, 101, 102, 103, 105, 106, 107, 108, and 109, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the CDRs of the sequence of SEQ ID NO: 1441, and an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1442, where the LCVD includes a histidine at one or more amino acid positions in the sequence of SEQ ID NO: 1442 selected from: 29, 32, 34, 50, 52, 53, 54, 55, 90, 91, 92, 94, 96, and 97, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0416] In some embodiments, the first or second ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1441, where the HCVD includes a histidine at two or more amino acid positions in the sequence of SEQ ID NO: 1441 selected from: 27, 28, 29, 30, 31, 32, 33, 34, 50, 51, 52, 53, 54, 55, 56, 59, 99, 100, 101, 102, 103, 105, 106, 107, 108, and 109, optionally wherein apart from the histidine at the two or more aminoAttorney Docket No: 45395-0070W01acid positions, the HCVD comprises the CDRs of the sequence of SEQ ID NO: 1441, and an LCVD comprising a sequence that is identical to, oris at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to. the sequence of SEQ ID NO: 1442, where the LCVD includes a histidine at two or more amino acid positions in the sequence of SEQ ID NO: 1442 selected from: 29, 32, 34. 50. 52. 53. 54, 55, 90, 91, 92, 94, 96, and 97, optionally wherein apart from the histidine at the two or more amino acid positions, the LCVD comprises the CDRs of the sequence of SEQ ID NO: 1442.

[0417] In some embodiments, the first or second ABD includes an HCVD comprising the sequence as set forth in SEQ ID NO: 1441, one of the sequences of SEQ ID NOs: 1449-1486. or one of the sequences of SEQ ID NOs: 1514-1533.

[0418] In some embodiments, the first or second ABD includes an LCVD comprising the sequence as set forth in SEQ ID NO: 1442, one of the sequences of SEQ ID NOs: 1487-1513, or one of the sequences of SEQ ID NOs: 1534-1553.

[0419] In some embodiments, the first or second ABD includes an HCVD comprising the sequence as set forth in SEQ ID NO: 1441, one of the sequences of SEQ ID NOs: 1449-1486. or one of the sequences of SEQ ID NOs: 1514-1533, and an LCVD comprising the sequence as set forth in SEQ ID NO: 1442, one of the sequences of SEQ ID NOs: 1487-1513, or one of the sequences of SEQ ID NOs: 1534-1553.

[0420] In some embodiments of tire bispecific anti-LRRC15 antibody, the first or second ABD includes an HCVD and an LCVD comprising the HCDRs and the LCDRs of the HCVD and the LCVD sequences, respectively, as set forth in one of the following pairs of sequences: SEQ ID NO: 1453 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1453 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1495, respectively: SEQ ID NO: 1485 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1495, respectively: SEQ ID NO: 1453 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1497, respectively: SEQ ID NO: 1477 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1453 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1503, respectively: SEQ ID NO: 1453 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1507, respectively: SEQ ID NO: 1477 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1507, respectively: SEQ ID NO: 1486 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1495, respectively: SEQ ID NO: 1520 and SEQ ID NO: 1495,Attorney Docket No: 45395-0070W01respectively; SEQ ID NO: 1523 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1497, respectively: SEQ ID NO: 1523 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1497, respectively: SEQ ID NO: 1514 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1507, respectively: SEQ ID NO: 1523 and SEQ ID NO: 1507, respectively; and SEQ ID NO: 1526 and SEQ ID NO: 1507.

[0421] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 765 and 792.

[0422] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 777 and 792.

[0423] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 785 and 792.

[0424] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 786 and 792.

[0425] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 753 and 795.

[0426] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 765 and 795.

[0427] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 777 and 795.

[0428] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 785 and 795.

[0429] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 786 and 795.

[0430] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 753 and 797.

[0431] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 765 and 797.

[0432] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 777 and 797.

[0433] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 785 and 797.

[0434] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 786 and 797.

[0435] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 753 and 803.

[0436] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 765 and 803.

[0437] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 777 and 803.

[0438] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 785 and 803.

[0439] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 786 and 803.

[0440] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 753 and 807.

[0441] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 765 and 807.

[0442] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 777 and 807.

[0443] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 785 and 807.

[0444] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 786 and 807.

[0445] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 814 and 792.Attorney Docket No: 45395-0070W01

[0446] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 817 and 792.

[0447] In some examples, the first ABD comprises tire sequences of SEQ ID NOs: 820 and 792.

[0448] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 823 and 792.

[0449] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 826 and 792.

[0450] In some examples, the first ABD comprises tire sequences of SEQ ID NOs: 814 and 795.

[0451] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 817 and 795.

[0452] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 820 and 795.

[0453] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 823 and 795.

[0454] In some examples, the first ABD comprises tire sequences of SEQ ID NOs: 826 and 795.

[0455] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 814 and 797.

[0456] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 817 and 797.

[0457] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 820 and 797.

[0458] In some examples, the first ABD comprises tire sequences of SEQ ID NOs: 823 and 797.

[0459] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 826 and 797.

[0460] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 814 and 803.

[0461] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 817 and 803.

[0462] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 820 and 803.

[0463] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 823 and 803.

[0464] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 826 and 803.

[0465] In some examples, the first ABD comprises tire sequences of SEQ ID NOs: 814 and 807.

[0466] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 817 and 807.

[0467] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 820 and 807.

[0468] In some examples, the first ABD comprises tire sequences of SEQ ID NOs: 823 and 807.

[0469] In some examples, the first ABD comprises the sequences of SEQ ID NOs: 826 and 807.

[0470] In some examples, the ABPC further comprises a second ABD.

[0471] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 765 and 792.

[0472] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 777 and 792.

[0473] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 785 and 792.

[0474] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 786 and 792.

[0475] In some examples, tire second ABD comprises the sequences of SEQ ID NOs: 753 and 795.

[0476] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 765 and 795.

[0477] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 777 and 795.

[0478] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 785 and 795.

[0479] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 786 and 795.Attorney Docket No: 45395-0070W01

[0480] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 753 and 797.

[0481] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 765 and 797.

[0482] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 777 and 797.

[0483] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 785 and 797.

[0484] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 786 and 797.

[0485] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 753 and 803.

[0486] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 765 and 803.

[0487] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 777 and 803.

[0488] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 785 and 803.

[0489] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 786 and 803.

[0490] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 753 and 807.

[0491] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 765 and 807.

[0492] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 777 and 807.

[0493] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 785 and 807.

[0494] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 786 and 807.

[0495] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 814 and 792.

[0496] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 817 and 792.

[0497] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 820 and 792.

[0498] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 823 and 792.

[0499] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 826 and 792.

[0500] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 814 and 795.

[0501] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 817 and 795.

[0502] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 820 and 795.

[0503] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 823 and 795.

[0504] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 826 and 795.

[0505] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 814 and 797.

[0506] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 817 and 797.

[0507] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 820 and 797.

[0508] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 823 and 797.

[0509] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 826 and 797.

[0510] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 814 and 803.

[0511] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 817 and 803.

[0512] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 820 and 803.

[0513] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 823 and 803.Attorney Docket No: 45395-0070W01

[0514] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 826 and 803.

[0515] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 814 and 807.

[0516] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 817 and 807.

[0517] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 820 and 807.

[0518] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 823 and 807.

[0519] In some examples, the second ABD comprises the sequences of SEQ ID NOs: 826 and 807.

[0520] In some embodiments of the composition, the first or second ABD includes an HCVD and an LCVD comprising an HCVD sequence and an LCVD sequence, respectively, that are each identical to, or are at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the HCVD sequence and tire LCVD sequence, respectively, set forth in one of the following pairs of HCVD and LCVD sequences: SEQ ID NO: 1453 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1453 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1453 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1497. respectively; SEQ ID NO: 1485 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1453 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1453 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1465 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1477 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1485 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1486 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1492, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1495, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1497, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1526 and SEQ ID NO: 1503, respectively; SEQ ID NO: 1514 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1517 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1520 and SEQ ID NO: 1507, respectively; SEQ ID NO: 1523 and SEQ ID NO: 1507, respectively; and SEQ ID NO: 1526 and SEQ ID NO: 1507.Attorney Docket No: 45395-0070W01

[0521] In some embodiments, the first ABD comprises an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine. In some embodiments, the first ABD comprises an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine. In some embodiments, the first ABD includes: an HCVD comprising a CDR1, a CDR2. and a CDR3 having the sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine; and an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine.

[0522] In some embodiments, the first ABD comprises an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine. In some embodiments, the first ABD comprises an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine. In some embodiments, the first ABD includes: an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 743, 744, and 745, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 743, 744, and 745 substituted with a histidine; and an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 746, 747, and 748, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 746, 747, and 748 substituted with a histidine.

[0523] In some embodiments, the first ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 741, optionally where the HCVD includes a histidine at one or more total amino acid positions in the HCDRs SEQ ID NO: 741, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of SEQ ID NO: 741.

[0524] In some embodiments, the first ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 741, optionally where the HCVD includes a histidine at two or more total amino acid positions in the HCDRs SEQ ID NO: 741, optionally wherein apart from the histidine at the two or more amino acid positions, theAttorney Docket No: 45395-0070W01HCVD comprises the HCDRs of SEQ ID NO: 741.

[0525] In some embodiments, the first ABD includes an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%. 95%.96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 742, optionally where the LCVD includes a histidine at one or more total amino acid positions in the LCDRs SEQ ID NO: 742, optionally wherein apart from the histidine at the one or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 742.

[0526] In some embodiments, the first ABD includes an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%. 95%.96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 742, optionally where the LCVD includes a histidine at two or more total amino acid positions in the LCDRs SEQ ID NO: 742, optionally wherein apart from the histidine at the two or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 742.

[0527] In some embodiments, the first ABD comprises an HCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 741, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs SEQ ID NO: 741. optionally wherein apart from the histidine at the one or more positions, the HCVD comprises the HCDRs of SEQ ID NO: 741; and an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 742, optionally where the LCVD includes a histidine at one or more total amino acid positions in the LCDRs SEQ ID NO: 742, optionally wherein apart from the histidine at the one or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 742.

[0528] In some embodiments, the first ABD comprises an HCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 741, wherein the HCVD includes a histidine at two or more total amino acid positions in the HCDRs SEQ ID NO: 741, optionally wherein apart from the histidine at the two or more positions, the HCVD comprises the HCDRs of SEQ ID NO: 741; and an LCVD that is identical to, or is at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 742, optionally where the LCVD includes a histidine at two or more total amino acid positions in the LCDRs SEQ ID NO: 742, optionally wherein apart from the histidine at the two or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 742.

[0529] In some embodiments, the first ABD includes an HCVD of 56F3, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 56F3, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 56F3, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 56F3, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 56F3 comprises SEQ ID NO: 749. In some embodiments, the LCVD of 56F3 comprises SEQ ID NO: 750. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 749 comprise a total of one or more amino acid positions in SEQ ID NO: 749Attorney Docket No: 45395-0070W01substituted with a histidine selected from SEQ ID NO: 749 positions 31, 32, 33, 34, 35, 50, 51, 52, 53, 54, 55, 56, 57, 101, 102, and 105, and / or the CDRs of the LCVD of SEQ ID NO: 750 comprise a total of one or more positions in SEQ ID NO: 750 substituted with a histidine selected from SEQ ID NO: 750 positions 29, 30, 31, 32, 50, and 92. In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 749 comprise a total of one or more positions in SEQ ID NO: 749 substituted with a histidine selected from SEQ ID NO: 749 positions 26, 27, 28, 29, 30, 58, 59, 60, 61, 63, 64, 65, 66, 100, 106, 108, and 109, and / or the CDRs of the LCVD of SEQ ID NO: 750 comprise a total of one or more positions in SEQ ID NO: 750 substituted with a histidine selected from SEQ ID NO: 750 positions 24, 25, 27, 28, 33, 51, 52, 53, 54, 55, 56, 89, 90, 93, 95, 96, 97, 98, and 99, each such substitution reflecting a tolerated substitution.

[0530] In some embodiments, the first ABD comprises an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 751, 752, and 753, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine. In some embodiments, the first ABD comprises an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 754, 755. and 756. respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine. In some embodiments, the first ABD includes: an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 751, 752, and 753, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine; and an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 754, 755, and 756, respectively, optionally with collectively a total of one or more total amino acid positions in the sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine.

[0531] In some embodiments, the first ABD comprises an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 751, 752, and 753, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine. In some embodiments, the first ABD comprises an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 754, 755, and 756, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine. In some embodiments, the first ABD includes: an HCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 751, 752, and 753, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 751, 752, and 753 substituted with a histidine; and an LCVD comprising a CDR1, a CDR2, and a CDR3 having the sequences set forth in SEQ ID NOs: 754, 755, and 756, respectively, optionally with collectively a total of two or more total amino acid positions in the sequences of SEQ ID NOs: 754, 755, and 756 substituted with a histidine.Attorney Docket No: 45395-0070W01

[0532] In some embodiments, the first ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 749. optionally where the HCVD includes a histidine at one or more total amino acid positions in the HCDRs SEQ ID NO: 749, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of SEQ ID NO: 749.

[0533] In some embodiments, the first ABD includes an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 749. optionally where the HCVD includes a histidine at two or more total amino acid positions in the HCDRs SEQ ID NO: 749, optionally wherein apart from the histidine at the two or more amino acid positions, the HCVD comprises the HCDRs of SEQ ID NO: 749.

[0534] In some embodiments, the first ABD includes an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 750, optionally where the LCVD includes a histidine at one or more total amino acid positions in the LCDRs SEQ ID NO: 750, optionally wherein apart from the histidine at the one or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 750.

[0535] In some embodiments, the first ABD includes an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 750, optionally where the LCVD includes a histidine at two or more total amino acid positions in the LCDRs SEQ ID NO: 750, optionally wherein apart from the histidine at the two or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 750.

[0536] In some embodiments, the first ABD comprises an HCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 749, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs SEQ ID NO: 749, optionally wherein apart from the histidine at the one or more positions, the HCVD comprises the HCDRs of SEQ ID NO: 749; and an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 750, optionally where the LCVD includes a histidine at one or more total amino acid positions in the LCDRs SEQ ID NO: 750, optionally wherein apart from the histidine at the one or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 750.

[0537] In some embodiments, the first ABD comprises an HCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 749, wherein the HCVD includes a histidine at two or more total amino acid positions in the HCDRs SEQ ID NO: 749, optionally wherein apart from the histidine at the two or more positions, the HCVD comprises the HCDRs of SEQ ID NO: 749; and an LCVD that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 750, optionally where the LCVD includes a histidine at two or more total amino acid positions in the LCDRs SEQ ID NO: 750. optionally wherein apart from the histidine at theAttorney Docket No: 45395-0070W01two or more positions, the LCVD comprises the LCDRs of SEQ ID NO: 750.

[0538] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of hu15G7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of hul5G7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of hul5G7, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of hul5G7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of hu15G7 comprises the sequence of SEQ ID NO: 382. In some embodiments, the LCVD of hu15G7 comprises the sequence of SEQ ID NO: 455. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 382 comprise a total of one or more positions in SEQ ID NO: 382 substituted with a histidine selected from 32, 34, 53, 60, 104, 105, 106, 110, and 111 and / or the CDRs of the LCVD of SEQ ID NO: 455 comprise a total of one or more positions in SEQ ID NO: 455 substituted with a histidine selected from 29, 30, 32, 34, 50, 92, 93, 95, 96, and 97. In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 382 comprise a total of one or more positions in SEQ ID NO: 382 substituted with a histidine (or alanine where histidine was already present) selected from 26, 27, 28, 29, 30. 31. 33. 35, 36, 51, 52, 54, 55. 56. 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 98, 99, 100, 101, 102, 103, 107, and 109 and / or the CDRs of the LCVD of SEQ ID NO: 455 comprise a total of one or more positions in SEQ ID NO: 455 substituted with a histidine (or alanine where histidine was already present) selected from 24, 25, 26, 27, 28, 31, 33, 51, 52, 53, 54, 55, 56, 89, 91, 98, 99, and 100.

[0539] In some embodiments, the first ABD includes one of (a) to (c): (a) an HCV domain of hul5G7, optionally with one or more amino acids substituted with a histidine; and / or an LCV domain of hul5G7, optionally with one or more amino acids substituted with a histidine; (b) an HCV domain of hu24D9, optionally with one or more amino acids substituted with a histidine; and / or an LCV domain of hu24D9, optionally with one or more amino acids substituted with a histidine; and (c) an HCV domain of hu29Fl, optionally with one or more amino acids substituted with a histidine, an aspartate, or a glutamate; and / or an LCV domain of hu29Fl, optionally with one or more amino acids substituted with a histidine, an aspartate, or a glutamate. In cases where the wildtype amino acid is already histidine, an alanine may be substituted instead.

[0540] In some embodiments, the HCVD includes one of (a) to (c): (a) an HCVD of hul5G7 including SEQ ID NO: 382; (b) an HCVD of hu24D9 including SEQ ID NO: 516; and (c) an HCVD of hu29Fl including SEQ ID NO: 576. In some embodiments, the LCVD includes one of: (a) an LCVD of hul5G7 including SEQ ID NO: 455; (b) an LCVD of hu24D9 including SEQ ID NO: 522; and (c) an LCVD of hu29Fl including SEQ ID NO: 581.

[0541] In some embodiments, the first LRRC15 binding domain includes an HCVD of one of: (a) an HCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 379-381, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 379-381 substituted with a histidine; (b) an HCVDAttorney Docket No: 45395-0070W01including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 513-515, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 513-515 substituted with a histidine; and (c) an HCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 573-575, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 573-575 substituted with a histidine, an aspartate, or a glutamate.

[0542] In some embodiments, the first LRRC 15 -binding domain includes an LCVD of one of (a) to (c): (a) an LCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 452-454, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 452-454 substituted with a histidine; (b) an LCVD including a CDR1, a CDR2, and aCDR3 of SEQ ID NOs: 519-521, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 519-521 substituted with a histidine; and (c) an LCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 578-580, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 578-580 substituted with a histidine, an aspartate, or a glutamate.

[0543] In some embodiments, the first LRRC 15 -binding domain includes one of: (a) an HCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 379-381, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 379-381 substituted with a histidine; and / or an LCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 452-454, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 452-454 substituted with a histidine; (b) an HCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 513-515, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 513-515 substituted with a histidine: and / or an LCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 519-521, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 519-521 substituted with a histidine; and (c) an HCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 573-575, respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 573-575 substituted with a histidine, an aspartate, or a glutamate; and / or an LCVD including a CDR1, a CDR2, and a CDR3 of SEQ ID NOs: 578-580. respectively, optionally with collectively a total of one or more amino acid positions in SEQ ID NOs: 578-580 substituted with a histidine, an aspartate, or a glutamate.

[0544] In some embodiments, the first ABD includes an HCVD of one of: (a) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 382, where the HCVD includes a histidine (or alanine where a histidine is already present) at one or more positions in SEQ ID NO: 382 selected from the group consisting of: 32. 34. 53, 60, 104, 105, 106, 110, and 111; (b) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 516, where the HCVD includes a histidine at one or more positions in SEQ ID NO: 516 selected from the group consisting of: 30, 31, 32, 52, 53, 58, 59, 60, 100, 107, 108, and 112; and (c) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 576, where the HCVD includes a histidine, an aspartate, or a glutamate at one or more positions in SEQ ID NO: 576 selected from the group consisting of:Attorney Docket No: 45395-0070W0131, 56, 59, and 99. In some embodiments, the first ABD includes an LCVD of one of: (a) an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 455, where the LCVD includes a histidine at one or more positions in SEQ ID NO: 455 selected from the group consisting of: 29, 30. 32. 34, 50, 92, 93, 95, 96, and 97; (b) an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 522. where the LCVD includes a histidine at one or more positions in SEQ ID NO: 522 selected from the group consisting of: 35 and 97; and (c) an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 581, where the LCVD includes a histidine, an aspartate (D), or a glutamate (E) at one or more positions in SEQ ID NO: 581 selected from the group consisting of: D positions selected from 27, 28, 31, 52, and 56; and E positions selected from 51 and 56. In a particular embodiment, the non-identical amino acids are located in positions exclusively in the framework regions.

[0545] In some embodiments, the first ABD includes an HCVD of one of: (a) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 382, where the HCVD includes a histidine at two or more positions in SEQ ID NO: 382 including one pair of positions including one pair selected from the group consisting of: 34,53; 34,105; 34,106; 34.107; 53,105; 53,106 and 53,107; and (b) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 516. where the HCVD includes a histidine at one or more positions in SEQ ID NO: 516. In some embodiments, the first ABD includes an LCVD of one of: (a) an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 455, where the LCVD includes a histidine at two or more positions in SEQ ID NO: 455 including one pair of positions selected from the group consisting of: 30,32; 30,92; 30,93; 30,96; 32,92; 32,93; 32,96; 92,93; 92,96; and 93,96; and (b) an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 522, where the LCVD includes a histidine at one or more positions in SEQ ID NO: 522. In a particular embodiment, the non-identical amino acids are located in positions exclusively in the framework regions.

[0546] In some embodiments, the first ABD includes one of: (a) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 382, where the HCVD includes a histidine at one or more positions in SEQ ID NO: 382 selected from the group consisting of: 32, 34, 53, 60, 104, 105, 106, 110, and 111; and / or an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 455. where the LCVD includes a histidine at one or more positions in SEQ ID NO: 455 selected from the group consisting of: 29, 30, 32, 34, 50, 92, 93, 95, 96, and 97; and (b) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 516, where the HCVD includes a histidine at one or more positions in SEQ ID NO: 516 selected from the group consisting of: 30, 31, 32, 52, 53, 58, 59, 60, 100, 107, 108, and 112; and / or an LCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 522, where the LCVD includes a histidine at one or more positions in SEQ ID NO: 522 selected from the group consisting of: 35 and 97; and (c) an HCVD that is at least 90% identical to the sequence set forth in SEQ ID NO: 576, where the HCVD includes an aspartate (D) or a glutamate (E) at one or more positions in SEQ ID NO: 576 selected from the group consisting of: D positions selected from 31, 56 and 99; or E position 59; and / or an LCVD that is at least 90% identical to the sequence setAttorney Docket No: 45395-0070W01forth in SEQ ID NO: 581, where the LCVD includes an aspartate (D) or a glutamate (E) at one or more positions in SEQ ID NO: 581 selected from the group consisting of: D positions selected from 27, 28, 31, 52 and 56; and E positions selected from 51 and 56. In a particular embodiment, the non-identical amino acids are located in positions exclusively in the framework regions.

[0547] In some embodiments, the first ABD includes an HCVD of one of (a) to (c): (a) an HCVD comprising the sequence of one of SEQ ID NO: 382, one of SEQ ID NOs: 383-424, and one of SEQ ID NOs: 425-450; (b) an HCVD comprising the sequence of one of SEQ ID NO: 516, one of SEQ ID NOs: 523-567, and one of SEQ ID NOs: 568-571; and (c) an HCVD comprising the sequence of one of SEQ ID NO: 576, one of SEQ ID NOs: 582-624, and one of SEQ ID NOs: 653-695; and / or the first ABD includes an LCVD of one of (a) to (c): (a) an LCVD having the sequence of one of SEQ ID NO: 455, one of SEQ ID NOs: 456-485, and one of SEQ ID NOs: 486-511; (b) an LCVD comprising the sequence of SEQ ID NO: 522, the sequence of SEQ ID NO: 522 with a histidine substitution at position 35, and the sequence of SEQ ID NO: 522 with a histidine substitution at position 97; and (c) an LCVD comprising the sequence of one of SEQ ID NO: 581, one of SEQ ID NOs: 625-652, and one of SEQ ID NOs: 696-723.

[0548] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 6F7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 6F7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 6F7, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 6F7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 6F7 comprises the sequence of SEQ ID NO: 963. In some embodiments, the LCVD of 6F7 comprises the sequence of SEQ ID NO: 964. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 963 comprise a total of one or more amino acid positions in SEQ ID NO: 963 substituted with a histidine selected from SEQ ID NO: 963 positions 30, 31, 33, 34, 35, 50, 51, 53, 54, 57, 58, 60, 103, 107, 109, 110, 111, 112, 114, and 116, and / or the CDRs of the LCVD of SEQ ID NO: 964 comprise a total of one or more positions in SEQ ID NO: 964 substituted with a histidine selected from SEQ ID NO: 964 positions 92, 93, 97, 99, and 100, each such substitution reflecting a '‘pH-dependent binding substitution”. In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 963 comprise a total of one or more amino acid positions in SEQ ID NO: 963 substituted with a histidine selected from SEQ ID NO: 963 positions 25, 26, 27, 28, 29, 32, 55, 56, 59, 61, 62, 63, 64, 65, 66, 67, 97, 98, 100, 102, 104, 105, 106, 108, 113, 115, 117, and 118, and / or the CDRs of the LCVD of SEQ ID NO: 964 comprise a total of one or more positions in SEQ ID NO: 964 substituted with a histidine selected from SEQ ID NO: 964 positions 24, 25, 26, 27, 28, 29, 30, 31. 32. 33. 34, 35, 52, 53, 54, 55, 56, 57, 58, 91, 94, 95, 96, 98, and 101, each such substitution reflecting a '‘tolerated substitution”.

[0549] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 16D12, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments,Attorney Docket No: 45395-0070W01the first ABD includes an LCVD of 16D12, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, tire first ABD includes an HCVD of 16D12, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 16D12, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 16D12 comprises the sequence of SEQ ID NO: 1391. In some embodiments, the LCVD of 16D12 comprises the sequence of SEQ ID NO: 1392.

[0550] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of IE 10, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of IE 10. optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 1 E 10, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 1E10, optionally with one or more total amino acids in tire CDRs substituted with a histidine. In some embodiments, the HCVD of 1E10 comprises the sequence of SEQ ID NO: 1375. In some embodiments, the LCVD of 1E10 comprises the sequence of SEQ ID NO: 1376.

[0551] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 17D8, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 17D8, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 17D8, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 17D8, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 17D8 comprises the sequence of SEQ ID NO: 1431. In some embodiments, the LCVD of 17D8 comprises the sequence of SEQ ID NO: 1432.

[0552] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 26D11, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 26D11, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 26D11, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 26D1 1, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 26D11 comprises the sequence of SEQ ID NO: 1053. In some embodiments, the LCVD of 26D11 comprises the sequence of SEQ ID NO: 1054. In a particular embodiment, the CDRs of tire HCVD of SEQ ID NO: 1053 comprise a total of one or more amino acid positions in SEQ ID NO: 1053 substituted with a histidine selected from SEQ ID NO: 1053 positions 35, 36, 51, 53, 54, 57, 59, 61, and 101, and / or the CDRs of the LCVD of SEQ ID NO: 1054 comprise a total of one or more positions in SEQ ID NO: 1054 substituted with a histidine selected from SEQ ID NO: 1054 positions 32, 50, 90, 91, 93, and 97, each such substitution reflecting a "pH-dependent binding substitution'’. In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1053 compriseAttorney Docket No: 45395-0070W01a total of one or more amino acid positions in SEQ ID NO: 1053 substituted with a histidine selected from SEQ ID NO: 1053 positions 26, 27, 28, 29, 30, 31, 32, 33, 52, 55, 56, 58, 60, 62, 63, 64, 65, 66, 67, 68, 97, 98, 100, 102, 104, 105, 109, 110. and 111, and / or the CDRs of the LCVD of SEQ ID NO: 1054 comprise a total of one or more positions in SEQ ID NO: 1054 substituted with a histidine selected from SEQ ID NO: 1054 positions 24, 25, 26, 27, 28, 29, 30, 31, 33, 51, 52, 53, 54, 55, 56, 89, 92, 94, 95, 96, and 98, each such substitution reflecting a “tolerated substitution”.

[0553] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 17D2, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 17D2. optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 17D2, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 17D2, optionally with one or more total amino acids in tire CDRs substituted with a histidine. In some embodiments, the HCVD of 17D2 comprises the sequence of SEQ ID NO: 1133 or 1407. In some embodiments, the LCVD of 17D2 comprises the sequence of SEQ ID NO: 1134 or 1408. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1133 comprise a total of one or more amino acid positions in SEQ ID NO: 1133 substituted with a histidine selected from SEQ ID NO: 1133 positions 99, 100, 101, 102, 103, 106, 107, 110, 111, 112, and 113, and / or the CDRs of the LCVD of SEQ ID NO: 1134 comprise a total of one or more positions in SEQ ID NO: 1134 substituted with a histidine selected from SEQ ID NO: 1134 positions 24, 25, 26, 30, 31, 32, 33, 34, 53, 54, 55, 93, 95, and 101, each such substitution reflecting a “pH-dependent binding substitution”. In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1133 comprise a total of one or more amino acid positions in SEQ ID NO: 1133 substituted with a histidine selected from SEQ ID NO: 1133 positions 26, 27, 28, 29, 30. 31. 32. 33, 34, 35, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 98, 104, 105, 108, and 109, and / or the CDRs of the LCVD of SEQ ID NO: 1134 comprise a total of one or more positions in SEQ ID NO: 1134 substituted with a histidine selected from SEQ ID NO: 1134 positions 27, 28, 29, 35, 36, 56, 57, 58, 91, 94, 96, 97, 98, 99, 100, and 102, each such substitution reflecting a “tolerated substitution”.

[0554] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 12D1. optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 12D1, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 12D 1, optionally with one or more total amino acids in tire CDRs substituted with a histidine; and an LCVD of 12D1, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 12D1 comprises the sequence of SEQ ID NO: 1216 or 1415. In some embodiments, the LCVD of 12D1 comprises the sequence of SEQ ID NO: 1217 or 1416. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1216 comprise a total of one or more amino acid positions in SEQ ID NO: 1216 substituted with a histidine selected from SEQ ID NO: 1216 positions 33, 50, 55, 57, 60, 62, and 101, and / or the CDRs of the LCVD of SEQ ID NO: 1217Attorney Docket No: 45395-0070W01comprise a total of one or more positions in SEQ ID NO: 1217 substituted with a histidine selected from SEQ ID NO: 1217 positions 29, 31, 32, 93, 94, 95, 96, 97, and 98, each such substitution reflecting a “pH-dependent binding substitution". In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1216 comprise a total of one or more amino acid positions in SEQ ID NO: 1216 substituted with a histidine selected from SEQ ID NO: 1216 positions 25, 26, 27, 28, 30, 31, 32, 34, 35, 51, 52, 53, 54, 56, 58, 59, 61, 63, 64, 65, 66, 67, 97, 98, 100, 102, 103, 104, 105, 106, 107, and 108, and / or the CDRs of the LCVD of SEQ ID NO: 1217 comprise a total of one or more positions in SEQ ID NO: 1217 substituted with a histidine selected from SEQ ID NO: 1217 positions 24, 25, 26, 27, 28, 30, 33, 34, 50, 51, 52, 53. 54, 55, 56, 89, 90, and 99, each such substitution reflecting a "‘tolerated substitution".

[0555] In some embodiments, the first antigen-binding domain (ABD) includes an HCVD of 12D7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an LCVD of 12D7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the first ABD includes an HCVD of 12D7, optionally with one or more total amino acids in the CDRs substituted with a histidine; and an LCVD of 12D7, optionally with one or more total amino acids in the CDRs substituted with a histidine. In some embodiments, the HCVD of 12D7 comprises the sequence of SEQ ID NO: 1296 or 1423. In some embodiments, the LCVD of 12D7 comprises the sequence of SEQ ID NO: 1297 or 1424. In a particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1296 comprise a total of one or more amino acid positions in SEQ ID NO: 1296 substituted with a histidine selected from SEQ ID NO: 1296 positions 27, 28, 31, 33, 35, 36, 51, 53, 55, 57, 58, 97, 98, 100, and 104, and / or the CDRs of the LCVD of SEQ ID NO: 1297 comprise a total of one or more positions in SEQ ID NO: 1297 substituted with a histidine selected from SEQ ID NO: 1297 positions 50, 90, 91, 93. 98. and 99. each such substitution reflecting a ‘‘pH-dependent binding substitution". In another particular embodiment, the CDRs of the HCVD of SEQ ID NO: 1296 comprise a total of one or more amino acid positions in SEQ ID NO: 1296 substituted with a histidine selected from SEQ ID NO: 1296 positions 26, 29, 30, 32, 34, 54, 56, 59, 60, 61, 62, 63, 64, 65, 66, 99, 101, 102, 103, 106, 107, 108, and 109, and / or the CDRs of the LCVD of SEQ ID NO: 1297 comprise a total of one or more positions in SEQ ID NO: 1297 substituted with a histidine selected from SEQ ID NO: 1297 positions 24, 25, 26, 27. 28. 29, 30, 31, 33, 51, 52, 53, 54. 55. 56. 89, 92, 94, 95, 96, 97, and 100. each such substitution reflecting a ‘‘tolerated substitution".

[0556] Also provided herein are compositions, including pharmaceutical compositions, which comprise any of the ABPCs described herein. Also provided herein are methods of treating a subject in need thereof that include administering a therapeutically effective amount of any of the ABPCs described herein to the subject.

[0557] In some embodiments, a composition including the ABPC (e.g., any of the ABPCs, including biparatopic ADCs described herein) can provide increased killing of LRRC 15 -positive stromal cells in vitro and in vivo in a subject or patient having a cancer characterized comprising and / or being associated with such LRRC 15 -positive stromal cells.Attomey Docket No: 45395-0070W01

[0558] In some embodiments, a composition including the ABPC (e.g., any of the ABPCs described herein) can provide for an increase (e.g., a detectable increase) (e.g., any of the percents increase or ranges of percents increase recited in US 2022 / 0281984 at paragraph

[0753] , which are incorporated by reference herein in their entirety) in toxin liberation in the target mammalian cell (e.g., any of the target mammalian cells described herein) as compared to a composition including the same amount of a control ABPC (e.g., any of the exemplary control ABPCs described herein).

[0559] In some embodiments, a composition including the ABPC (e.g., any of the ABPCs described herein) can provide for an increase (e.g.. a detectable increase) (e.g., any of the folds increase or ranges of folds increase recited in US 2022 / 0281984 at paragraph

[0754] , which are incorporated by reference herein in their entirety) in toxin liberation in the target mammalian cell (e g., any of the target mammalian cells described herein) as compared to a composition including the same amount of a control ABPC (e.g., any of the exemplary control ABPCs described herein).

[0560] In some embodiments, a composition including the ABPC (e.g., any of the ABPCs described herein) can provide for an increase (e.g., a detectable increase) (e.g.. at least a 1%, 2%. 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 120%, 140%, 160%, 180%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 1,000%, 2,000%, 3,000%, 4,000%, 5,000%, 6,000%, 7,000%, 8,000%, 9,000%, or a 10,000% increase, or about a 1% to 10,000% increase (e.g., or any of the subranges)) in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC.

[0561] In some embodiments, a composition including the ABPC (e.g., any of the ABPCs described herein) can provide for an increase (e.g., a detectable increase) (e g., at least a 0.1-, 0.2-, 0.3-, 0.4-, 0.5-, 0.6-, 0.7-, 0.8-, 0.9-, 1.0-, 1.2-, 1.4-, 1.5-, 1.6-, 1.8-, 2.0-, 2.2-, 2.4-, 2.5-, 2.6-, 2.8-, 3.0-, 3.5-, 4.0-, 4.5-, 5.0-, 5.5-, 6.0-, 6.5-, 7.0-, 7.5-, 8.0-, 8.5-, 9.0-, 9.5-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 80-, 85-, 90-, 95-fold increase, or at least a 100-fold increase, or a 0.1-100-fold increase in target mammalian cell killing, including an increase in the depth of killing, as compared to a composition including the same amount of a control ABPC.

[0562] In some embodiments, a composition including any of the ABPCs described herein (e.g., upon contacting target mammalian cells presenting LRRC15 on their surface) results in decreased (e.g., > a 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%. 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%. 80%, 85%, 90%, 95% decrease, or at least a 99% decrease, about a l%-99% decrease, or any of the subranges of this range described herein) IC50 (for target mammalian cell killing) as compared to the IC50 for a composition including the same amount of a control ABPC.

[0563] In some embodiments, a composition including any of the ABPCs described herein (e.g., upon contacting target mammalian cells presenting URRC15 on their surface) can provide for an increase (e.g., at least a 0.1-, 0.2-, 0.4-, 0.6-, 0.8-. 1-, 2-, 5-. 10-, 15-, 20-. 25-, 30-, 35-, 40-, 45-, 50-, 55-. 60-, 65-, 70-. 75-, 80-Attorney Docket No: 45395-0070W01, 85-, 90-, 95-fold increase, or at least a 100-fold increase, or about a 0.1-500-fold increase (or any of the subranges of this range described herein) in the ratio of KD on target mammalian cells presenting LRRC15 on their surface at a neutral pH to IC50 at the neutral pH on the same target cells, e.g., as compared to a control ABPC.

[0564] In some embodiments, a composition including the ABPC (e.g., any of the ABPCs described herein) can provide for an increase (e.g., a detectable increase) (e.g., at least a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 120%, 140%, 160%, 180%, 200%, 250%, 300%, 350%, 400%, 450%, 500%. 1,000%, 2,000%, 3,000%, 4,000%, 5,000%, 6.000%, 7,000%. 8,000%, 9,000% increase, or at least a 10.000% increase, or about a l%-10,000% increase (e.g.. or any of the subranges of this range described herein)) in endolysosomal delivery in the target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0565] In some embodiments, a composition including the ABPC can provide for an increase (e.g., > a 0.1-, 0.2-. 0.3-, 0.4-, 0.5-. 0.6-, 0.7-, 0.8-, 0.9-, 1.0-, 1.2-, 1.4-, 1.5-, 1.6-, 1.8-, 2.0-, 2.2-, 2.4-, 2.5-, 2.6-, 2.8-, 3.0-, 3.5-. 4.0-, 4.5-, 5.0-. 5.5-, 6.0-, 6.5-. 7.0-, 7.5-, 8.0-. 8.5-, 9.0-, 9.5-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-. 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-fold increase, or at least a 100-fold increase, or about a 0.1-100-fold increase in endolysosomal delivery in the target mammalian cell as compared to a composition including the same amount of a control ABPC.

[0566] In embodiments of any of the ABPCs described herein, the target mammalian cell does not express an FcRn receptor, or expresses a lower (e.g., a detectably lower) level (e.g.. at least a 1% decreased, at least a 2%, 5%, 10% decrease, at least a 15%. 20%. 25%. 30%. 35%. 40%. 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% decreased, or at least a 99% decreased level) of FcRn receptor as compared to a FcRn expressing control cell (e.g., HUVEC, ThermoFisher C0035C). In some embodiments, the target mammalian cell is a cancer cell. In some embodiments, the ABPC is cytotoxic or cytostatic to the target mammalian cell.

[0567] In some embodiments, a composition including any of the ABPCs described herein (e.g., upon administration to a subject) results in less (e.g., a 1% decrease to about a 99% decrease, or any of the subranges of this range described herein) of a reduction in the level of LRRC 15 presented on the surface of the target cell as compared to a composition including tire same amount of a control ABPC (e.g., any of the control ABPCs described herein). In some embodiments, the composition does not result in a detectable reduction in the level of the LRRC 15 presented on the surface of the target mammalian cell.

[0568] In some embodiments, the ABPC is cross-reactive with a non-human primate LRRC 15 and a human LRRC15. In some embodiments, the ABPC is cross-reactive with a non-human primate LRRC15, a human LRRC15, and one or both of rat LRRC15 and a mouse LRRC15. In some embodiments, the ABPC is cross-reactive with a non-human primate LRRC 15, a human LRRC 15, a rat LRRC 15, and a mouse LRRC15. In some embodiments, tire ABPC is cross-reactive with mouse LRRC 15 and rat LRRC 15. In some embodiments, the first and / or second ABD binds to an epitope of LRRC 15 that is present on the surface of cells from an OldAttorney Docket No: 45395-0070W01World Monkey.

[0569] Some embodiments of any of the ABPCs described herein can further include a second ABD (e.g., any of the exemplary ABDs described herein). Non-limiting aspects of these methods are described below, and can be used in any combination without limitation. Additional aspects of these methods are known in the art.LRRC15 or Epitope of LRRC15

[0570] Multiple LRRC 15 -binding monoclonal antibodies have been described in the literature and can be used as a template for engineering pH-dependent binding and / or producing multispecific (including multiparatopic) antigen binding protein constructs (ABPC) according to this disclosure. The amino acid sequence of the mature human LRRC15 can be found in SEQ ID NO: 9 and the amino acid sequence of the extracellular domain of LRRC 15 can be found in SEQ ID NO: 11.Antigen-Binding Protein Constructs

[0571] Any of the antigen-binding protein constructs (ABPCs) described herein can be a single polypeptide, or can include 2, 3, 4, 5, 6, 7, 8, 9, or 10 (the same or different) polypeptides. In some embodiments where the ABPC is a single polypeptide, the ABPC can include a single ABD or two ABDs. In some embodiments where the ABPC is a single polypeptide and includes two ABDs, the first and second ABDs can be identical or different from each other (and can specifically bind to the same or different antigens or epitopes).

[0572] In some embodiments where the ABPC is a single polypeptide, the first ABD and the second ABD (if present) can each be independently selected from the group of: a VH domain, a VHH domain, a VNAR domain, and a scFv. In some embodiments where the ABPC is a single polypeptide, the antigen-binding protein construct can be a BiTe. a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HAS, a tandem-scFv, an Adnectin, a DARPin, a fibronectin, a DEP conjugate, and a PROTAB. Additional examples of ABDs that can be used when the ABPC is a single polypeptide are known in the art.

[0573] A VHH domain is a single monomeric variable antibody domain that can be found in camelids. A VNAR domain is a single monomeric variable antibody domain that can be found in cartilaginous fish. Non-limiting aspects of VHH domains and VNAR domains are described in, e.g., Cromie et al., Curr. Top. Med. Chem.15:2543-2557, 2016; De Genst et al., Dev. Comp. Immunol. 30:187-198, 2006; De Meyer et al.. Trends Biotechnol. 32:263-270, 2014; Kijanka et al., Nanomedicine 10: 161-174, 2015; Kovaleva et al., Expert. Opin. Biol. Ther. 14:1527-1539, 2014; Krah et al., Immunopharmacol. Immunotoxicol. 38:21-28, 2016; Mujic-Delic etal., Trends Pharmacol. Sci. 35:247-255, 2014; Muyldemians, J. Biotechnol. 74:277-302, 2001; Muyldermans et aL, Trends Biochem. Sci. 26:230-235, 2001; Muyldermans, Ann. Rev. Biochem. 82:775-797, 2013; Rahbarizadeh et al., Immunol. Invest. 40:299-338, 2011; Van Audenhove et aL, EBioMedicine 8:40-48, 2016; Van Bockstaele et al., Curr. Opin. Investig. Drugs 10:1212-1224, 2009; Vincke et al., Methods Mol. Biol.911:15-26, 2012; and Wesolowski et al., Med. Microbiol. Immunol. 198: 157-174, 2009.Attorney Docket No: 45395-0070W01

[0574] In some embodiments where the ABPC is a single polypeptide and includes two ABDs, the first ABD and the second ABD can both be VHH domains, or at least one ABD can be a VHH domain. In some embodiments where the ABPC is a single polypeptide and includes two ABDs. the first ABD and the second ABD are both VNAR domains, or at least one ABD is a VNAR domain. In some embodiments where the ABPC is a single polypeptide, the first ABD is a scFv domain. In some embodiments where the ABPC is a single polypeptide and includes two ABDs, the first ABD and the second ABD can both be scFv domains, or at least one ABD can be a scFv domain.

[0575] In some embodiments, the ABPC can include two or more polypeptides (e.g., 2. 3, 4, 5, 6. 7, 8, 9. or 10 polypeptides). In some embodiments where the ABPC includes two or more polypeptides, two, three, four, five or six of the polypeptides of the two or more polypeptides can be identical.

[0576] In some embodiments where tire ABPC includes two or more polypeptides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 polypeptides), two or more of the polypeptides of the ABPC can assemble (e.g., non-covalently assemble) to form one or more ABDs, e.g., an antigen-binding fragment of an antibody (e.g., any of the antigen-binding fragments of an antibody described herein), 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 assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a KZ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L, H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab’)2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, a VHH-Fc, a tandem VHH-Fc, a VHH-Fc KiH, a Fab-VHH-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, a scFvl-PEG-scFv2, an Adnectin, a DARPin, a fibronectin, and a DEP conjugate. See, e.g., Spiess et al., Mol. Immunol. 67:95-106, 2015, incorporated in its entirety herewith, for a description of these elements. Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an IgG (e.g.. an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgG, e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgA 1 or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.g.. an antigenbinding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g.. an antigenbinding fragment of a human or humanized IgE); or an antigen-binding fragment of an IgM (e.g., an antigenbinding fragment of a human or humanized IgM).

[0577] In some embodiments, antigen binding protein constructs (ABPCs) having two or more antigen binding domains (ABDs) exhibit a significantly greater degree of internalization into LRRC15+ cells asAttorney Docket No: 45395-0070W01compared to a monoparatopic monoclonal antibody, Samrotamab

[0578] In some embodiments, the pair of ABDs producing superior internalizing anti-LRRC15 biparatopic antibodies includes one or more of the following:

[0579] An epitope bin 1 -binding ABD of hu IE 10 and an epitope bin 2.1 -binding ABD of hul5G7:

[0580] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 2.2-binding ABD ofhul6D12;

[0581] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 2.2-binding ABD ofhu26Dll;

[0582] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 2.2-binding ABD of hu54Fl;

[0583] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 2.4-binding ABD of hul39.10;

[0584] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 2.3-binding ABD of hul7D2;

[0585] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 3-binding ABD of hul2Dl;

[0586] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 4-binding ABD of hul2D7;

[0587] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 4 / 2.3-binding ABD of hul7D8;

[0588] An epitope bin 2.1-binding ABD of hul5G7 and an epitope bin 5-binding ABD of hu56F3;

[0589] An epitope bin 2.1-binding ABD of hul5G7-var (pH-dependent) and an epitope bin 1-binding ABD of hu6F7;

[0590] An epitope bin 2.1-binding ABD of hul5G7-var (pH-dependent) and an epitope bin 2.2-binding ABD ofhul6D12;

[0591] An epitope bin 2.1-binding ABD of hu15G7-var (pH-dependent) and an epitope bin 2.2-binding ABD ofhu26Dll;

[0592] An epitope bin 2.1-binding ABD of hul5G7-var (pH-dependent) and an epitope bin 2.2-binding ABD of hu54Fl;

[0593] An epitope bin 2.1-binding ABD of hul5G7-var (pH-dependent) and an epitope bin 2.4-binding ABD ofhul39.10;

[0594] An epitope bin 2.1-binding ABD of hul5G7-var (pH-dependent) and an epitope bin 2.3-binding ABD ofhul7D2;

[0595] An epitope bin 2.1-binding ABD of hul5G7-var (pH-dependent) and an epitope bin 4 / 2.3-binding ABD of hul7D8;

[0596] An epitope bin 2.1-binding ABD of hu15G7-var (pH-dependent) and an epitope bin 5-binding ABD ofhu56F3;

[0597] An epitope bin 2.1-binding ABD of hu24D9 and an epitope bin 2.2-binding ABD ofhul6D12;

[0598] An epitope bin 2.1-binding ABD of hu24D9 and an epitope bin 2.2-binding ABD of hu26Dll:

[0599] An epitope bin 2.1-binding ABD of hu24D9 and an epitope bin 3-binding ABD of hul2Dl;

[0600] An epitope bin 2.1-binding ABD of hu24D9 and an epitope bin 4-binding ABD ofhul2D7;

[0601] An epitope bin 2.1-binding ABD of hu24D9 and an epitope bin 4 / 2.3-binding ABD of hul7D8;Attorney Docket No: 45395-0070W01

[0602] An epitope bin 2.1-binding ABD of hu24D9 and an epitope bin 5-binding ABD of hu56F3;

[0603] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.2-binding ABD of hul6D12:

[0604] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.2-binding ABD of hu26Dll;

[0605] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.2-binding ABD of hu54Fl;

[0606] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.4-binding ABD of hul39.10;

[0607] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.3-binding ABD of hul7D2;

[0608] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 4 / 2.3-binding ABD ofhul7D8;

[0609] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 5-binding ABD of hu56F3;

[0610] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 1 -binding ABD of hu6F7;

[0611] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.2-binding ABD of hul6D12;

[0612] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.2-binding ABD of hu26Dll:

[0613] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.2-binding ABD of hu54Fl;

[0614] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.4-binding ABD of hul39.10;

[0615] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 2.3-binding ABD of hul7D2;

[0616] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 4 / 2.3-binding ABD ofhul7D8;

[0617] An epitope bin 2.1-binding ABD of hu29Fl (pH-dependent) and an epitope bin 5-binding ABD of hu56F3;

[0618] An epitope bin 2.2-binding ABD of hul6D12 and an epitope bin 4-binding ABD of hul2D7;

[0619] An epitope bin 5-binding ABD of hu56F3 and an epitope bin 2.1-binding ABD of hul5G7;

[0620] An epitope bin 5-binding ABD of hu56F3 and an epitope bin 2.1-binding ABD of hul5G7 (pH-dependent);Attorney Docket No: 45395-0070W01

[0621] An epitope bin 5 -binding ABD of hu56F3 and an epitope bin 2.1 -binding ABD of hu24D9;

[0622] An epitope bin 5 -binding ABD of hu56F3 and an epitope bin 2.1 -binding ABD of hu29Fl (pH-dependent);

[0623] An epitope bin 5-binding ABD of hu56F3 and an epitope bin 2.1-binding ABD of hu29Fl (pH-dependent);

[0624] An epitope bin 5-binding ABD of hu56F3 and an epitope bin 2.2-binding ABD of hul6D12;

[0625] An epitope bin 5-binding ABD ofhu56F3 and an epitope bin 2.2-binding ABD of hu54Fl;

[0626] An epitope bin 5-binding ABD ofhu56F3 and an epitope bin 2.4-binding ABD of hul39.10;

[0627] An epitope bin 5-binding ABD of hu56F3 and an epitope bin 2.3-binding ABD of hul7D2; and

[0628] An epitope bin 5-binding ABD of hu56F3 and an epitope bin 4 / 2.3-binding ABD of hul7D8.

[0629] A half-pH-dependent bin 1 -binding ABD of hulElO and a bin 2.1-binding ABD of hul5G7;

[0630] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and abin 2.2-binding ABD of hul6D12;

[0631] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and abin 2.2-binding ABD of hu26Dl 1;

[0632] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and a bin 2.2-binding ABD of hu54Fl;

[0633] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and abin 2.4-binding ABD of hu 139.10;

[0634] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and a bin 2.3-binding ABD of hul7D2;

[0635] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and a bin 3-binding ABD of hul2Dl:

[0636] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and a bin 4-binding ABD of hul2D7;

[0637] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and abin 4 / 2.3-binding ABD of hul7D8;

[0638] A half-pH-dependent bin 2.1-binding ABD of hul5G7 and a bin 5-binding ABD of hu56F3;

[0639] A half-pH-dependent bin 2.1-binding ABD of hul5G7-var (pH-dependent) and a bin 1-binding ABD ofhu6F7;

[0640] A half-pH-dependent bin 2.1-binding ABD ofhul5G7-var (pH-dependent) and abin 2.2-binding ABD ofhul6D12;

[0641] A half-pH-dependent bin 2.1-binding ABD of hul5G7-var (pH-dependent) and abin 2.2-binding ABD ofhu26Dll;

[0642] A half-pH-dependent bin 2.1-binding ABD of hu 15G7-var (pH-dependent) and abin 2.2-binding ABD of hu54Fl;

[0643] A half-pH-dependent bin 2.1-binding ABD of hul5G7-var (pH-dependent) and abin 2.4-binding ABD ofhul39.10;

[0644] A half-pH-dependent bin 2.1-binding ABD of hul5G7-var (pH-dependent) and abin 2.3-binding ABD ofhul7D2;

[0645] A half-pH-dependent bin 2.1-binding ABD of hul5G7-var (pH-dependent) and a bin 4 / 2.3-binding ABD of hul7D8;Attorney Docket No: 45395-0070W01

[0646] A half-pH-dcpcndcnt bin 2.1 -binding ABD of hul5G7-var (pH-dcpcndcnt) and a bin 5-binding ABD of hu56F3;

[0647] A half-pH-dependent bin 2.1-binding ABD of hu24D9 and a bin 2.2-binding ABD of hu!6D12;

[0648] A half-pH-dependent bin 2.1-binding ABD of hu24D9 and a bin 2.2-binding ABD of hu26Dl 1;

[0649] A half-pH-dcpcndcnt bin 2.1-binding ABD of hu24D9 and a bin 3 -binding ABD of hul2Dl;

[0650] A half-pH-dependent bin 2.1-binding ABD of hu24D9 and a bin 4-binding ABD of hul2D7:

[0651] A half-pH-dependent bin 2.1-binding ABD of hu24D9 and a bin 4 / 2.3-binding ABD of hul7D8;

[0652] A half-pH-dependent bin 2.1-binding ABD of hu24D9 and a bin 5-binding ABD of hu56F3;

[0653] A half-pH-dependent bin 2.1-binding ABD of liu29Fl (pH-dependent) and a bin 2.2-binding ABD of hul6D12;

[0654] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 2.2-binding ABD of hu26Dl l;

[0655] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 2.2-binding ABD of hu54Fl;

[0656] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 2.4-binding ABD of hu!39.10;

[0657] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 2.3-binding ABD of hul7D2;

[0658] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 4 / 2.3-binding ABD ofhul7D8;

[0659] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 5-binding ABD of hu56F3;

[0660] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 1-binding ABD of hu6F7;

[0661] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and abin 2.2-binding ABD of hul6D12;

[0662] A half-pH-dependent bin 2.1-binding ABD of liu29Fl (pH-dependent) and a bin 2.2-binding ABD of hu26Dll;

[0663] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and abin 2.2-binding ABD of hu54Fl;

[0664] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and abin 2.4-binding ABD of hul39.10;

[0665] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and abin 2.3-binding ABD of hul7D2;Attorney Docket No: 45395-0070W01

[0666] A half-pH-dcpcndcnt bin 2.1-binding ABD of hu29Fl (pH-dcpcndcnt) and a bin 4 / 2.3-binding ABD ofhul7D8;

[0667] A half-pH-dependent bin 2.1-binding ABD of hu29Fl (pH-dependent) and a bin 5 -binding ABD of hu56F3;

[0668] A half-pH-dependent bin 2.2-binding ABD of hul6D12 and a bin 4-binding ABD of hul2D7;

[0669] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.1-binding ABD of hul5G7;

[0670] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.1-binding ABD of hul5G7 (pH-dependent);

[0671] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.1-binding ABD of hu24D9;

[0672] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.1-binding ABD of hu29Fl (pH-dependent);

[0673] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.1-binding ABD of hu29Fl (pH-dependent);

[0674] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.2-binding ABD of hul6D12;

[0675] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.2-binding ABD of hu54Fl;

[0676] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.4-binding ABD of hul39.10;

[0677] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 2.3-binding ABD of hul7D2; and

[0678] A half-pH-dependent bin 5-binding ABD of hu56F3 and a bin 4 / 2.3-binding ABD of hul7D8.

[0679] A “Fv” fragment includes a non-covalently-linked dimer of one HCVD and one LCVD.

[0680] A “Fab” fragment includes, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain, in addition to the heavy and LCVDs of the Fv fragment.

[0681] A “F(ab')2 ' fragment includes two Fab fragments joined, near the hinge region, by disulfide bonds.

[0682] A “dual variable domain immunoglobulin” or “DVD-Ig” refers to multivalent and multispecific binding proteins as described, e.g., in DiGiammarino et al., Methods Mol. Biol. 899: 145-156, 2012; Jakob et al., MABs 5:358-363, 2013; and U. S. Patent Nos. 7,612,181; 8,258,268; 8,586,714; 8,716,450; 8,722,855; 8,735,546; and 8,822,645, each of which is incorporated by reference in its entirety.

[0683] DARTs are described in, e.g., Garber, Nature Reviews Drug Discovery 13:799-801, 2014.

[0684] Additional aspects of ABPCs are known in the art.Antigen-Binding Domains

[0685] In some embodiments of any of the antigen-binding protein constructs (ABPCs) described herein, the dissociation rate of the first ABD (and optionally the second ABD, if present and if it is desired that tire first and second ABDs exhibit substantially similar binding properties in this respect) at a pH of about 4.0 to about 6.5 (e.g., about 4.0 to about 6.4. or any of the ranges of pH recited in published application US 2022 / 0281984 at paragraph

[0779] , which are incorporated by reference herein in their entirety) is faster (e.g., at least 5%Attorney Docket No: 45395-0070W01faster, or any of the % faster or ranges of % faster recited in US 2022 / 0281984 at paragraph [, which are incorporated by reference herein in their entirety) than the dissociation rate at a pH of about 7.0 to about 8.0 (e.g., about 7.0-7.9, 7.0-7.8, 7.0-7.7, 7.0-7.6. 7.0-7.5, 7.0-7.4, 7.0-7.3, 7.0-7.2, 7.0-7.1, 7.1-8.0. 7.1-7.9, 7.1-7.8, 7.1-7.7, 7.1-7.6. 7.1-7.5, 7.1-7.4, 7.1-7.3. 7.1-7.2, 7.2-8.0, 7.2-7.9, 7.2-7.8. 7.2-7.7, 7.2-7.6, 7.2-7.5. 7.2-7.4, 7.2-7.3, 7.3-8.0, 7.3-7.9, 7.3-7.8, 7.3-7.7, 7.3-7.6, 7.3-7.5, 7.3-7.4, 7.4-8.0, 7.4-7.9, 7.4-7.8, 7.4-7.7, 7.4-7.6, 7.4-7.5, 7.5-8.0, 7.5-7.9, 7.5-7.8, 7.5-7.7, 7.5-7.6, 7.5-8.0, 7.6-7.9, 7.6-7.8, 7.6-7.7, 7.7-8.0, 7.7-7.9, 7.7-7.8, 7.8-8.0, 7.8-7.9, or about 7.9-8.0).

[0686] In some embodiments of any of the ABPCs described herein, the dissociation constant (KD) of the first ABD (and optionally the second ABD, if present and if it is desired that the first and second ABDs exhibit substantially similar binding properties in this respect) at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein or in US 2022 / 0281984 at paragraph

[0779] ) is greater (e.g., detectably greater) (e.g., at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000. 7,000, 8.000, 9,000, or at least about 10,000% greater, or about 5% to about 10,000% greater, or any of the ranges of percents greater KD recited in US 2022 / 0281984 at paragraph

[0780] , which are incorporated by reference herein in their entirety) than the KD at a pH of about 7.0 to about 8.0 (e.g., any of the subranges of this range described herein).

[0687] In some embodiments of any of the antigen-binding protein constructs (ABPCs) described herein, the dissociation rate of the first ABD (and optionally the second ABD, if present and if it is desired that the first and second ABDs exhibit substantially similar binding properties in this respect) at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein or in US 2022 / 0281984 at paragraph

[0779] ) is faster (e.g., at least 0.2-fold faster, or any of the folds faster or ranges of folds faster recited in US 2022 / 0281984 at paragraph

[0779] , wh...

Claims

Attorney Docket No: 45395-0070W01WHAT IS CLAIMED IS:

1. An antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain (ABD) that is capable of specifically binding LRRC15 or an epitope of LRRC15 presented on the surface of a target mammalian cell, optionally wherein: the dissociation rate of the first ABD at a pH of -4.0-6.5 is faster than the dissociation rate at a pH of -7.0-8.0; and / or the KD of the first ABD at a pH of -4.0-6.5 is greater than the KD at a pH of -7.0-8.0.

2. The ABPC of claim 1, wherein the first ABD comprises a heavy chain variable domain (HCVD) of SEQ ID NO: 741, SEQ ID NO: 749, SEQ ID NO: 382, SEQ ID NO: 516, SEQ ID NO: 576, SEQ ID NO: 1375, SEQ ID NO: 1383, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO: 1423, SEQ ID NO: 1431, SEQ ID NO: 1441, SEQ ID NO: 1557, or SEQ ID NO: 1561, each HCVD optionally including one or more histidine substitution; and / or wherein the first ABD comprises a light chain variable domain (LCVD) of SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 700, SEQ ID NO: 1376, SEQ ID NO: 1384, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, SEQ ID NO: 1432, OR SEQ ID NO: 1442, each LCVD optionally including one or more histidine substitution;and / orwherein the ABD comprises one of (a) to (m): (a) an HCVD of hu54Fl and / or an LCVD of hu54Fl; (b) an HCVD of hu56F3 and / or an LCVD of hu56F3; (c) an HCVD of hul5G7 and / or an LCVD of hul5G7; (d) an HCVD of hu24D9 and / or an LCVD of hu24D9; (e) an HCVD of hu29Fl and / or an LCVD of hu29Fl; (f) an HCVD of hulElO and / or an LCVD of hulElO; (g) an HCVD of hu6F7 and / or an LCVD of hu6F7; (h) an HCVD of hul6D12 and / or an LCVD of hul6D12; (i) an HCVD of hu26Dl 1 and / or an LCVD of hu26Dl 1; (j) an HCVD of hul7D2 and / or an LCVD of hul7D2; (k) an HCVD of hul2Dl and / or an LCVD of hul2Dl; (1) an HCVD of hul2D7 and / or an LCVD of hul2D7; and (m) an HCVD of hul7D8 and / or an LCVD of hul7D8, each HCVD and / or LCVD optionally including one or more histidine substitution;and / orAttorney Docket No: 45395-0070W01wherein the HCVD comprises the sequence of: SEQ ID NO: 741, SEQ ID NO: 749, SEQ ID NO: 382, SEQ ID NO: 516, SEQ ID NO: 576, SEQ ID NO: 1375, SEQ ID NO: 1383, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO: 1423, SEQ ID NO: 1431, SEQ ID NO: 1441, SEQ ID NO: 1557, or SEQ ID NO: 1561, each HCVD optionally comprising at least one total histidine substitution in the CDRs; and wherein the LCVD comprises the sequence of: SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 700, SEQ ID NO: 1376, SEQ ID NO: 1384, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, SEQ ID NO: 1432, OR SEQ ID NO: 1442, each LCVD optionally comprising at least one total histidine substitution in the CDRs;and / orwherein the first ABD comprises an HCVD comprising the HCDR1,2,3 sequences set forth in one of (a) to (m): (a) SEQ ID NOs: 743, 744, and 745; (b) SEQ ID NOs: 751, 752, and 753; (c) SEQ ID NOs: 379, 380, and 381; (d) SEQ ID NOs: 513, 514, and 515; (e) SEQ ID NOs: 573, 574, and 575; (f) SEQ ID NOs: 1377-1379; (g) SEQ ID NOs: 1385-1387; (h) SEQ ID NOs: 1393-1395; (i) SEQ ID NOs: 1401-1403; (j) SEQ ID NOs: 1409-1411; (k) SEQ ID NOs: 1417-1419; (1) SEQ ID NOs: 1425-1427; and (m) SEQ ID NOs: 1433-1435, wherein each set of three HCDRs and / or three LCDRs has a total of one or more position(s) substituted with a histidine.

3. The ABPC of claim 2, wherein the first ABD comprises an HCVD and an LCVDone of (a) to (m):(a) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 743, 744, and 745; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 746, 747, and 748;(b) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 751, 752, and 753; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 754, 755, and 756;(c) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 379, 380, and 381; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 452, 453, and 454;Attorney Docket No: 45395-0070W01(d) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 513, 514, and 515; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 519, 520, and 521;(e) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 573, 574, and 575; and an LCVD comprising the LCDR1,2,3 sequences set forth in SEQ ID NOs: 578, 579, and 580;(f) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1377, 1378, and 1379; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1380, 1381, and 1382;(g) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1385- 1387; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1388- 1390;(h) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1393- 1395; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1396- 1398;(i) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1401- 1403; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1404- 1406;(j) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1409- 1411; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1412- 1414;(k) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1417- 1419; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1420- 1422;(l) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1425- 1427; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1428- 1430; and(m) an HCVD comprising the HCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1433-1435; and an LCVD comprising the LCDR1, 2, 3 sequences set forth in SEQ ID NOs: 1436-1438; andoptionally wherein each set of six CDRs, comprising the three HCDRs and the three LCDRs, has a total of one or more amino acid position(s) substituted with a histidine.Attorney Docket No: 45395-0070W014. The ABPC of any one of the preceding claims, wherein the first ABD comprises one of (a) to (o):(a) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 741, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs of SEQ ID NO: 741, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 741 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 742, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 742, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 742;(b) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 749, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs of SEQ ID NO: 749, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 749 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 750, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 750, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 750;(c) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 382, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs of SEQ ID NO: 382, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 382 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 455, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 455, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 455;(d) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 382, wherein theAttorney Docket No: 45395-0070W01HCVD includes a histidine at one or more total amino acid positions in the HCDRs of SEQ ID NO: 382, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 382 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 489, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 489, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 489;(e) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 516, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs of SEQ ID NO: 516, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 516 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 522, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 522, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 522; and(f) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 576, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 576, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 576 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 581, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 581, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 581;(g) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 576, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 576, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 576 and anAttorney Docket No: 45395-0070W01LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 700, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 700, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 700;(h) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1375, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1375, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1375 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1376, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1376, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1376;(i) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1383, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1383, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1383 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1384, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1384, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1384;(j) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1391, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1391, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1391 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1392, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1392,Attorney Docket No: 45395-0070W01optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1392;(k) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1399, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1399, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1399 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1400, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1400, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1400;(l) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1407, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1407, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1407 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1408, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1408, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1408;(m) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1415, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1415, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1415 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1416, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1416, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1416;Attorney Docket No: 45395-0070W01(n) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1423, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1423, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1423 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1424, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 1424, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 1424; and(o) an HCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 1431, wherein the HCVD includes a histidine at one or more total amino acid positions in the HCDRs in the CDRs in the sequence of SEQ ID NO: 1431, optionally wherein apart from the histidine at the one or more amino acid positions, the HCVD comprises the HCDRs of the sequence of SEQ ID NO: 1431 and an LCVD comprising a sequence that is identical to, or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, the sequence of SEQ ID NO: 581, wherein the LCVD includes a histidine at one or more total amino acid positions in the LCDRs of SEQ ID NO: 581, optionally wherein apart from the histidine at the one or more amino acid positions, the LCVD comprises the LCDRs of the sequence of SEQ ID NO: 581.

5. The ABPC of any one of the preceding claims, wherein the HCVD comprises the sequence of one of the following: SEQ ID NO: 741, SEQ ID NO: 749, SEQ ID NO: 382, SEQ ID NO: 516, SEQ ID NO: 576, SEQ ID NO: 1391, SEQ ID NO: 1399, SEQ ID NO: 1407, SEQ ID NO: 1415, SEQ ID NO: 1423, and SEQ ID NO: 1431; and wherein the LCVD comprises the sequence of one of the following: SEQ ID NO: 742, SEQ ID NO: 750, SEQ ID NO: 455, SEQ ID NO: 489, SEQ ID NO: 700, SEQ ID NO: 522, SEQ ID NO: 581, SEQ ID NO: 1392, SEQ ID NO: 1400, SEQ ID NO: 1408, SEQ ID NO: 1416, SEQ ID NO: 1424, and SEQ ID NO: 1432; orwherein the first ABD comprises one of (a) to (m):(a) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 741, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 741, and / or (3) the sequence of SEQ ID NO: 741 or the sequence of SEQ ID NO: 741Attorney Docket No: 45395-0070W01substituted with a histidine at position 34, 35, 54, 55, 58, 97, 103, 110, or 111, and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 742, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 742, and / or (3) the sequence of SEQ ID NO: 742 substituted with a histidine at one or more position;(b) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 749, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 749, and / or (3) the sequence of SEQ ID NO: 749 or the sequence of SEQ ID NO: 749 substituted with a histidine at position 31, 32, 33, 34, 35, 50, 51, 52, 53, 54, 55, 56, 57, 101, 102, or 105 and an LCVD comprising (1) the CDRs of, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 750, and / or (3) the sequence of SEQ ID NO: 750 substituted with a histidine at position 29, 30, 31, 32, 50, or 92;(c) an HCVD comprising (1) the CDRs of, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to, and / or (3) the sequence of SEQ ID NO: 382 or the sequence of SEQ ID NO: 382 substituted with a histidine at position 32, 34, 53, 60, 104, 105, 106, 110, or 111 and an LCVD comprising (1) the CDRs of, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to, and / or (3) the sequence of SEQ ID NO: 455 substituted with a histidine at position 29, 30, 32, 34, 50, 92, 93, 95, 96, or 97;(d) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 516, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 516, and / or (3) the sequence of SEQ ID NO: 516 or the sequence of SEQ ID NO: 516 substituted with a histidine at position 30, 31, 32, 52, 53, 58, 59, 60, 100, 107, 108, or 112 and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 522, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 522, and / or (3) the sequence of SEQ ID NO: 522 substituted with a histidine at position 35 or 97;(e) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 576, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 576, and / or (3) the sequence of SEQ ID NO: 576 or the sequence of SEQ ID NO: 576 substituted with a histidine and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 581, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 581, and / or (3) the sequence of SEQ ID NO: 581 substituted with a histidine;(I) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1375, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence ofAttorney Docket No: 45395-0070W01SEQ ID NO: 1375, and / or (3) the sequence of SEQ ID NO: 1375 and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1376, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1376, and / or (3) the sequence of SEQ ID NO: 1376 substituted with a histidine;(g) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1383, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1383, and / or (3) the sequence of SEQ ID NO: 1383and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1384, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1384, and / or (3) the sequence of SEQ ID NO: 1384 substituted with a histidine at position 92, 93, 97, 99, or 100;(h) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1391, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1391, and / or (3) the sequence of SEQ ID NO: 1391 or the sequence of SEQ ID NO: 1391 substituted with a histidine at position 35, 36, 51, 53, 54, 57, 59, 61, or 101 and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1392, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1392, and / or (3) the sequence of SEQ ID NO: 1392 substituted with a histidine at position 32, 50, 90, 91, 93, or 97;(i) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1399, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1399, and / or (3) the sequence of SEQ ID NO: 1399 or the sequence of SEQ ID NO: 1399 substituted with a histidine and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1400, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1400, and / or (3) the sequence of SEQ ID NO: 1400 substituted with a histidine;(j) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1407, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1407, and / or (3) the sequence of SEQ ID NO: 1407 or the sequence of SEQ ID NO: 1407 substituted with a histidine at position 99, 100, 101, 102, 103, 106, 107, 110, 111, 112, or 113 and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1408, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1408, and / or (3) the sequence of SEQ ID NO: 1408 substituted with a histidine at position 24, 25, 26, 30, 31, 32, 33, 34, 53, 54, 55, 93, 95, or 101;Attorney Docket No: 45395-0070W01(k) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1415, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1415, and / or (3) the sequence of SEQ ID NO: 1415 or the sequence of SEQ ID NO: 1415 substituted with a histidine at position 33, 50, 55, 57, 60, 62, or 101 and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1416, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1416, and / or (3) the sequence of SEQ ID NO: 1416 substituted with a histidine at position 29, 31, 32, 93, 94, 95, 96, 97, or 98;(l) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1423, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1423, and / or (3) the sequence of SEQ ID NO: 1423 or the sequence of SEQ ID NO: 1423 substituted with a histidine at position 27, 28, 31, 33, 35, 36, 51, 53, 55, 57, 58, 97, 98, 100, or 104 and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1424, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1424, and / or (3) the sequence of SEQ ID NO: 1424 substituted with a histidine at position 50, 90, 91, 93, 98, or 99; and(m) an HCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1431, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1431, and / or (3) the sequence of SEQ ID NO: 1431 or the sequence of SEQ ID NO: 1431 substituted with a histidine and an LCVD comprising (1) the CDRs of the sequence of SEQ ID NO: 1432, (2) an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the sequence of SEQ ID NO: 1432, and / or (3) the sequence of SEQ ID NO: 1432 substituted with a histidine.

6. The ABPC of any one of the preceding claims, comprising a first ABD comprising an HCVD and an LCVD comprising the HCDR1,2,3 and LCDR1,2,3 sequences, respectively, of one of (a) to (m):(a) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 743, 744, and 745 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 746, 747, and 748;(b) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 751, 752, and 753 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 754, 755, and 756;(c) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 379, 380, and 381 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 452, 453, and 454;Attorney Docket No: 45395-0070W01(d) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 513, 514, and 515 and anLCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 519, 520, and 521;(e) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 573, 574, and 575 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 578, 579, and 580;(f) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1377, 1378, and 1379 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1380, 1381, and 1382;(g) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1385-1387 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1388-1390;(h) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1393-1395 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1396-1398;(i) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1401-1403 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1404-1406;(j) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1409-1411 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1412-1414;(k) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1417-1419 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1420-1422;(l) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1425-1427 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1428-1430; and(m) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1433-1435 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1436-1438; optionally wherein each set of three HCDR1,2,3 sequences and / or set of three LCDR1,2,3 sequences has collectively one or more amino acid position substituted with a histidine or an alanine in the case where a histidine was already present.

7. The ABPC of any one of the preceding claims, wherein the first ABD comprises one of (a) to (m):(a) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 743, 744, and 745 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 746, 747, and 748;(b) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 751, 752, and 753 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 754, 755, and 756;(c) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 379, 380, and 381 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 452, 453, and 454;Attorney Docket No: 45395-0070W01(d) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 513, 514, and 515 and anLCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 519, 520, and 521;(e) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 573, 574, and 575 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 578, 579, and 580;(f) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1377, 1378, and 1379 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1380, 1381, and 1382;(g) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1385-1387 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1388-1390;(h) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1393-1395 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1396-1398;(i) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1401-1403 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1404-1406;(j) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1409-1411 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1412-1414;(k) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1417-1419 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1420-1422;(l) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1425-1427 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1428-1430; and(m) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1433-1435 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1436-1438; optionally wherein each set of three HCDR1,2,3 sequences and / or set of three LCDR1,2,3 sequences has collectively one or more amino acid position substituted with a histidine, and wherein said histidine substitution causes the ABPC to exhibit pH-dependent binding for LRRC15 relative to its corresponding unsubstituted parent ABPC.

8. The ABPC of any one of the preceding claims, wherein the first ABD comprises one of (al) to (ml):(al) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 743, 744, and 745 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 746, 747, and 748;(bl) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 751, 752, and 753 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 754, 755, and 756;Attorney Docket No: 45395-0070W01(cl) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 379, 380, and 381 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 452, 453, and 454;(dl) an HCVD comprising the HCDR1, 2, 3 sequences of SEQ ID NOs: 513, 514, and 515 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 519, 520, and 521;(el) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 573, 574, and 575 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 578, 579, and 580;(fl) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1377, 1378, and 1379 and an LCVD comprising the LCDR1, 2, 3 sequences of SEQ ID NOs: 1380, 1381, and 1382;(gl) an HCVD comprising the HCDR1, 2, 3 sequences of SEQ ID NOs: 1385-1387 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1388-1390;(hl) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1393-1395 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1396-1398;(il) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1401-1403 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1404-1406;(j 1) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1409-1411 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1412-1414;(kl) an HCVD comprising the HCDR1, 2, 3 sequences of SEQ ID NOs: 1417-1419 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1420-1422;(11) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1425-1427 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1428-1430; and(ml) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1433-1435 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1436-1438; and optionally wherein each set of six CDRs recited in al, bl, cl, dl, el, fl, gl, hl, il, jl, kl, 11, and ml has a total of one or more amino acid positions substituted with a histidine, and wherein said histidine substitution causes the ABPC to exhibit pH-dependent binding for LRRC15 relative to its corresponding unsubstituted control ABPC; andwherein the second ABD comprises one of (a2) to (m2):(a2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 743, 744, and 745 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 746, 747, and 748;(b2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 751, 752, and 753 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 754, 755, and 756;Attorney Docket No: 45395-0070W01(c2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 379, 380, and 381 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 452, 453, and 454;(d2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 513, 514, and 515 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 519, 520, and 521;(e2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 573, 574, and 575 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 578, 579, and 580;(f2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1377, 1378, and 1379 and an LCVD comprising the LCDR1, 2, 3 sequences of SEQ ID NOs: 1380, 1381, and 1382;(g2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1385-1387 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1388-1390;(h2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1393-1395 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1396-1398;(i2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1401-1403 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1404-1406;(j2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1409-1411 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1412-1414;(k2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1417-1419 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1420-1422;(12) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1425-1427 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1428-1430; and(m2) an HCVD comprising the HCDR1,2,3 sequences of SEQ ID NOs: 1433-1435 and an LCVD comprising the LCDR1,2,3 sequences of SEQ ID NOs: 1436-1438; and optionally wherein each set of six CDRs recited in a2, b2, c2, d2, e2, f2, g2, h2, i2, j2, k2, 12, and m2 has a total of one or more amino acid positions substituted with a histidine, and wherein said histidine substitution causes the ABPC to exhibit pH-dependent binding for LRRC15 relative to its corresponding unsubstituted control ABPC; andwherein only the first or second ABD, but not both the first and second ABD, exhibit said pH-dependent binding.

9. The ABPC of claim 8, wherein the first ABD and second ABD pairs are selected from one of the following pairs: al and a2, al and b2, al and c2, al and d2, al and e2, al and 12, al and g2, al and h2, al and i2, al and j2, al and k2, al and 12, al and m2, bl and a2, bl and b2, bl and c2, bl and d2,Attorney Docket No: 45395-0070W01bl and e2, bl and £2, bl and g2, bl and h2, bl and i2, bl and j2, bl and k2, bl and 12, bl and m2, cl and a2, cl and b2, cl and c2, cl and d2, cl and e2, cl and f2, cl and g2, cl and h2, cl and i2, cl and j2, cl and k2, cl and 12, cl and m2, dl and a2, dl and b2, dl and c2, dl and d2, dl and e2, dl and 12, dl and g2, dl and h2, dl and i2, dl and j2, dl and k2, dl and 12, dl and m2, el and a2, el and b2, el and c2, el and d2, el and e2, el and 12, el and g2, el and h2, el and i2, el and j2, el and k2, el and 12, el and m2, fl and a2, fl and b2, fl and c2, fl and d2, fl and e2, fl and 12, fl and g2, fl and h2, fl and i2, fl and j2, fl and k2, fl and 12, fl and m2, l and a2, l and b2, gl and c2, gl and d2, gl and e2, gl and 12, gl and g2, gl and h2, gl and i2, gl and j2, gl and k2, gl and 12, gl and m2, hl and a2, hl and b2, hl and c2, hl and d2, hl and e2, hl and 12, hl and g2, hl and h2, hl and i2, hl and j2, hl and k2, hl and 12, hl and m2, il and a2, il and b2, il and c2, il and d2, il and e2, il and f2, il and g2, il and h2, il and i2, il and j2, il and k2, il and 12, il and m2, jl and a2, jl and b2, j 1 and c2, j 1 and d2, j 1 and e2, j 1 and £2, j 1 and g2, j 1 and h2, j 1 and i2, j 1 and j2, j 1 and k2, j 1 and 12, j 1 and m2, kl and a2, kl and b2, kl and c2, kl and d2, kl and e2, kl and 12, kl and g2, kl and h2, kl and i2, kl and j2, kl and k2, kl and 12, kl and m2, 11 and a2, 11 and b2, 11 and c2, 11 and d2, 11 and e2, 11 and £2, 11 and g2, 11 and h2, 11 and i2, 11 and j2, 11 and k2, 11 and 12, 11 and m2, ml and a2, ml and b2, ml and c2, ml and d2, ml and e2, ml and f2, ml and g2, ml and h2, ml and i2, ml and j2, ml and k2, ml and 12, ml and m2.

10. The ABPC of claim 9, comprising one of (a) to (m):(a) a first ABD according to 9(a) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(b) a first ABD according to 9(b) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(0, 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(c) a first ABD according to 9(c) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(d) a first ABD according to 9(d) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(e) a first ABD according to 9(e) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);Attorney Docket No: 45395-0070W01(f) a first ABD according to 9(f) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(g) a first ABD according to 9(g) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(h) a first ABD according to 9(h) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(i) a first ABD according to 9(i) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(0, 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(j) a first ABD according to 9(j) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(0, 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(k) a first ABD according to 9(k) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(0, 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m);(l) a first ABD according to 9(1) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(0, 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m); and(m) a first ABD according to 9(m) and a second ABD according to 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g), 9(h), 9(i), 9(j), 9(k), 9(1), or 9(m).

11. The ABPC of any one of the preceding claims, which is a multispecific ABPC, comprising a first LRRC 15 -binding domain that specifically binds to a first epitope of LRRC15 and a second LRRC15-binding domain that specifically binds to a second distinct epitope of LRRC 15, wherein one of the following (a) to (q) applies:(a) the first domain binds to epitope 1 and the second domain binds to epitope 2.1; or wherein the first domain binds to epitope 2.1 and the second domain binds to epitope 1;(b) the first domain binds to epitope 2.1 and the second domain binds to epitope 2.2; or wherein the first domain binds to epitope 2.2 and the second domain binds to epitope 2.1; (c) the first domain binds to epitope 2.1 and the second domain binds to epitope 5; or wherein the first domain binds to epitope 5 and the second domain binds to epitope 2.1;(d) the first domain binds to epitope 2.2 and the second domain binds to epitope 4; or wherein the first domain binds to epitope 4 and the second domain binds to epitope 2;Attorney Docket No: 45395-0070W01(e) the first domain binds to epitope 5 and the second domain binds to epitope 2.2; or wherein the first domain binds to epitope 2.2 and the second domain binds to epitope 5;(f) the first domain binds to epitope 5 and the second domain binds to epitope 2.2; or wherein the first domain binds to epitope 2.2 and the second domain binds to epitope 5;(g) the first domain binds to epitope 5 and the second domain binds to epitope 2.3; or wherein the first domain binds to epitope 2.3 and the second domain binds to epitope 5; and (h) the first domain binds to epitope 1 and the second domain binds to compatible epitope; (i) the first domain binds to epitope 2 and the second domain binds to compatible epitope; (j) the first domain binds to epitope 2.1 and the second domain binds to compatible epitope; (k) the first domain binds to epitope 2.2 and the second domain binds to compatible epitope; (l) the first domain binds to epitope 2.3 and the second domain binds to compatible epitope; (m) the first domain binds to epitope 2.4 and the second domain binds to compatible epitope; (n) the first domain binds to epitope 3 and the second domain binds to compatible epitope; (o) the first domain binds to epitope 4 and the second domain binds to compatible epitope; (p) the first domain binds to epitope 5 and the second domain binds to compatible epitope; and(q) the first domain binds to epitopes 4 and 2.3 and the second domain binds to compatible epitope.

12. The multispecific ABPC of claim 11, wherein the first ABD and second ABD are selected from the following pairs of ABDs, respectively: a hulElO ABD and a hul5G7 ABD; a hul5G7 and a hul6D12 ABD; a hul5G7 ABD and a hu26Dl 1 ABD; a hul5G7 ABD and a hu54Fl ABD; a hul5G7 ABD and a hul39.10 ABD; a hul5G7 ABD and a hul7D2 ABD; a hul5G7 ABD and a hul2Dl ABD; a hu15G7 ABD and a hu!2D7 ABD; a hul5G7 ABD and a hul7D8 ABD; a hu15G7 ABD and a hu56F3 ABD; a pH-dependent hul5G7 ABD and a hu6F7 ABD; a pH-dependent hul5G7 ABD and a hul6D12 ABD; a pH-dependent hul5G7 ABD and a hu26Dl 1 ABD; a pH-dependent hul5G7 ABD and a hu54Fl ABD; a pH-dependent hul5G7 ABD and a hul39.10 ABD; a pH-dependent hul5G7 ABD and a hul7D2 ABD; a pH-dependent hul5G7 ABD and a hul7D8 ABD; a pH-dependent hul5G7 ABD and a hu56F3 ABD; a hu24D9 ABD and a hul6D12 ABD; a hu24D9 ABD and a hu26Dl 1 ABD; a hu24D9 ABD and a hul2Dl ABD; a hu24D9 ABD and a hul2D7 ABD; a hu24D9 ABD and a hul7D8 ABD; a hu24D9 ABD and a hu56F3 ABD; a hu29Fl ABD and a hul6D12 ABD; a hu29Fl ABD and a hu26Dl 1 ABD; a hu29Fl ABD and a hu54Fl ABD; a hu29Fl ABD and a hu 139.10 ABD; a hu29Fl ABD and a hul7D2 ABD; a hu29Fl ABDAttorney Docket No: 45395-0070W01and a hul7D8 ABD; a hu29Fl ABD and a hu56F3 ABD; a pH-dependent hu29Fl ABD and a hu6F7 ABD; a pH-dependent hu29Fl ABD and a hul6D12 ABD; a pH-dependent hu29Fl ABD and a hu26Dl 1 ABD; a pH-dependent hu29Fl ABD and a hu54Fl ABD; a pH-dependent hu29Fl ABD and a hul39.10 ABD; a pH-dependent hu29Fl ABD and a hul7D2 ABD; a pH-dependent hu29Fl ABD and a hu!7D8 ABD; a pH-dependent hu29Fl ABD and a hu56F3 ABD; a hu!6D12 ABD and a hul2D7 ABD; a hu56F3 ABD and a hul5G7 ABD; a hu56F3 ABD and a pH-dependent hul5G7 ABD; a hu56F3 ABD and a hu24D9 ABD; a hu56F3 ABD and a hu29Fl ABD; a hu56F3 ABD and a pH-dependent hu29Fl ABD; a hu56F3 ABD and a hul6D12 ABD; a hu56F3 ABD and a hu54Fl ABD; a hu56F3 ABD and a hul39.10 ABD; a hu56F3 ABD and a hul7D2 ABD; and, a hu56F3 ABD and a hul7D8.

13. The multispecific ABPC of claim 11 or 12, wherein the epitope 2.1 binding domain comprises a heavy chain variable domain (HCVD) and light chain variable domain (LCVD) of hul5G7, hu24D9, hu29Fl, or a pH-dependent variant of any one of them; and / or wherein the epitope 2.2 binding domain comprises an HCVD and LCVD of hu54Fl or a pH-dependent variant thereof, an HCVD and LCVD of hul6D12 or a pH-dependent variant thereof, or an HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof; optionallywherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu15G7 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu54Fl or a pH-dependent variant thereof, the HCVD and LCVD of hul6D12 or a pH-dependent variant thereof, or the HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu15G7 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu54Fl or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hul5G7 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hul6D12 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hul5G7 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof; orAttorney Docket No: 45395-0070W01wherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu24D9 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu54Fl or a pH-dependent variant thereof, the HCVD and LCVD of hul6D12 or a pH-dependent variant thereof, or the HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu24D9 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu54Fl or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu24D9 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hul6D12 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu24D9 or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu29Fl or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu54Fl or a pH-dependent variant thereof, the HCVD and LCVD of hul6D12 or a pH-dependent variant thereof, or the HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu29Fl or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu54Fl or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu29Fl or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hul6D12 or a pH-dependent variant thereof; orwherein the epitope 2.1 binding domain comprises the HCVD and LCVD of hu29Fl or a pH-dependent variant thereof; and the epitope 2.2 binding domain comprises the HCVD and LCVD of hu26Dl 1 or a pH-dependent variant thereof.

14. The multi specific ABPC of any one of claims 11 to 13, wherein:Attorney Docket No: 45395-0070W01(a) the epitope 2.1 binding domain comprises the HCDR1,2,3 and LCDR1,2,3 sequences of the HCVD and LCVD amino acid sequences of (1) SEQ ID NOs: 382 and 455 (reciting the hul5G7 VH and VL sequences, respectively), (2) SEQ ID NOs: 382 and 489 (reciting the pH-dependent var-hul5G7 VH and VL sequences, respectively), (3) SEQ ID NOs: 516 and 522 (reciting the hu24D9 VH and VL sequences, respectively), (4) SEQ ID NOs 576 and 581 (reciting the hu29F l VH and VL sequences, respectively), (5) SEQ ID NOs 576 and 700 (reciting the hu29Fl-var VH and VL sequences, respectively), or epitope 2.1 binding variants of any of (1), (2), (3), (4), and (5), optionally wherein the HCDR1,2,3 amino acid sequences and / or the LCDR1,2,3 amino acid sequences further include a total of one or more additional histidine substitution; and(b) the epitope 2.2 binding domain comprises the HCDR1,2,3 and LCDR1,2,3 sequences of (6) a hu54Fl ABD or a pH-dependent variant thereof, (7) a hul6D12 ABD or a pH-dependent variant thereof, or (8) a hu26Dl 1 ABD or a pH-dependent variant thereof.

15. The multispecific ABPC of claim 14, comprising (a)(1) and (b)(6); (a)(1) and (b)(7); (a)(1) and (b)(8); (a)(2) and (b)(6); (a)(2) and (b)(7); (a)(2) and (b)(8); (a)(3) and (b)(6); (a)(3) and (b)(7); (a)(3) and (b)(8); (a)(4) and (b)(6); (a)(4) and (b)(7);(a)(4) and (b)(8); (a)(5) and (b)(6); (a)(5) and (b)(7); (a)(5) and (b)(8), optionally wherein only one of the (a) and (b) components is pH-dependent, or optionally wherein both the (a) and (b) components are pH-dependent; and preferably wherein either the (a) component is included as ABDI and the (b) component is included as ABD2, or wherein the (a) component is included as ABD2 and the (b) component is included as ABDI.

16. An antigen binding protein construct (ABPC) comprising a heavy chain variable domain (HCVD) and a light chain variable domain (LCVD) comprising one of (a) to (f):(a) one of the pairs of HCVD and LCVD sequences set forth in one of the following pairs of SEQ ID NOs: SEQ ID NOs: 382 and 455; SEQ ID NOs: 382 and 489; SEQ ID NOs: 741 and 742; SEQ ID NOs: 749 and 750; SEQ ID NOs: 576 and 581, SEQ ID NOs: 576 and 700; SEQ ID NOs: 1375 and 1376; SEQ ID NOs: 1383 and 1384; SEQ ID NOs: 1391 and 1392; SEQ ID NOs: 1399 and 1400; SEQ ID NOs: 1407 and 1408; SEQ ID NOs: 1415 and 1416; SEQ ID NOs: 1423 and 1424; SEQ ID NOs: 1431 and 1432; and SEQ ID NOs: 1441 and 1442;(b) an HCVD sequence and an LCVD sequence each having the same HCDRs and LCDRs of, and at least 90%, at least 95%, or at least 98% identity to the HCVD and LCVD sequences set forth in one of the following pairs of SEQ ID NOs: SEQ ID NOs: 382 and 455;Attorney Docket No: 45395-0070W01SEQ ID NOs: 382 and 489; SEQ ID NOs: 741 and 742; SEQ ID NOs: 749 and 750; SEQ ID NOs: 576 and 581, SEQ ID NOs: 576 and 700; SEQ ID NOs: 1375 and 1376; SEQ ID NOs: 1383 and 1384; SEQ ID NOs: 1391 and 1392; SEQ ID NOs: 1399 and 1400; SEQ ID NOs: 1407 and 1408; SEQ ID NOs: 1415 and 1416; SEQ ID NOs: 1423 and 1424; SEQ ID NOs: 1431 and 1432; and SEQ ID NOs: 1441 and 1442;(c) an HCVD sequence and an LCVD sequence each having the same HCDRs and LCDRs (as determined by the Kabat system) of, and at least 90%, at least 95%, or at least 98% identity to, the HCVD and LCVD sequences set forth in one of the pairs of SEQ ID NOs: recited in (a);(d) an HCVD sequence and an LCVD sequence each having the same HCDRs and LCDRs (as determined by the IMGT system) of, and at least 90%, at least 95%, or at least 98% identity to, the HCVD and LCVD sequences set forth in one of the pairs of SEQ ID NOs: recited in (a);(e) an HCVD sequence and an LCVD sequence each having the same HCDRs and LCDRs (as determined by the additive Kabat-IMGT method) of, and at least 90%, at least 95%, or at least 98% identity to, the HCVD and LCVD sequences set forth in one of the pairs of SEQ ID NOs: recited in (a); and(! an HCVD sequence and an LCVD sequence each having the same HCDRs and LCDRs (as determined by the additive Kabat-IMGT method) of, and at least 98% identity to, the HCVD and LCVD sequences set forth in one of the pairs of SEQ ID NOs: recited in (a).

17. A multispecific antibody comprising (a) a first antigen binding domain that specifically binds a first epitope of human LRRC15, and (b) a second antigen binding domain that specifically binds to a second epitope of human LRRC15, wherein the first epitope is distinct from the second epitope, or wherein the first antigen binding domain is distinct from the second antigen binding domain, or wherein the first antigen binding domain does not compete with the second antigen binding domain, preferably wherein, the first antigen binding domain that specifically binds to the first epitope of human LRRC15 comprises:(1) a VH comprising the amino acid sequence of SEQ ID NO: 741 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 742 or a pH- dependent variant thereof;Attorney Docket No: 45395-0070W01(2) a VH comprising the amino acid sequence of SEQ ID NO: 749 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 750 or a pH-dependent variant thereof;(3) a VH comprising the amino acid sequence of SEQ ID NO: 382 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 455 or a pH-dependent variant thereof;(4) a VH comprising the amino acid sequence of SEQ ID NO: 382 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 489 or a pH-dependent variant thereof;(5) a VH comprising the amino acid sequence of SEQ ID NO: 516 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 522 or a pH-dependent variant thereof;(6) a VH comprising the amino acid sequence of SEQ ID NO: 576 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 581 or a pH-dependent variant thereof;(7) a VH comprising the amino acid sequence of SEQ ID NO: 576 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 700 or a pH-dependent variant thereof;(8) a VH comprising the amino acid sequence of SEQ ID NO: 1375 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1376 or a pH-dependent variant thereof;(9) a VH comprising the amino acid sequence of SEQ ID NO: 1383 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1384 or a pH-dependent variant thereof;(10) a VH comprising the amino acid sequence of SEQ ID NO: 1391 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1392 or a pH-dependent variant thereof;(11) a VH comprising the amino acid sequence of SEQ ID NO: 1399 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1400 or a pH-dependent variant thereof;(12) a VH comprising the amino acid sequence of SEQ ID NO: 1407 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1408 or a pH-dependent variant thereof;Attorney Docket No: 45395-0070W01(13) a VH comprising the amino acid sequence of SEQ ID NO: 1415 or a pH- dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1416 or a pH-dependent variant thereof;(14) a VH comprising the amino acid sequence of SEQ ID NO: 1423 or a pH- dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1424 or a pH-dependent variant thereof;(15) a VH comprising the amino acid sequence of SEQ ID NO: 1431 or a pH- dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1432 or a pH-dependent variant thereof;(16) a VH comprising the amino acid sequence of SEQ ID NO: 1441 or a pH-dependent variant thereof and a VL comprising the amino acid sequence of SEQ ID NO: 1442 or a pH- dependent variant thereof.

18. The multispecific antibody of claim 17, wherein the first antigen binding domain that specifically binds to the first epitope of human LRRC15 comprises a first heavy chain constant domain comprising a sequence having the sequence of one of the following:(1) a sequence of SEQ ID NO: 761 (HC Constant swap with knob and “RDEL”)(2) a sequence of SEQ ID NO: 818 (HC Constant swap with knob and “V98C”);(3) a sequence of SEQ ID NO: 762 (HC Constant with knob and “RDEL”);(4) a sequence of SEQ ID NO: 768 (HC Constant with knob and “REEM”); andwherein the second antigen binding domain that specifically binds to the second epitope of human LRRC15 comprises a second heavy chain constant domain comprising a sequence having the sequence of one of the following:(5) a sequence of SEQ ID NO: 764 (HC Constant swap with hole and “RDEL”);(6) a sequence of SEQ ID NO: 819 (HC Constant swap with hole with “V98C”);(7) a sequence of SEQ ID NO: 763 (HC Constant with hole and “RDEL”);(8) a sequence of SEQ ID NO: 769 (HC Constant with hole and “REEM”); orwherein the first antigen binding domain that specifically binds to the first epitope of human LRRC15 comprises a first heavy chain constant domain comprising a sequence having the sequence of one of the following:(5) a sequence of SEQ ID NO: 764 (HC Constant swap with hole and “RDEL”);(6) a sequence of SEQ ID NO: 819 (HC Constant swap with hole with “V98C”);Attorney Docket No: 45395-0070W01(7) a sequence of SEQ ID NO: 763 (HC Constant with hole and “RDEL”);(8) a sequence of SEQ ID NO: 769 (HC Constant with hole and “REEM”); andwherein the second antigen binding domain that specifically binds to the second epitope of human LRRC15 comprises a second heavy chain constant domain comprising a sequence having the sequence of one of the following:(1) a sequence of SEQ ID NO: 761 (HC Constant swap with knob and “RDEL”)(2) a sequence of SEQ ID NO: 818 (HC Constant swap with knob and “V98C”);(3) a sequence of SEQ ID NO: 762 (HC Constant with knob and “RDEL”);(4) a sequence of SEQ ID NO: 768 (HC Constant with knob and “REEM”).

19. The multispecific antibody of any one of claims 17 to 18, wherein the first antigen binding domain that specifically binds to the first epitope of human LRRC15 comprises a first light chain constant domain comprising a sequence having the sequence of one of the following:(1) a sequence of SEQ ID NO: 765 (LC Constant swap);(2) a sequence of SEQ ID NO: 353 (LC Constant kappa);(3) a sequence of SEQ ID NO: 770 (LC Constant kappa with V98C);and the second antigen binding domain that specifically binds to the second epitope of human LRRC15 comprises a second light chain constant domain comprising a sequence having the sequence of one of the following:(1) a sequence of SEQ ID NO: 765 (LC Constant swap);(2) a sequence of SEQ ID NO: 353 (LC Constant kappa);(3) a sequence of SEQ ID NO: 770 (LC Constant kappa with V98C).

20. The multispecific antibody of any one of claims 17 to 19, comprising the amino acid sequences set forth in one of the following series of SEQ ID NOs (a) to (h):(a) SEQ ID NOs: 382, 761, 489, 765, 741, 763, 742, and 353;(b) SEQ ID NOs: 741, 762, 742, 353, 382, 764, 489, and 765;(c) SEQ ID NOs: 382, 761, 489, 765, 749, 763, 750, and 353;(d) SEQ ID NOs: 749, 762, 750, 353, 382, 764, 489, and 765;(e) SEQ ID NOs: 382, 761, 455, 765, 741, 763, 742, and 353;(f) SEQ ID NOs: 741, 762, 742, 353, 382, 764, 455, and 765;(g) SEQ ID NOs: 382, 761, 455, 765, 749, 763, 750, and 353; andAttorney Docket No: 45395-0070W01(h) SEQ ID NOs: 749, 762, 750, 353, 382, 764, 455, and 765.

21. The multispecific antibody of any one of claims 17 to 19, comprising the amino acid sequences set forth in one of the following series of SEQ ID NOs (a) to (d):(a) SEQ ID NOs: 741, 762, 742, 353, 382, 764, 489, and 765;(b) SEQ ID NOs: 741, 762, 742, 770, 382, 819, 489, and 765;(c) SEQ ID NOs: 382, 761, 455, 765, 741, 763, 742, and 353; and(d) SEQ ID NOs: 382, 818, 455, 765, 741, 763, 742, and 770.

22. The multispecific antibody of any one of claims 17 to 19, comprising the amino acid sequences set forth in one of the following series of SEQ ID NOs (a) to (h):(a) SEQ ID NOs: 382, 818, 489, 765, 741, 763, 742, and 770;(b) SEQ ID NOs: 741, 762, 742, 770, 382, 819, 489, and 765;(c) SEQ ID NOs: 382, 818, 489, 765, 749, 763, 750, and 770;(d) SEQ ID NOs: 749, 762, 750, 770, 382, 819, 489, and 765;(e) SEQ ID NOs: 382, 818, 455, 765, 741, 763, 742, and 770;(f) SEQ ID NOs: 741, 762, 742, 770, 382, 819, 455, and 765;(g) SEQ ID NOs: 382, 818, 455, 765, 749, 763, 750, and 770; and(h) SEQ ID NOs: 749, 762, 750, 770, 382, 819, 455, and 765.

23. The ABPC or multispecific antibody of any one of the preceding claims, comprising a biparatopic anti-huLRRC15 antibody comprising VH1, HC1, VL1, LC1, VH2, HC2, VL2, and LC2 domains comprising the amino acid sequences set forth in one of the following sets of SEQ ID NOs (a) to (h), respectively:(a) SEQ ID NOs: 382, 761, 489, 765, 741, 763, 742, and 353;(b) SEQ ID NOs: 741, 762, 742, 353, 382, 764, 489, and 765;(c) SEQ ID NOs: 382, 761, 489, 765, 749, 763, 750, and 353;(d) SEQ ID NOs: 749, 762, 750, 353, 382, 764, 489, and 765;(e) SEQ ID NOs: 382, 761, 455, 765, 741, 763, 742, and 353;(f) SEQ ID NOs: 741, 762, 742, 353, 382, 764, 455, and 765;(g) SEQ ID NOs: 382, 761, 455, 765, 749, 763, 750, and 353; and(h) SEQ ID NOs: 749, 762, 750, 353, 382, 764, 455, and 765.Attorney Docket No: 45395-0070W0124. The ABPC or multispecific antibody of any one of the preceding claims, comprising a biparatopic anti-huLRRC15 antibody comprising VH1, HC1, VL1, LC1, VH2, HC2, VL2, andLC2 domains comprising the amino acid sequences set forth in one of the following sets of SEQ ID NOs (a) to (h), respectively:(a) SEQ ID NOs: 382, 818, 489, 765, 741, 763, 742, and 770;(b) SEQ ID NOs: 741, 762, 742, 770, 382, 819, 489, and 765;(c) SEQ ID NOs: 382, 818, 489, 765, 749, 763, 750, and 770;(d) SEQ ID NOs: 749, 762, 750, 770, 382, 819, 489, and 765;(e) SEQ ID NOs: 382, 818, 455, 765, 741, 763, 742, and 770;(f) SEQ ID NOs: 741, 762, 742, 770, 382, 819, 455, and 765;(g) SEQ ID NOs: 382, 818, 455, 765, 749, 763, 750, and 770; and(h) SEQ ID NOs: 749, 762, 750, 770, 382, 819, 455, and 765.

25. The ABPC or multispecific antibody of any one of the preceding claims, comprising a biparatopic anti-huLRRC 15 antibody comprising VH1, VL1, VH2, and VL2 domains comprising the amino acid sequences set forth in one of the following sets of SEQ ID NOs (a) to (h), respectively:(a) SEQ ID NOs: 382, 489, 741, and 742;(b) SEQ ID NOs: 741, 742, 382, and 489;(c) SEQ ID NOs: 382, 489, 749, and 750;(d) SEQ ID NOs: 749, 750, 382, and 489;(e) SEQ ID NOs: 382, 455, 741, and 742;(f) SEQ ID NOs: 741, 742, 382, and 455;(g) SEQ ID NOs: 382, 455, 749, and 750; and(h) SEQ ID NOs: 749, 750, 382, and 455.

26. A biparatopic anti-huLRRC15 antibody comprising VH1, VL1, VH2, and VL2 domains comprising the amino acid sequences set forth in (a) SEQ ID NOs: 741, 742, 382, and 489, respectively, or (b) SEQ ID NOs: 382, 455, 741, and 742, respectively.

27. A bispecific anti-LRRC15 x anti-Tumor- Associated Antigen (TAA) antigen binding protein construct (ABPC) comprising:Attorney Docket No: 45395-0070W01(a) a monoparatopic or biparatopic anti-LRRC15 antibody comprising an ABPC, an antibody, a multispecific antibody, or a biparatopic antibody according to any one of the preceding claims; and(b) a tumor-associated antigen binding domain (TAABD) that specifically binds to a human TAA other than LRRC 15, preferably wherein the TAA is selected from any TAA expressed, overexpressed, or amplified in a tumor associated with LRRC 15 -positive cancer associated fibroblasts (CAFs) and / or other LRRC 15 -positive stromal cells.

28. The bispecific ABPC of claim 27, wherein the TAABD is selected from a B7H3 TAABD, a B7H4 TAABD, a CEACAM5 TAABD, a MET TAABD, a DLL3 TAABD, an EGFR TAABD, a F0LR1 TAABD, a HER2 TAABD, a HER3 TAABD, an IGF1R TAABD, an ITGB6 TAABD, a MUC1 TAABD, aNECTIN4 TAABD, a PTK7 TAABD, an RNF43 TAABD, a TR0P2 TAABD, and a ZNRF3 TAABD, preferably wherein the TAABD comprises one of the following:a B7H4 binding domain described in Section 2, preferably wherein the B7H4 binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1589 and 1590, respectively;an ITGB6 binding domain described in Section 11, preferably wherein the ITGB6 binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1613 and 1614, respectively;a MET binding domain described in Section 4, preferably wherein the MET binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1597 and 1598, respectively;an EGFR binding domain described in Section 6, preferably wherein the EGFR binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1565 and 1566, respectively;a TROP2 binding domain described in Section 16, preferably wherein the TROP2 binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1505 and 1506, respectively;a NECTIN4 binding domain described in Section 13, preferably wherein the NECTIN4 binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1581 and 1582, respectively or aMUCl binding domain described in Section 12, optionally wherein the MUC1 binding domain comprises the CDRs of the HCVD and LCVD having the sequences of SEQ ID NOs: 1573 and 1574, respectively.Attorney Docket No: 45395-0070W0129. The bispecific ABPC of claim 154, wherein the B7H3 TAABD, the B7H4 TAABD, the CEACAM5 TAABD, the MET TAABD, the DLL3 TAABD, the EGFR TAABD, the F0LR1 TAABD, the HER2 TAABD, the HER3 TAABD, the IGF1R TAABD, the ITGB6 TAABD, the MUC1 TAABD, the NECTIN4 TAABD, the PTK7 TAABD, the RNF43 TAABD, the TROP2 TAABD, or the ZNRF3 TAABD comprise an HCVD and / or an LCVD including a total of one or more histidine substitutions in the amino acid position(s) of the HCDRs of the HCVD and / or the LCDRs of the LCVD.

30. The bispecific ABPC of any one of claims 27 to 29, comprising:a B7H4 binding domain comprising the HCVD and LCVD of one of the antibodies as disclosed in Section 2, preferably wherein the HCVD comprises the HCDRs of and / or the sequence of SEQ ID NO: 1589 and the LCVD comprises the LCDRs of and / or the sequence of SEQ IDNO: 1590;a MET binding domain comprising the HCVD and LCVD of one of the antibodies as disclosed in Section 4, preferably wherein the HCVD comprises the HCDRs of and / or the sequence of SEQ ID NO: 1597 and the LCVD comprises the LCDRs of and / or the sequence of SEQ IDNO: 1598;an EGFR binding domain comprising the HCVD and LCVD of one of the antibodies as disclosed in Section 6, preferably wherein the HCVD comprises the HCDRs of and / or the sequence of SEQ ID NO: 1565 and the LCVD comprises the LCDRs of and / or the sequence of SEQ IDNO: 1566;an ITGB6 binding domain comprising the HCVD and LCVD of one of the antibodies as disclosed in Section 11, preferably wherein the HCVD comprises the HCDRs of and / or the sequence of SEQ ID NO: 1613 and the LCVD comprises the LCDRs of and / or the sequence of SEQ IDNO: 1614;a NECTIN4 binding domain comprising the HCVD and LCVD of one of the antibodies as disclosed in Section 13, preferably wherein the HCVD comprises the HCDRs of and / or the sequence of SEQ ID NO: 1581 and the LCVD comprises the LCDRs of and / or the sequence of SEQ IDNO: 1582; ora TROP2 binding domain comprising the HCVD and LCVD of one of the antibodies as disclosed in Section 16, preferably wherein the HCVD comprises the HCDRs of and / or the sequence of SEQ ID NO: 1605 and the LCVD comprises the LCDRs of and / or the sequence of SEQ IDNO: 1606.Attorney Docket No: 45395-0070W0131. The bispecific ABPC of any one of claims 27 to 30, comprising:(a) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain; a first LRRC15- binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain; a second LRRC15-binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and a linker connecting the first and second LRRC 15 -binding domains;(b) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain; a first LRRC15- binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain; a second LRRC15-binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and a linker connecting the first and second LRRC15-binding domains;(c) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain; a first LRRC15- binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC1 domain; a second LRRC15-binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and a linker connecting the first and second LRRC15-binding domains;(d) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765; a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain comprising the sequence of SEQ ID NO: 763, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC1 domain comprising the sequence of SEQ ID NO: 770; a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and a linker connecting the first and second LRRC15- binding domains;(e) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 819, a VL1 domain comprising the sequence ofAttorney Docket No: 45395-0070W01SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765; a first LRRC15-binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain comprising the sequence of SEQ ID NO: 770; a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and a linker connecting the first and second LRRC 15-binding domains;(f) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765; a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 576, an HC1 domain comprising the sequence of SEQ ID NO: 763, a VL1 domain comprising the sequence of SEQ ID NO: 700, and an LC1 domain comprising the sequence of SEQ ID NO: 770; a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and (d) a linker connecting the first and second LRRC15-binding domains;(g) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 819, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765; a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain comprising the sequence of SEQ ID NO: 762, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC1 domain comprising the sequence of SEQ ID NO: 770; a second LRRC 15 -binding domain comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and a linker connecting the first and second LRRC15-binding domains;(h) a VH1 domain comprising the sequence of SEQ ID NO: 1597, an HC1 domain comprising the sequence of SEQ ID NO: 818, a VL1 domain comprising the sequence of SEQ ID NO: 1598, and an LC1 domain comprising the sequence of SEQ ID NO: 765; a first LRRC 15 -binding domain comprising a VH1 domain comprising the sequence of SEQ ID NO: 1441, an HC1 domain comprising the sequence of SEQ ID NO: 763, a VL1 domain comprising the sequence of SEQ ID NO: 1442, and an LC1 domain comprising the sequence of SEQ ID NO: 770; a second LRRC 15 -binding domain comprising an HCAb comprisingAttorney Docket No: 45395-0070W01the sequence of SEQ ID NO: 1561; and a linker connecting the first and second LRRC15-binding domains;(i) a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 819, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765; a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 576, an HC1 domain having the sequence of SEQ ID NO: 762, a VL1 domain having the sequence of SEQ ID NO: 700, and an LC1 domain having the sequence of SEQ ID NO: 770; a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and a linker connecting the first and second LRRC15 ABDs, preferably wherein the linker comprises the sequence of SEQ ID NO: 1556;(j) a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 818, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765; a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 576, an HC1 domain having the sequence of SEQ ID NO: 763, a VL1 domain having the sequence of SEQ ID NO: 700, and an LC1 domain having the sequence of SEQ ID NO: 770; a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1557; and a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 1556;(k) a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 819, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765; a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 1441, an HC1 domain having the sequence of SEQ ID NO: 762, a VL1 domain having the sequence of SEQ ID NO: 1442, and an LC1 domain having the sequence of SEQ ID NO: 770; a second LRRC15 ABD comprising an HCAb comprising the sequence of SEQ ID NO: 1561; and a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 774;(l) a VH domain having the sequence of SEQ ID NO: 1597, an HC1 domain having the sequence of SEQ ID NO: 818, a VL1 domain having the sequence of SEQ ID NO: 1598, and an LC1 domain having the sequence of SEQ ID NO: 765; a first LRRC15 ABD comprising a VH1 domain having the sequence of SEQ ID NO: 1441, an HC1 domain having the sequence of SEQ ID NO: 763, a VL1 domain having the sequence of SEQ ID NO: 1442, and an LC1 domain having the sequence of SEQ ID NO: 770; a second LRRC15 ABD comprising anAttorney Docket No: 45395-0070W01HCAb comprising the sequence of SEQ ID NO: 1561; and a linker connecting the first and second LRRC15 ABDs having the sequence of SEQ ID NO: 774;preferably wherein when the ABPC comprises a linker, the linker is selected from an amino acid sequence set forth in one of the following SEQ ID NOs: 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 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, 1556, and 162432. The ABPC or antibody of any one of the preceding claims, further comprising a linker-payload conjugated either to a cysteine of a sequence of the ABPC or antibody at an amino acid position corresponding to position 98 of the sequence of SEQ ID NO: 700 or a cysteine of a sequence of the ABPC at an amino acid position corresponding to position 14 of the sequence of SEQ ID NO: 1622.

33. The ABPC or antibody of claim 32, wherein the linker-payload is conjugated to the cysteine at amino acid position 14 of the sequence of SEQ ID NO: 1622 and / or the cysteine at amino acid position 14 of the sequence of SEQ ID NO: 1623, optionally wherein the linker-payload is conjugated to the cysteine at amino acid position 98 of the sequence of SEQ ID NO: 700, preferably wherein the linker is not cleavable by peptidases or wherein the linker more resistant to extracellular cleavage as compared with more labile linkers.

34. The ABPC or antibody of claim 33, wherein the linker is a glucuronide linker cleavable by glucuronidase, preferably wherein the linker is a 0-glucuronide linker capable of yielding a 0-glucuronide-MMAE linker-payload, preferably wherein when the resulting 0-glucuronide-MMAE linker-payload is resistant to extracellular cleavage in vivo relative to a dipeptide-PAB-MMAE linker.

35. The ABPC or antibody of claim 33, wherein the linker is a haloacetamide linker capable of forming a dipeptide-PAB-payload linker-payload, optionally wherein the payload is MMAE, and / or wherein the linker is a haloacetamide linker capable of forming a Val-Cit-PAB-payload linkerpayload, optionally wherein the payload is MMAE, and / or wherein the linker is a haloacetamide linker capable of forming a Val-Ala-PAB-payload linker payload, optionally wherein the payload is MMAE.

36. An antibody-payload conjugate (APC) comprising a glucuronide linker-payload, wherein said APC yields a lower serum level of free payload when administered in vivo to an animal as comparedAttorney Docket No: 45395-0070W01to a corresponding control APC comprising a dipeptide-PAB-payload, preferably wherein the linkerpayload of the APC and the linker-payload of the control APC are each conjugated to the same amino acid position of the antibody component of each APC.

37. An antibody-payload conjugate (APC) comprising a linker-payload produced using a haloacetamide linker, wherein the APC yields a lower serum level of free payload when administered in vivo to an animal as compared to a corresponding control APC comprising a linker payload produced using a non-haloacetamide linker-payload, preferably wherein the haloacetamide linker-payload is conjugated to the C at an amino acid position of a sequence corresponding to amino acid position 14 of the sequence of SEQ ID NO: 1622 and the non-haloacetamide linkerpayload is conjugated to a C at an amino acid position corresponding to amino acid position 98 of the sequence of SEQ ID NO: 700.

38. The ABPC or antibody of claim 33, wherein a molecule of the linker (and / or linker-payload) is conjugated to the cysteine of a serine to cysteine substitution of an amino acid sequence according to one or more of the following:(a) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 353; (b) an S to C substitution at amino acid position 121 of the sequence of SEQ ID NO: 359; (c) an S to C substitution at amino acid position 126 of the sequence of SEQ ID NO: 365; (d) an S to C substitution at amino acid position 124 of the sequence of SEQ ID NO: 371; (e) an S to C substitution at amino acid position 121 of the sequence of SEQ ID NO: 377; (f) an S to C substitution at amino acid position 121 of the sequence of SEQ ID NO: 725; (g) an S to C substitution at amino acid position 126 of the sequence of SEQ ID NO: 727; (h) an S to C substitution at amino acid position 124 of the sequence of SEQ ID NO: 729; (i) an S to C substitution at amino acid position 124 of the sequence of SEQ ID NO: 731; (j) an S to C substitution at amino acid position 124 of the sequence of SEQ ID NO: 732; (k) an S to C substitution at amino acid position 127 of the sequence of SEQ ID NO: 734; (l) an S to C substitution at amino acid position 127 of the sequence of SEQ ID NO: 736; (m) an S to C substitution at amino acid position 122 of the sequence of SEQ ID NO: 738; (n) an S to C substitution at amino acid position 122 of the sequence of SEQ ID NO: 739; (o) an S to C substitution at amino acid position 122 of the sequence of SEQ ID NO: 740; (p) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 876; (q) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 879;Attorney Docket No: 45395-0070W01(r) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 885; (s) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 933; (t) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 934 (u) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 1625; and(v) an S to C substitution at amino acid position 14 of the sequence of SEQ ID NO: 1626.

39. The ABPC or antibody of claim 38, wherein one molecule of the linker (and / or linker-payload) is conjugated to the C at position 14 of the sequence set forth in SEQ ID NO: 1622.

40. The ABPC or antibody of claim 38, wherein one molecule of the linker (and / or linker-payload) is conjugated to the C at position 14 of the sequence set forth in SEQ ID NO: 1623.

41. The ABPC or antibody of claim 38, wherein one molecule of the linker (and / or linker-payload) is conjugated to the C at an amino acid position corresponding to position 98 of the sequence of SEQ ID NO: 770.

42. The ABPC or antibody of claim 41, wherein the molecule is conjugated to the C of a at position 98 of the sequence of SEQ ID NO: 770.

43. An ABPC or antibody comprising a VH1 domain having the HCDRs of the sequence of SEQ ID NO: 741, a VL1 domain having the LCDRs of the sequence of SEQ ID NO: 742, a VH2 domain having HCDRs of the sequence of SEQ ID NO: 382, and a VL2 domain having the LCDRs of the sequence of SEQ ID NO: 489, preferably wherein the VH1 domain includes the sequence of SEQ ID NO: 741, a VL1 domain having the sequence of SEQ ID NO: 742, a VH2 domain having the sequence of SEQ ID NO: 382, and a VL2 domain having the sequence of SEQ ID NO: 489; and / or comprising a VH1 domain having the sequence of SEQ ID NO: 741, an HC1 domain having the sequence of SEQ ID NO: 762, a VL1 domain having the sequence of SEQ ID NO: 742, an LC1 domain having the sequence of SEQ ID NO: 1625, a VH2 domain having the sequence of SEQ ID NO: 382, an HC2 domain having the sequence of SEQ ID NO: 1626, a VL2 domain having the sequence of SEQ ID NO: 489, and an LC2 domain having the sequence of SEQ ID NO: 765.

44. The ABPC or antibody of claim 43, comprising a VH1 domain having the sequence of SEQ ID NO: 741, an HC1 domain having the sequence of SEQ ID NO: 762, a VL1 domain having the sequence of SEQ ID NO: 742, an LC1 domain having the sequence of SEQ ID NO: 1622, a VH2Attorney Docket No: 45395-0070W01domain having the sequence of SEQ ID NO: 382, an HC2 domain having the sequence of SEQ ID NO: 1623, a VL2 domain having the sequence of SEQ ID NO: 489, and an LC2 domain having the sequence of SEQ ID NO: 765.

45. The ABPC or antibody of any one of the preceding claims, wherein the first ABD binds specifically to a first epitope of LRRC15 and the second ABD binds to a second epitope of LRRC15, optionally wherein the first and second epitope are distinct epitopes wherein the binding of the first ABD to the first epitope does not compete with the binding of the second ABD to the second epitope.

46. The ABPC or antibody of any one of the preceding claims, wherein the ABPC or antibody comprises an ABD comprising at least one polypeptide, optionally wherein the ABD is selected from a VH domain, a VHH domain, a VNAR domain, and a scFv; and / or wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, aHSAbody, scDiabody-HSA, a tandem-scFv, or a PROTAB; and / or wherein the ABPC comprises two or more polypeptides.

47. The ABPC or antibody of any one of the preceding claims, wherein the ABPC or antibody further comprises a conjugated toxin, radioisotope, drug, nucleic acid, or small molecule.

48. A composition comprising an effective amount of an ABPC or antibody according to any one of the preceding claims,49. The ABPC or antibody of any one of the preceding claims formatted as an scFV, or wherein the ABPC or antibody comprises a first ABD that is formatted as an IgG antibody and a second ABD comprising a heavy chain only (HCAb) domain linked via a polypeptide linker to the heavy chain constant domain of the first ABD, preferably wherein the first ABD and / or the second ABD are each conjugated to a linker; optionally wherein the linker is conjugated to a linker-cargo, preferably wherein the cargo is selected from a toxin, a radioisotope, a drug, a nucleic acid, or a small molecule.

50. Use of the ABPC or antibody of any one of the preceding claims for one or more of the following methods:Attorney Docket No: 45395-0070W01a method of treating a cancer characterized by having a population of cancer cells and / or CAFs that have a predetermined level of LRRC15 or an epitope of LRRC15 presented on their surface;a method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells and / or CAFs that have a predetermined level of LRRC15 or an epitope of LRRC15 presented on their surface;a method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells and / or CAFs that have a predetermined level of LRRC15 or an epitope of LRRC15 presented on their surface, method of inducing cell death in a cancer cell and / or CAF in a subject, wherein the cancer cell and / or CAF has a predetermined level of LRRC15 or an epitope of LRRC15 presented on its surface;a method of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells, CAFs, and / or stromal cells that have a predetermined level of LRRC15 or an epitope of LRRC15 presented on their surface.

51. A pharmaceutical composition comprising an effective amount of the ABPC or antibody of any one of the preceding claims and a pharmaceutically acceptable carrier.

51. An isolated nucleic acid that encodes the ABPC of any one of the preceding claims.

52. A vector comprising the nucleic acid of claim 51.

53. A host cell comprising the nucleic acid of claim 51 or the vector of claim 52.

54. A process for producing an ABPC or antibody comprising cultivating the host cell of claim 53 and recovering the ABPC or antibody from the culture.

55. The ABPC, antibody, multispecific antibody or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant domain of the subclass of IgGl, IgG2, IgG3, or IgG4, and / or a light chain constant region of the type of kappa or lambda, preferably wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant domain of the subclass of IgGl, and a kappa light chain constant region, preferably wherein the antibody or antigen-binding fragment thereof has antibodyAttorney Docket No: 45395-0070W01dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC).

56. A kit comprising at least one dose of the ABPC, antibody, or composition of any one of the preceding claims.

57. The use of claim 50, wherein the cancer is an LRRC 15-positive cancer and / or is a cancer associated with LRRC 15 -positive stromal cells, preferably wherein the cancer is breast cancer, gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, kidney cancer, or brain cancer, preferably wherein the cancer is TNBC or an HR-negative / Her2+ breast cancer.

58. The use of claim 57, wherein the breast cancer is TNBC.

59. The use of claim 57, wherein cancer is a lung cancer, preferably a NSCLC cancer, or wherein the cancer is a head and neck cancer, preferably a head and neck squamous cell carcinoma.

60. The use of any one of claims 57 to 59, wherein the ABPC, antibody, or composition is administered in combination with another therapeutic agent.

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