BMP-7 antibody compositions & methods for treating cancer

Abstract

Aspects of the disclosure relate to BMP-7-binding proteins. Aspects include methods for treating one or more conditions, for example cancer, using a BMP-7-binding protein. In some aspects, the disclosed methods and compositions involve one or more antibodies that are capable of binding BMP-7.

Description

BMP-7 ANTIBODY COMPOSITIONS & METHODS FOR TREATING CANCER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the U.S. provisional application number 63 / 518,669 filed August 10, 2023, the disclosure of which is herein incorporated by reference in its entirety. SEQUENCE LISTING

[0002] This application contains a Sequence Listing that has been submitted via Patent Center in a computer readable format and is hereby incorporated by reference in its entirety. The computer readable file, created on August 9, 2024, is named MDACP1370WO_SequenceListing.xml and is about 89,100 bytes in size. BACKGROUND OF THE DISCLOSURE Field of the Disclosure

[0003] This disclosure relates generally to the fields of molecular biology, immunology, immunotherapy, and medicine. Background

[0004] Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies, and the mechanisms underlying this resistance are still poorly understood. For example, although antibodies blocking PD1 / PDL1 have led to impressive clinical responses in some patients with melanoma, lung cancer, or renal cell carcinoma, the objective response rates to single-agent anti-PD1 or -PDL1 therapies are only 15–25% in chemotherapy-refractory non-small cell lung cancer (NSCLC). That many patients either do not respond to or develop recurrence after immunotherapy indicates the presence of intrinsic or acquired resistance. Thus, there is a need in the art for methods and compositions for targeting the mechanisms underlying non-response to immunotherapies and for enhancing antitumor immune function to overcome treatment resistance.202424720.3 1SUMMARY

[0005] Described herein, in some aspects, are methods and compositions for effectively treating subjects with cancer (e.g., solid tumors such as non-small cell lung cancer and triple- negative breast cancer) and for sensitizing a subject with cancer to immunotherapy using polypeptides (e.g., antibodies) targeting BMP-7. In certain aspects, the BMP-7-binding proteins, for example BMP-7-neutralizing antibodies, described herein are unique in that they can specifically bind BMP-7 to overcome resistance to immunotherapies including anti-PD1, anti-PDL1, anti-TIM3, anti-LAG3, and anti-CTLA4. Thus, the methods and compositions described herein provide a novel way to treat patients with resistance to immunotherapies. In certain aspects, the BMP-7-binding proteins, for example BMP-7-neutralizing antibodies, described herein are further unique in that they can improve the efficacy of cancer therapies such as CAR-T cell therapies. Thus, the methods and compositions described herein provide a novel way to treat patients with immunotherapies.

[0006] Accordingly, provided herein, in some aspects, are methods and compositions for treating a subject with cancer comprising providing a therapy comprising a BMP-7-binding protein to the subject, where the subject has been diagnosed with or is suspected of having cancer. In some aspects, the disclosed methods comprise providing the therapy to a subject who was previously treated for cancer and was determined to be resistant to the previous treatment. In some aspects, the previous cancer treatment comprised an immunotherapy.

[0007] Aspects of the present disclosure include, inter alia, antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14, and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16. In some aspects, the VL has at least 85% identity to SEQ ID NO:14 and the VH has at least 85% identity to SEQ ID NO:16. In some aspects, the VL has at least 90% identity to SEQ ID NO:14 and the VHhas at least 90% identity to SEQ ID NO:16. In some aspects, the VLhas at least 95% identity to SEQ ID NO:14 and the VHhas at least 95% identity to SEQ ID NO:16. In some aspects, the VL comprises SEQ ID NO:14 and the VH comprises SEQ ID NO:16.202424720.3 2

[0008] Aspects of the present disclosure include, inter alia, antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:34, and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:40. In some aspects, the VL has at least 85% identity to SEQ ID NO:34 and the VH has at least 85% identity to SEQ ID NO:40. In some aspects, the VLhas at least 90% identity to SEQ ID NO:34 and the VHhas at least 90% identity to SEQ ID NO:40. In some aspects, the VLhas at least 95% identity to SEQ ID NO:34 and the VH has at least 95% identity to SEQ ID NO:40. In some aspects, the VL comprises SEQ ID NO:34 and the VH comprises SEQ ID NO:40.

[0009] Aspects of the present disclosure include, inter alia, antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:36, and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:42. In some aspects, the VL has at least 85% identity to SEQ ID NO:36 and the VH has at least 85% identity to SEQ ID NO:42. In some aspects, the VL has at least 90% identity to SEQ ID NO:36 and the VHhas at least 90% identity to SEQ ID NO:42. In some aspects, the VLhas at least 95% identity to SEQ ID NO:36 and the VH has at least 95% identity to SEQ ID NO:42. In some aspects, the VL comprises SEQ ID NO:36 and the VH comprises SEQ ID NO:42.

[0010] Aspects of the present disclosure include, inter alia, antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:38, and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:42. In some202424720.3 3aspects, the VLhas at least 85% identity to SEQ ID NO:38 and the VHhas at least 85% identity to SEQ ID NO:42. In some aspects, the VL has at least 90% identity to SEQ ID NO:38 and the VH has at least 90% identity to SEQ ID NO:42. In some aspects, the VL has at least 95% identity to SEQ ID NO:38 and the VHhas at least 95% identity to SEQ ID NO:42. In some aspects, the VL comprises SEQ ID NO:38 and the VH comprises SEQ ID NO:42.

[0011] Aspects of the present disclosure include, inter alia, antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:79, and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:81. In some aspects, the VLhas at least 85% identity to SEQ ID NO:79 and the VHhas at least 85% identity to SEQ ID NO:81. In some aspects, the VL has at least 90% identity to SEQ ID NO:79 and the VH has at least 90% identity to SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:79 and the VHhas at least 95% identity to SEQ ID NO:81. In some aspects, the VL comprises SEQ ID NO:79 and the VH comprises SEQ ID NO:81.

[0012] In some aspects, the disclosed antigen-binding proteins, antibodies, antibody-like molecules, and fragments thereof are bone morphogenetic protein (BMP)-7-binding proteins (i.e., are capable of binding to BMP-7). In some aspects, disclosed herein are monoclonal anti- BMP-7 antibodies. In some aspects, disclosed herein are chimeric anti-BMP-7 antibodies. In some aspects, disclosed herein are humanized anti-BMP-7 antibodies. Antigen-binding proteins described herein may be used in treating one or more conditions associated with expression or activity of a BMP-7 protein such as, for example, cancer. In some aspects, BMP- 7-binding proteins are be used in treating one or more BMP-7-associated conditions with reduced risk of toxicity and improved efficacy as compared to previously disclosed BMP-7- binding proteins.

[0013] Aspects include compositions comprising one or more antigen-binding proteins (e.g., BMP-7-binding proteins). Aspects include an antigen-binding protein comprising one or more regions (e.g., heavy chain variable region, light chain variable region, etc.). Aspects include monoclonal antibodies, chimeric antibodies, humanized antibodies, and antibody-like molecules. Aspects also include nucleic acid molecules encoding for one or more antigen- binding proteins or portions thereof. Aspects include recombinant, transformed, or modified202424720.3 4cells, vectors, and / or expression cassettes comprising such nucleic acid molecules. In some aspects, the compositions contemplated herein can comprise 1, 2, 3, 4, 5, or more of the following components: an antigen-binding protein, a nucleic acid, a vector, a cell, a polypeptide, an oligonucleotide, a complementarity determining region, a light chain variable region, a heavy chain variable region, a light chain constant region, a heavy chain constant region, and complementarity determining regions. Any one or more of these components may be excluded from the disclosed compositions.

[0014] Aspects of the disclosure include methods and compositions for treating a subject having cancer, methods for diagnosing a subject with cancer, methods for prognosing a subject with cancer, methods and compositions for sensitizing a subject with cancer to immunotherapy, methods for identifying a subject with cancer as a candidate for a combination therapy, and methods and compositions for treating a subject having solid tumor cancer. Methods of the disclosure can include 1, 2, 3, 4, 5, 6, or more of the following steps: providing a BMP-7 binding protein therapy to a subject, providing an immunotherapy to a subject, providing both a BMP-7 binding protein therapy and an immunotherapy to a subject, providing an alternative therapy to a subject, determining a subject to have cancer, providing two or more types of cancer therapy to a subject, identifying a subject as having had resistance to a previous cancer treatment, testing a subject for resistance to previous cancer treatments, and identifying a subject as being a candidate for a BMP-7 binding protein therapy or a double therapy comprising a BMP-7 binding protein therapy and an immunotherapy. Certain aspects of the disclosure may exclude one or more of the preceding elements and / or steps.

[0015] Aspects also include methods of generating an antigen-binding protein, methods of producing an antigen-binding protein, methods of expressing an antigen-binding protein, methods of antigen-binding proteins, methods of detecting BMP-7, methods of treating one or more conditions, methods of purifying BMP-7, methods of treating cancer, and methods of eliminating one or more cells expressing BMP-7. The steps and aspects discussed in this disclosure are contemplated as part of any of these methods. In some aspects, the methods contemplated herein can comprise or exclude 1, 2, 3, 4, 5, or more of the following steps: providing an antigen-binding protein, providing a nucleic acid to a cell, subjecting a cell to conditions sufficient to express a nucleic acid, providing an additional therapeutic, covalently attaching a therapeutic to an antigen-binding protein, non-covalently attaching a therapeutic to an antigen-binding protein, expressing a vector in a cell, and providing a pharmaceutical composition to a subject. Any one or more of these steps may be excluded from the disclosed methods.202424720.3 5

[0016] In some aspects, the disclosure relates to a bone morphogenetic protein-7 (BMP-7)- binding protein comprising: a light chain variable region (VL) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a heavy chain variable region (VH) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0017] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0018] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.202424720.3 6

[0019] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0020] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0021] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VL comprises a CDR-L1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0022] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VLcomprises a CDR-L1 having at least 85% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 85% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 85% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.202424720.3 7

[0023] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VLcomprises a CDR-L1 having at least 90% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 90% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 90% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0024] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VL comprises a CDR-L1 having at least 95% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 95% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 95% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0025] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VLcomprises a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0026] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VH comprises a CDR-H1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0027] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VH comprises a CDR-H1 having at least 85% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 85% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 85% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.202424720.3 8

[0028] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VHcomprises a CDR-H1 having at least 90% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 90% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 90% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0029] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VHcomprises a CDR-H1 having at least 95% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 95% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 95% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0030] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VH comprises a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0031] In some aspects, the VH and the VL are on the same polypeptide. In some aspects, the VH and the VL are on different polypeptides.

[0032] In some aspects, the BMP-7-binding protein has an affinity for BMP-7. In some aspects, the BMP-7-binding protein has an affinity for BMP-7 of between 0.001 and 1000 nM. In some aspects, the BMP-7-binding protein has an affinity for BMP-7 of between 0.01 and 100 nM. In some aspects, the BMP-7-binding protein has an association constant for a BMP-7 protein of between 0.1 and 50 nM. In some aspects, the BMP-7-binding protein has an association constant for a BMP-7 protein of between 1 and 20 nM. In some aspects, the BMP- 7-binding protein has an association constant for a BMP-7 protein of at least, at most, exactly, or between (inclusive or exclusive) any two of 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0.19.5, 20.0, 20.5, 21, 21.5, 22, 22.5, 23, 23.5,202424720.3 924, 24.5, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 410, 420, 425, 430, 440, 441, 450, 460, 470, 475, 480, 490, 500, 510, 520, 525, 530, 540, 550, 560, 570, 575, 580, 590, 600, 610, 620, 625, 630, 640, 650, 660, 670, 675, 680, 690, 700, 710, 720, 725, 730, 740, 750, 760, 770, 775, 780, 790, 800, 810, 820, 825, 830, 840, 850, 860, 870, 875, 880, 890, 900, 910, 920, 925, 930, 940, 950, 960, 970, 975, 980, 990, or 1000 nM, or any range derivable therein. In some aspects, the BMP-7-binding protein has an affinity for BPM-7 of about 10 nM.

[0033] In some aspects, the BMP-7-binding protein specifically binds to human BMP-7. In some aspects, the BMP-7-binding protein is an antibody, an antibody-like molecule, or an antigen-binding fragment thereof. In some aspects, the BMP-7-binding protein is an antibody, a nanobody, a minibody, an scFv fragment, or a Fab fragment. In some aspects, the BMP-7- binding protein is a human antibody, humanized antibody, recombinant antibody, chimeric antibody, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody. In some aspects, the BMP-7-binding protein is a monoclonal antibody. In some aspects, the BMP-7-binding protein is a murine antibody. In some aspects, the BMP-7- binding protein is a chimeric antibody. In some aspects, the BMP-7-binding protein is a humanized antibody. In some aspects, the BMP-7-binding protein is a human antibody.

[0034] Some aspects are directed to a nucleic acid encoding for a polypeptide or fragment thereof that specifically binds BMP-7. In some aspects, the nucleic acid encodes both the heavy chain variable region and the light chain variable region of the BMP-7-binding protein. In some aspects, the nucleic acid encodes the light chain variable region of the BMP-7-binding protein. In some aspects, the nucleic acid encodes the heavy chain variable region of the BMP-7- binding protein.

[0035] In some aspects, the nucleic acid encoding the light chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:78. In some aspects, the nucleic acid encoding the light chain variable region comprises a nucleotide sequence having at least 85%202424720.3 10identity to SEQ ID NO:13. In some aspects, the nucleic acid encoding the light chain variable region comprises a nucleotide sequence having at least 90% identity to SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:78. In some aspects, the nucleic acid encoding the light chain variable region comprises a nucleotide sequence having at least 95% identity to SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:78. In some aspects, the nucleic acid encoding the light chain variable region comprises SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:78.

[0036] In some aspects, the nucleic acid encoding the heavy chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:80. In some aspects, the nucleic acid encoding the heavy chain variable region comprises a nucleotide sequence having at least 85% identity to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:80. In some aspects, the nucleic acid encoding the heavy chain variable region comprises a nucleotide sequence having at least 90% identity to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:80. In some aspects, the nucleic acid encoding the heavy chain variable region comprises a nucleotide sequence having at least 95% identity to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:80. In some aspects, the nucleic acid encoding the heavy chain variable region comprises SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:80.

[0037] In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:13; and a heavy chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:15. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 85% identity to SEQ ID NO:13, and a heavy chain variable region comprising a nucleotide sequence having at least 85% identity to SEQ ID NO:15. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 90% identity to SEQ ID NO:13, and a heavy chain variable region comprising a nucleotide sequence having at least 90% identity to SEQ ID NO:15. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence202424720.3 11having 95% identity to SEQ ID NO:13, and a heavy chain variable region comprising a nucleotide sequence having at least 95% identity to SEQ ID NO:15. In some aspects, the nucleic acid encodes a light chain variable region comprising SEQ ID NO:13, and a heavy chain variable region comprising SEQ ID NO:15.

[0038] In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:33; and a heavy chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:39. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 85% identity to SEQ ID NO:33, and a heavy chain variable region comprising a nucleotide sequence having at least 85% identity to SEQ ID NO:39. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 90% identity to SEQ ID NO:33, and a heavy chain variable region comprising a nucleotide sequence having at least 90% identity to SEQ ID NO:39. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 95% identity to SEQ ID NO:33, and a heavy chain variable region comprising a nucleotide sequence having at least 95% identity to SEQ ID NO:39. In some aspects, the nucleic acid encodes a light chain variable region comprising SEQ ID NO:33, and a heavy chain variable region comprising SEQ ID NO:39.

[0039] In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:35; and a heavy chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 85% identity to SEQ ID NO:35, and a heavy chain variable region comprising a nucleotide sequence having at least 85% identity to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 90% identity to SEQ ID NO:35, and a heavy chain variable region202424720.3 12comprising a nucleotide sequence having at least 90% identity to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 95% identity to SEQ ID NO:35, and a heavy chain variable region comprising a nucleotide sequence having at least 95% identity to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising SEQ ID NO:35, and a heavy chain variable region comprising SEQ ID NO:41.

[0040] In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:37; and a heavy chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 85% identity to SEQ ID NO:37, and a heavy chain variable region comprising a nucleotide sequence having at least 85% identity to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 90% identity to SEQ ID NO:37, and a heavy chain variable region comprising a nucleotide sequence having at least 90% identity to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 95% identity to SEQ ID NO:37, and a heavy chain variable region comprising a nucleotide sequence having at least 95% identity to SEQ ID NO:41. In some aspects, the nucleic acid encodes a light chain variable region comprising SEQ ID NO:37, and a heavy chain variable region comprising SEQ ID NO:41.

[0041] In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:78; and a heavy chain variable region comprises a nucleotide sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:80. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 85% identity to SEQ ID NO:78, and a heavy chain variable region comprising a nucleotide sequence having at least 85% identity to SEQ202424720.3 13ID NO:80. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 90% identity to SEQ ID NO:78, and a heavy chain variable region comprising a nucleotide sequence having at least 90% identity to SEQ ID NO:80. In some aspects, the nucleic acid encodes a light chain variable region comprising a nucleotide sequence having 95% identity to SEQ ID NO:78, and a heavy chain variable region comprising a nucleotide sequence having at least 95% identity to SEQ ID NO:80. In some aspects, the nucleic acid encodes a light chain variable region comprising SEQ ID NO:78, and a heavy chain variable region comprising SEQ ID NO:80.

[0042] Also disclosed is a vector comprising one or more of the nucleic acids disclosed herein. In some aspects, the nucleic acid(s) comprised in the vector is operably linked to an expression control sequence.

[0043] Certain aspects are directed to a cell comprising a polypeptide that specifically binds BMP-7 (the BMP-7-binding protein), a nucleic acid, and / or a vector of the present disclosure. In some aspects, the cell is an immune cell. In some aspects, the cell comprises the BMP-7-binding protein and can secrete the BMP-7-binding protein outside the cell. In some aspects, the cell is a B cell. In some aspects, the cell comprises the BMP-7-binding protein, and the BMP-7-binding protein is attached to a surface of the cell. In some aspects, the BMP-7- binding protein is a chimeric antigen receptor. In some aspects, the BMP-7-binding protein is a T cell receptor. In some aspects, the cell is a T cell.

[0044] Certain aspects are directed to a composition comprising a BMP-7-binding protein, such as a BMP-7-binding protein described herein, and one or more additional therapeutics. In some aspects, the one or more additional therapeutics comprise one or more immunotherapies. In some aspects, the one or more immunotherapies comprise a cytotoxic T-lymphocyte- associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, a programmed death-ligand 1 (PDL-1) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, or a T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor. In some aspects, the one or more immunotherapies comprise a CAR-T cell therapy. In some aspects, the CAR- T cell therapy comprises EGFR-targeted CAR-T cells.

[0045] Certain aspects are directed to a composition comprising a BMP-7-binding protein, such as a BMP-7-binding protein described herein, a nucleic acid encoding for the BMP-7- binding protein, a vector comprising the nucleic acid, or a cell comprising the BMP-7-binding protein, the nucleic acid, or the vector; and a pharmaceutically acceptable excipient. In some aspects, the composition further comprises an additional therapeutic. In some aspects, the additional therapeutic comprises a biotherapeutic, a chemotherapeutic, an immunotherapeutic,202424720.3 14a toxin, an antisense oligonucleotide, a small inhibitory RNA (siRNA), an enzyme, a protein (e.g., a toxin, an enzyme, etc.), a viral vector, or a nanodrug.

[0046] In some aspects, the immunotherapeutic comprises a cytotoxic T-lymphocyte- associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, a programmed death-ligand 1 (PDL-1) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, or a T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor. In some aspects, the CTLA4 inhibitor is an anti-CTLA4 antibody. In some aspects, the PD1 inhibitor is an anti- PD1 antibody. In some aspects, the PDL-1 inhibitor is an anti-PDL-1 antibody. In some aspects, the LAG3 inhibitor is an anti-LAG3 antibody. In some aspects, the TIM-3 inhibitor is an anti-TIM-3 antibody.

[0047] In some aspects, the one or more immunotherapies comprise a CAR-T cell therapy. In some aspects, the CAR-T cell therapy comprises EGFR-targeted CAR-T cells. In some aspects, the CAR-T cell therapy comprises CAR-T cells genetically modified to have disrupted or reduced expression of one or more Bone Morphogenetic Protein (BMP) receptors (e.g., Bone Morphogenetic Protein Receptor Type 1A (BMPR1A), Bone Morphogenetic Protein Receptor Type 1B (BMPR1B), Activin A receptor type I (ACVR1), Activin receptor type 2A (ACVR2A), Activin receptor type 2B (ACVR2B), Bone morphogenetic protein receptor type 2 (BMPR2), or any combination thereof).

[0048] Other aspects are directed to a use of a composition comprising a polypeptide that specifically binds BMP-7 which in some aspects comprises an additional therapeutic agent, in the manufacture of a medicament for the treatment or prevention of cancer. Certain aspects are directed to use of the composition comprising the BMP-7-binding protein in the manufacture of a medicament for the treatment or prevention of cancer.

[0049] A further aspect is directed to a polypeptide that specifically binds BMP-7 prepared by a method described herein. Some aspects are directed to a method for generating a BMP-7- binding protein, such as a BMP-7-binding protein described herein, by culturing a cell described herein under conditions sufficient to express a BMP-7-binding protein disclosed herein in the cell. Some aspects are directed to a method for generating a BMP-7-binding protein, such as a BMP-7-binding protein described herein, comprising (a) providing to a cell a nucleic acid encoding for the BMP-7-binding protein; and (b) subjecting the cell to conditions sufficient to express the nucleic acid in the cell.

[0050] In some aspects, provided herein is a method for treating cancer in a subject comprising providing to the subject a therapeutically effective amount of a BMP-7-binding protein or a composition, such as a pharmaceutical composition, comprising a BMP-7-binding202424720.3 15protein, such as a BMP-7-binding protein described herein; a nucleic acid encoding for the BMP-7-binding protein; an expression vector comprising the nucleic acid; or a cell comprising the BMP-7-binding protein, the nucleic acid, or the vector. In some aspects, the method further comprises, prior to administering to the subject the therapeutically effective amount of a BMP- 7-binding protein or a composition, such as a pharmaceutical composition, comprising a BMP- 7-binding protein, such as a BMP-7-binding protein described herein; the nucleic acid encoding for the BMP-7-binding protein; the expression vector comprising the nucleic acid; or the cell comprising the BMP-7-binding protein, the nucleic acid, or the vector, diagnosing the subject with cancer.

[0051] In some aspects, the subject was previously treated for the cancer with a cancer therapy. In some aspects, the cancer therapy comprises one or more immunotherapies. In some aspects, the one or more immunotherapies comprise a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, a programmed death-ligand 1 (PDL-1) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, or a T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor. In some aspects, the subject was determined to be resistant to the cancer therapy.

[0052] In some aspects, the cancer is a solid tumor. In some aspects, the cancer is lung cancer, gastric cancer, brain cancer, colon cancer, melanoma, or breast cancer. In some aspects, the cancer is lung cancer. In some aspects, the lung cancer is non-small cell lung cancer. In some aspects, the cancer is breast cancer. In some aspects, the breast cancer is triple-negative breast cancer.

[0053] In some aspects, the cancer cells overexpress BMP-7 compared to non-cancerous cells. In some aspects, the cancer is pancreatic cancer, osteosarcoma, prostate cancer, colorectal cancer, malignant melanoma, breast cancer, ovarian cancer, esophageal cancer, gastric cancer, or renal cell cancer. In some aspects, the cancer is pancreatic cancer.

[0054] In some aspects, the method further comprises providing to the subject one or more additional therapies. In some aspects, the one or more additional therapies are radiotherapy, chemotherapy, or immunotherapy.

[0055] Also disclosed herein, in some aspects, is a method of increasing the efficacy of a cancer therapy administered to a subject for treatment of cancer, the method comprising administering to the subject a therapeutically effective amount of the cancer therapy and a BMP-7-binding protein or a composition, such as a pharmaceutical composition, comprising a BMP-7-binding protein, such as a BMP-7-binding protein described herein; a nucleic acid encoding for the BMP-7-binding protein; an expression vector comprising the nucleic acid; or202424720.3 16a cell comprising the BMP-7-binding protein, the nucleic acid, or the vector. In some aspects, the cancer therapy and the a BMP-7-binding protein or a composition, such as a pharmaceutical composition, comprising a BMP-7-binding protein, such as a BMP-7-binding protein described herein; a nucleic acid encoding for the BMP-7-binding protein; an expression vector comprising the nucleic acid; or a cell comprising the BMP-7-binding protein, the nucleic acid, or the vector, are comprised in the same composition. In some aspects, the cancer therapy and a BMP-7-binding protein or a composition, such as a pharmaceutical composition, comprising a BMP-7-binding protein, such as a BMP-7-binding protein described herein; a nucleic acid encoding for the BMP-7-binding protein; an expression vector comprising the nucleic acid; or a cell comprising the BMP-7-binding protein, the nucleic acid, or the vector, are comprised in the different compositions. In some aspects, the cancer therapy comprises an immunotherapy. In some aspects, the immunotherapy comprises a CAR-T cell therapy. In some aspects, the immunotherapy comprises EGFR-targeted CAR-T cells. In some aspects, the cancer cells overexpress BMP-7 compared to non-cancerous cells. In some aspects, the cancer is pancreatic cancer, osteosarcoma, prostate cancer, colorectal cancer, malignant melanoma, breast cancer, ovarian cancer, esophageal cancer, gastric cancer, or renal cell cancer. In some aspects, the cancer is pancreatic cancer.

[0056] Some aspects are directed to a monoclonal antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0057] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID202424720.3 17NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0058] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0059] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0060] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0061] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises a CDR-L1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%,202424720.3 1895%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0062] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VLcomprises a CDR-L1 having at least 85% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 85% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 85% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0063] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VLcomprises a CDR-L1 having at least 90% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 90% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 90% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0064] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises a CDR-L1 having at least 95% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 95% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 95% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0065] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0066] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VHcomprises a CDR-H1 having at least, at most, exactly, or202424720.3 19between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0067] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VH comprises a CDR-H1 having at least 85% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 85% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 85% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0068] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VH comprises a CDR-H1 having at least 90% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 90% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 90% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0069] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VHcomprises a CDR-H1 having at least 95% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 95% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 95% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0070] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VHcomprises a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.202424720.3 20

[0071] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14 and the VH comprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16. In some aspects, the VL has at least 85% identity to SEQ ID NO:14 and the VH has at least 85% identity to SEQ ID NO:16. In some aspects, the VLhas at least 90% identity to SEQ ID NO:14 and the VHhas at least 90% identity to SEQ ID NO:16. In some aspects, the VLhas at least 95% identity to SEQ ID NO:14 and the VH has at least 95% identity to SEQ ID NO:16. In some aspects, the VL comprises SEQ ID NO:14 and the VH comprises SEQ ID NO:16. In some aspects, the disclosed monoclonal antibody or antigen-binding fragment thereof is a BMP-7-binding protein (i.e., are capable of binding to BMP-7).

[0072] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VLcomprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:34 and the VHcomprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:40. In some aspects, the VL has at least 85% identity to SEQ ID NO:34 and the VHhas at least 85% identity to SEQ ID NO:40. In some aspects, the VL has at least 90% identity to SEQ ID NO:34 and the VH has at least 90% identity to SEQ ID NO:40. In some aspects, the VL has at least 95% identity to SEQ ID NO:34 and the VHhas at least 95% identity to SEQ ID NO:40. In some aspects, the VLcomprises SEQ ID NO:34 and the VH comprises SEQ ID NO:40. In some aspects, the disclosed monoclonal antibody or antigen-binding fragment thereof is a BMP-7-binding protein (i.e., are capable of binding to BMP-7).

[0073] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value202424720.3 21derivable therein, to SEQ ID NO:36 and the VHcomprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:42. In some aspects, the VLhas at least 85% identity to SEQ ID NO:36 and the VH has at least 85% identity to SEQ ID NO:42. In some aspects, the VL has at least 90% identity to SEQ ID NO:36 and the VH has at least 90% identity to SEQ ID NO:42. In some aspects, the VLhas at least 95% identity to SEQ ID NO:36 and the VH has at least 95% identity to SEQ ID NO:42. In some aspects, the VL comprises SEQ ID NO:36 and the VH comprises SEQ ID NO:42. In some aspects, the disclosed monoclonal antibody or antigen-binding fragment thereof is a BMP-7-binding protein (i.e., are capable of binding to BMP-7).

[0074] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:38 and the VH comprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:42. In some aspects, the VL has at least 85% identity to SEQ ID NO:38 and the VHhas at least 85% identity to SEQ ID NO:42. In some aspects, the VLhas at least 90% identity to SEQ ID NO:38 and the VHhas at least 90% identity to SEQ ID NO:42. In some aspects, the VL has at least 95% identity to SEQ ID NO:38 and the VH has at least 95% identity to SEQ ID NO:42. In some aspects, the VL comprises SEQ ID NO:38 and the VHcomprises SEQ ID NO:42. In some aspects, the disclosed monoclonal antibody or antigen-binding fragment thereof is a BMP-7-binding protein (i.e., are capable of binding to BMP-7).

[0075] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:79 and the VHcomprises an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:81. In some aspects, the VLhas at least 85%202424720.3 22identity to SEQ ID NO:79 and the VHhas at least 85% identity to SEQ ID NO:81. In some aspects, the VL has at least 90% identity to SEQ ID NO:79 and the VH has at least 90% identity to SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:79 and the VHhas at least 95% identity to SEQ ID NO:81. In some aspects, the VLcomprises SEQ ID NO:79 and the VH comprises SEQ ID NO:81. In some aspects, the disclosed monoclonal antibody or antigen-binding fragment thereof is a BMP-7-binding protein (i.e., are capable of binding to BMP-7).

[0076] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VHcomprising a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0077] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6; and a VH comprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:12. Some aspects are directed to an antibody comprising: a VLcomprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6; and a VHcomprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:32. Some aspects are directed to an antibody comprising: a VLcomprising a CDR-L1 comprising SEQ ID NO:20, a CDR-L2 comprising SEQ ID NO:22, and a CDR-L3 comprising SEQ ID NO:24; and a VH comprising a CDR-H1 comprising SEQ ID NO:26, a CDR-H2 comprising SEQ ID NO:28, and a CDR-H3 comprising SEQ ID NO:30. In some aspects, the VLcomprises SEQ ID NO:14. In some aspects, the VHcomprises SEQ ID NO:16.

[0078] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:50, a CDR-L2 comprising SEQ ID NO:53, and a CDR-L3 comprising SEQ ID NO:57; and a VHcomprising a CDR-H1 comprising SEQ ID NO:59, a CDR-H2 comprising SEQ ID NO:62, and a CDR-H3 comprising SEQ ID NO:65. In some aspects, the VL comprises SEQ ID NO:34. In some aspects, the VH comprises SEQ ID NO:40. In some aspects, the VLcomprises SEQ ID NO:36. In some aspects, the VHcomprises SEQ ID NO:42.202424720.3 23In some aspects, the VLcomprises SEQ ID NO:38. In some aspects, the VHcomprises SEQ ID NO:42.

[0079] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:71; and a VH comprising a CDR-H1 comprising SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:77. In some aspects, the VLcomprises SEQ ID NO:79. In some aspects, the VHcomprises SEQ ID NO:81.

[0080] Throughout this application, the terms “about” and “approximately” and “substantially” are used according to their plain and ordinary meaning in the area of cell and molecular biology to indicate a deviation of ±10% of the value(s) to which it is attached. Therefore, in any disclosed aspect, the terms may be substituted with “within [a percentage] of” what is specified. In one non-limiting aspect, the percentage includes 0.1, 0.5, 1, 5, and 10 percent.

[0081] The use of the word “a,” “an,” and “the” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Thus, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0082] The phrase “and / or” means “and” or “or”. To illustrate, A, B, and / or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, “and / or” operates as an inclusive or.

[0083] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Thus, as used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the disclosure, yet open to the inclusion of unspecified elements, whether essential or not.

[0084] The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of” any of the ingredients or steps disclosed throughout the specification. As202424720.3 24used herein the term “consisting essentially of” refers to those elements required for a given aspect. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that aspect of the disclosure. With respect to pharmaceutical compositions, the term “consisting essentially of” includes the active ingredients recited, excludes any other active ingredients, but does not exclude any pharmaceutical excipients or other components that are not therapeutically active. The term “consisting of” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the aspect.

[0085] Any method in the context of a therapeutic, diagnostic, or physiologic purpose or effect may also be described in “use” claim language such as “use of” any compound, composition, or agent discussed herein for achieving or implementing a described therapeutic, diagnostic, or physiologic purpose or effect.

[0086] It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein and that different aspects may be combined.

[0087] Reference throughout this specification to “one aspect,” “an aspect,” “a particular aspect,” “a related aspect,” “a certain aspect,” “an additional aspect,” or “a further aspect” or combinations thereof means that a particular feature, structure, or characteristic described in connection with the aspect is included in at least one aspect of the present disclosure. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same aspect. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more aspects.

[0088] Use of the one or more sequences or compositions may be employed based on any of the methods described herein. Other aspects are discussed throughout this application. Any aspect discussed with respect to one aspect of the disclosure applies to other aspects of the disclosure as well and vice versa. For example, any step in a method described herein can apply to any other method. Moreover, any method described herein may have an exclusion of any step or combination of steps. The aspects in the Example section are understood to be aspects that are applicable to all aspects of the technology described herein.

[0089] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating certain aspects of the disclosure, are given by way of illustration only, since various changes and modifications202424720.3 25within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific aspects presented herein.

[0091] FIG.1 shows titration of an antibody generated to specifically target human BMP- 7 (BMP-7 mAb #5).

[0092] FIG. 2 shows functional validation of BMP-7 mAb in macrophages treated with BMP-7 protein for 48 hours. Macrophages were treated with BMP-7 for 48 hours and p38 alpha (MAPK14) expression were evaluated by using quantitative PCR. BMP-7 mAb number 344- 5-1 demonstrated highest upregulation of p38 alpha, a marker for Th1 cytokines / chemokines.

[0093] FIGs.3A-3B show tumor growth and survival analysis of mice 129 Sv (Females) with 344SQR tumors. FIG.3A. example FIG.3B. Mouse survival rates were analyzed by the Kaplan–Meier method and compared with log-rank tests.

[0094] FIGs. 4A-4B show tumor growth and survival analysis of mice 129 Sv (Males) with 344SQR tumors. FIG.4A. Mice were treated with IgG ctrl (n=5) or anti-PD1 (10 mg / kg) (n=5) and / or Human BMP-7344-5-1 (10 mg / kg) (n=5) 3 times a week for 2 weeks. FIG.4B. Mouse survival rates were analyzed by the Kaplan–Meier method and compared with log-rank tests.

[0095] FIG. 5 shows functional validation of BMP-7 mAb antibodies in macrophages treated with BMP-7 antibody for 48 hours.

[0096] FIG.6 shows representative images of immunohistochemical stains of CD8 T cells (CD8 – brown dots) and M2 macrophages (CD163 – M2 macrophage marker) in formalin- fixed paraffin-embedded tissue sections from 344SQR tumors treated with BMP-7 mAb plus anti-PD1.

[0097] FIGs. 7A-7B show tumor growth analysis of mice 129 Sv with 344SQR tumors (non-small cell lung cancer; FIG.7A) or mice BALB / c with 4T1 tumors (triple negative breast cancer’ FIG.7B) treated with IgG ctrl (n=5) or anti-PD1 (10 mg / kg) (n=5) or Human BMP-7 mAbs (10 mg / kg) (n=5) 3 times a week for 2 weeks.202424720.3 26

[0098] FIGs. 8A-8B show tumor growth of mice 129 Sv with 344SQR primary tumors (FIG.8A) and secondary tumors (FIG.8B) treated with IgG ctrl (n=5) or anti-PD1 (10 mg / kg) (n=5) or Human BMP-7 mAb (10 mg / kg) (n=5) 3 times a week for 2 weeks.

[0099] FIG.9 shows sensor-grams of chimeric antibody binding to human BMP-7.

[0100] FIGs. 10A-10B show alignment of sequenced humanized BMP-7 monoclonal antibody VH (FIG.10A) and VL chains (FIG.10B).

[0101] FIGs. 11A-11B show alignment of selected, sequenced humanized BMP-7 monoclonal antibody VH (FIG.11A) and VL chains (FIG.11B).

[0102] FIG. 12 shows 99% purification of selected humanized BMP-7 monoclonal antibodies by SDS-PAGE. Loading order: Marker (M); AHF17901, reduced (1); AHF17906, reduced (2); AHF17909, reduced (3); AHF17901, non-reduced (4); AHF17906, non-reduced (5); AHF17909, non-reduced (6); human IgG.

[0103] FIG.13 shows sensor-grams of chimeric BMP-7 monoclonal antibody binding to human BMP-7.

[0104] FIG. 14 shows BMP-7 gene expression in Capan-2 pancreatic cancer cells, GSU gastic cancer cells, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells. BMP- 7 gene expression was measured using quantitative PCR using primers specific for BMP-7 gene.

[0105] FIG.15 shows apoptosis of Capan-2 pancreatic cancer cells by CAR-T cells after treatment with an anti-BMP-7 antibody. Apoptosis was measured using the Caspase 3 / 7 green, fluorescent dye (Essen Bioscience) analyzed by the INCUCYTE® Live-Cell Analysis System. A higher Y-axis value indicates increased apoptosis and killing capability of the CAR-T cells.

[0106] FIG. 16 shows that addition of BMP7 protein blocks the effect of apoptosis of Capan-2 pancreatic cancer cells by CAR-T cells after treatment with an anti-BMP-7 antibody. Apoptosis was measured using the Caspase 3 / 7 green, fluorescent dye (Essen Bioscience) analyzed by the INCUCYTE® Live-Cell Analysis System. A higher Y-axis value indicates increased apoptosis and killing capability of the CAR-T cells.

[0107] FIG. 17 shows that addition of BMP7 protein blocks the effect of apoptosis of Capan-2 pancreatic cancer cells by CAR-T cells after treatment with an anti-BMP-7 antibody. Apoptosis was measured using the Caspase 3 / 7 green, fluorescent dye (Essen Bioscience) analyzed by the INCUCYTE® Live-Cell Analysis System. A higher Y-axis value indicates increased apoptosis and killing capability of the CAR-T cells.202424720.3 27

[0108] FIG. 18 shows predicted target-potential vs. off-target risk for different gRNAs targeting the BMPR1B gene locus, with unique gRNAs predicted to have high target specificity highlighted in light grey.

[0109] FIG. 19 shows predicted target-potential vs. off-target risk for different gRNAs targeting the BMPR1A gene locus, with unique gRNAs predicted to have high target specificity highlighted in light grey.

[0110] FIG. 20 is a plasmid map of a lentiviral vector (VB200329-1029jwu) encoding a hCas9:T2A:Puro construct and two gRNAs (#29757 and #29702) targeting the hBMPR1B gene locus.

[0111] FIG. 21 is a plasmid map of a lentiviral vector (VB200329-1005ytw) encoding a hCas9 endonuclease and two gRNAs (#29757 and #29702) targeting the hBMPR1B gene locus.

[0112] FIG. 22 is a plasmid map of a lentiviral vector (VB200328-7336rqg) encoding a hCas9:T2A:Puro construct and two gRNAs (#14262 and #14258) targeting the hBMPR1A gene locus.

[0113] FIG. 23 is a plasmid map of a lentiviral vector (VB200328-7298grx) encoding a hCas9 endonuclease and two gRNAs (#14262 and #14258) targeting the hBMPR1A gene locus. DETAILED DESCRIPTION

[0114] Immunotherapies have been produced which provide durable disease control in some cancer patients. However, most cancer patients do not respond to immunotherapy, and even patients responding to immunotherapy will often develop resistance to the immunotherapy. Thus, there remains a need for further therapeutics that target mechanisms underlying this resistance and help to enhance antitumor immune function to overcome resistance to immunotherapies.

[0115] The present disclosure is based, at least in part, on the surprising discovery that cancer resistant to immunotherapy is responsive to a therapy comprising a BMP-7 binding protein. Further, administering a BMP-7 binding protein therapy was surprisingly found to re- sensitize tumors to immunotherapeutics. As disclosed herein, administration of a BMP-7 binding protein therapy, when associated with cancer, for example, a solid tumor cancer, relieves immunosuppression and enables efficacy of immunotherapy. The BMP-7 binding202424720.3 28proteins described can interact with functional BMP-7 protein secreted by cancer cells, for example, solid tumor cells, to neutralize BMP-7 protein and initiate downstream signaling events associated with a reduction in pro-inflammatory signaling and re-sensitization of tumors to immunotherapeutics.

[0116] Accordingly, in some aspects, disclosed are methods and compositions for treating cancer comprising administering a BMP-7 binding protein therapy to a subject having or suspected or having cancer. In some aspects, the cancer is a solid tumor cancer. In some aspects, the subject has or has previously had resistance to immunotherapy. Further aspects disclose methods for stratifying cancer patients based on a history of resistance to immunotherapy. For example, aspects are directed to methods for identifying a subject as being a candidate for a BMP-7 binding protein therapy by identifying the subject as having or having previously had resistance to immunotherapy.

[0117] The clinical relevance of a novel BMP-7 antibody and the use of such antibody for therapeutic applications, such as treatment of resistance to immunotherapies in solid tumors, is described. Antibodies of the present disclosure and derivatives thereof (e.g., antibody fragments, antibody-like molecules, etc.) may therefore be useful in the treatment of various conditions including, for example, cancer. In some aspects, antibodies of the present disclosure are useful in the treatment of cancers which overexpress BMP-7, for example, solid tumor cancers such as lung cancer, including non-small cell lung cancer and small-cell lung cancer, breast cancer, including triple negative breast cancer, brain cancer, colon cancer, melanoma, and gastric cancer. I. Examples of Definitions

[0118] “Individual, “subject,” and “patient” are used interchangeably and can refer to a human or non-human.

[0119] The terms “lower,” “lowered,” “reduce,” “reduced,” “reduction,” “decrease,” “decreased,” “inhibit,” “inhibited,” or “inhibition” are all used herein generally to mean a decrease by a statistically significant amount. However, for avoidance of doubt, “lower,” “lowered,” “reduce,” “reduced,” “reduction,” “decrease,” “decreased,” “inhibit,” “inhibited,” or “inhibition” means a decrease by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%202424720.3 29or up to and including a 100% decrease (i.e., absent level as compared to a reference sample), or any decrease between 10-100% as compared to a reference level.

[0120] The terms “increased,” “increase,” “enhanced,” “enhance,” “activated,” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, “increased,” “increase,” “enhanced,” “enhance,” “activated,” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0121] As used herein, the terms “reference,” “standard,” or “control” describe a value relative to which a comparison is performed. For example, an agent, subject, population, sample, or value of interest is compared with a reference, standard, or control agent, subject, population, sample, or value of interest. A reference, standard, or control may be tested and / or determined substantially simultaneously and / or with the testing or determination of interest for an agent, subject, population, sample, or value of interest and / or may be determined or characterized under comparable conditions or circumstances to the agent, subject, population, sample, or value of interest under assessment.

[0122] A “nucleic acid,” as used herein, is a molecule comprising nucleic acid components and refers to DNA or RNA molecules. The term “nucleic acid” may be used interchangeably with the term “polynucleotide.” A nucleic acid molecule is a polymer comprising or consisting of nucleotide monomers, which are covalently linked to each other by phosphodiester-bonds of a sugar / phosphate-backbone. Nucleic acids may also encompass modified nucleic acid molecules, such as base-modified, sugar-modified, backbone-modified, etc. DNA or RNA molecules. Nucleic acids may exist in a variety of forms such as: isolated segments and recombinant vectors of incorporated sequences or recombinant polynucleotides encoding polypeptides, e.g., antigens or one or both chains of an antibody, or a fragment, derivative, mutein, or variant thereof; polynucleotides sufficient for use as hybridization probes, PCR primers or sequencing primers for identifying, analyzing, mutating or amplifying a polynucleotide encoding a polypeptide; anti-sense nucleic acids for inhibiting expression of a polynucleotide; mRNA; saRNA; and complementary sequences of the foregoing described202424720.3 30herein. The nucleic acids can be single-stranded or double-stranded and can comprise RNA and / or DNA nucleotides and artificial variants thereof (e.g., peptide nucleic acids).

[0123] Nucleic acids may be single-stranded or double-stranded and may comprise RNA and / or DNA nucleotides and artificial variants thereof (e.g., peptide nucleic acids). In some cases, a nucleic acid sequence may encode a polypeptide sequence with additional heterologous coding sequences, for example, to allow for purification of the polypeptide, transport, secretion, post-translational modification, or for therapeutic benefits such as targeting or efficacy. A tag or other heterologous polypeptide may be added to the modified polypeptide-encoding sequence, wherein “heterologous” refers to a polypeptide that is not the same as the modified polypeptide.

[0124] The term “polynucleotide” refers to a nucleic acid molecule that may be recombinant or has been isolated from total genomic nucleic acid. Included within the term “polynucleotide” are oligonucleotides (i.e., nucleic acids 100 residues or less in length) and recombinant vectors, including, for example, plasmids, cosmids, phage, viruses, and the like. Polynucleotides include, in certain aspects, regulatory sequences, isolated substantially away from their naturally occurring genes or protein encoding sequences. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be RNA, DNA (genomic, cDNA, or synthetic), analogs thereof, or a combination thereof. Additional coding or non- coding sequences may, but need not, be present within a polynucleotide.

[0125] A “gene,” “polynucleotide,” “coding region,” “sequence,” “segment,” “fragment,” or “transgene” which “encodes” a particular protein, is a nucleic acid molecule which is transcribed and optionally also translated into a gene product, e.g., a polypeptide, in vitro or in vivo when placed under the control of appropriate regulatory sequences. As will be understood by those in the art, this term encompasses genomic sequences, expression cassettes, cDNA sequences, and smaller engineered nucleic acid segments that express, or may be adapted to express, proteins, polypeptides, domains, peptides, fusion proteins, and mutants. A nucleic acid encoding all or part of a polypeptide may contain a contiguous nucleic acid sequence encoding all or a portion of such a polypeptide. The coding region may be present in either a cDNA, genomic DNA, or RNA form. When present in a DNA form, the nucleic acid molecule may be single-stranded (i.e., the sense strand) or double-stranded. The boundaries of a coding region are determined by a start codon at the 5’ (amino) terminus (N-terminus) and a translation stop codon at the 3’ (carboxy) terminus (C-terminus). A gene can include, but is not limited to, cDNA from prokaryotic or eukaryotic mRNA, genomic DNA sequences from prokaryotic or eukaryotic DNA, and synthetic DNA sequences. A transcription termination sequence will202424720.3 31usually be located 3’ to the gene sequence. It also is contemplated that a particular polypeptide may be encoded by nucleic acids containing variations having slightly different nucleic acid sequences but, nonetheless, encode the same or substantially similar protein.

[0126] As used herein, the term “expression” of a nucleic acid sequence refers to the generation of any gene product from the nucleic acid sequence. In some aspects, a gene product may be a transcript. In some aspects, a gene product may be a polypeptide. In some aspects, expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, etc.); (3) translation of an RNA into a polypeptide or protein; and / or (4) post-translational modification of a polypeptide or protein.

[0127] In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man. For example, a polynucleotide is considered to be “engineered” when two or more sequences that are not linked together in that order in nature are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide and / or when a particular residue in a polynucleotide is non-naturally occurring and / or is caused through action of the hand of man to be linked with an entity or moiety with which it is not linked in nature.

[0128] The term “DNA,” as used herein, means a nucleic acid molecule comprising nucleotides such as deoxy-adenosine-monophosphate, deoxy-thymidine-monophosphate, deoxy-guanosine-monophosphate and deoxy-cytidine-monophosphate monomers which are composed of a sugar moiety (deoxyribose), a base moiety and a phosphate moiety, and polymerize by a characteristic backbone structure. The backbone structure is, typically, formed by phosphodiester bonds between the sugar moiety of the nucleotide, e.g., deoxyribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific order of the monomers, e.g., the order of the bases linked to the sugar / phosphate-backbone, is called the DNA sequence. DNA may be single stranded or double stranded. In the double stranded form, the nucleotides of the first strand typically hybridize with the nucleotides of the second strand, e.g., by A / T-base-pairing and G / C-base-pairing. DNA may contain all, or a majority of, deoxyribonucleotide residues. As used herein, the term “deoxyribonucleotide” means a nucleotide lacking a hydroxyl group at the 2′ position of a β-D-ribofuranosyl group. Without any limitation, DNA may encompass double stranded DNA, antisense DNA, single stranded DNA, isolated DNA, synthetic DNA, DNA that is recombinantly produced, and modified DNA.202424720.3 32

[0129] The term “RNA,” as used herein, means a nucleic acid molecule comprising nucleotides such as adenosine-monophosphate, uridine-monophosphate, guanosine- monophosphate and cytidine-monophosphate monomers which are connected to each other along a so-called backbone. The backbone is formed by phosphodiester bonds between the sugar, e.g., ribose, of a first and a phosphate moiety of a second, adjacent monomer. RNA may be obtainable by transcription of a DNA-sequence, e.g., inside a cell. In eukaryotic cells, transcription is typically performed inside the nucleus or the mitochondria. In vivo, transcription of DNA may result in premature RNA which is processed into messenger-RNA (mRNA). Processing of the premature RNA, e.g., in eukaryotic organisms, comprises various posttranscriptional modifications such as splicing, 5′ capping, polyadenylation, and / or export from the nucleus or the mitochondria. Mature messenger RNA is processed and provides the nucleotide sequence that may be translated into an amino acid sequence of a peptide or protein. A mature mRNA may comprise a 5′ cap, a 5′ UTR, an open reading frame, a 3′ UTR and a poly-A tail sequence. RNA may contain all, or a majority of, ribonucleotide residues. As used herein, the term “ribonucleotide” means a nucleotide with a hydroxyl group at the 2′ position of a β-D-ribofuranosyl group. In one aspect, RNA may be messenger RNA (mRNA) that relates to an RNA transcript which encodes a peptide or protein. As known to those of skill in the art, mRNA generally contains a 5′ untranslated region (5′ UTR), a polypeptide coding region, and a 3′ untranslated region (3′ UTR). Without any limitation, RNA may encompass double stranded RNA, antisense RNA, single stranded RNA, isolated RNA, synthetic RNA, RNA that is recombinantly produced, and modified RNA (modRNA).

[0130] The terms “protein,” “polypeptide,” or “peptide” are used herein as synonyms and refer to a polymer of amino acid monomers, e.g., a molecule comprising at least two amino acid residues. Polypeptides may include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. Polypeptides may be a single molecule or may be a multi-molecular complex such as a dimer, trimer or tetramer. A protein comprises one or more peptides or polypeptides and may be folded into a 3-dimensional form, which may be required for the protein to exert its biological function.

[0131] As used herein, the terms “wild type” or “WT” or “native” refer to the endogenous version of a molecule that occurs naturally in an organism. In some aspects, wild type versions of a protein or polypeptide are employed, however, in other aspects of the disclosure, a modified protein or polypeptide is employed. The terms described above may be used interchangeably.202424720.3 33

[0132] A “modified protein” or “modified polypeptide” or a “variant” refers to a protein or polypeptide having a chemical structure, particularly an amino acid sequence, that is altered with respect to the wild type protein or polypeptide. In some aspects, a modified / variant protein or polypeptide has at least one modified activity or function (recognizing that proteins or polypeptides may have multiple activities or functions). It is specifically contemplated that a modified / variant protein or polypeptide may be altered with respect to one activity or function yet retain a wild type activity or function in other respects, such as immunogenicity.

[0133] Where a protein is specifically mentioned herein, it is in general a reference to a native (wild type) or recombinant (modified) protein. The protein may be isolated directly from the organism of which it is native, produced by recombinant DNA / exogenous expression methods, produced by solid-phase peptide synthesis (SPPS) (i.e., an automated method wherein molecules are immobilized on a solid support and synthesized step by step in a reactant solution), liquid phase peptide synthesis (i.e., sequential addition of monomer building blocks in a liquid phase), a combination of solid and liquid phase peptide synthesis, or other in vitro methods. Assembling nucleic acids by a ligase may also be used to promote intermolecular ligation of the 5ʹ and 3′ ends of polynucleotide chains through the formation of a phosphodiester bond. In particular aspects, there are isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide (e.g., an antigen or fragment thereof). The term “recombinant” may be used in conjunction with a polypeptide or the name of a specific polypeptide, and this generally refers to a polypeptide produced from a nucleic acid molecule that has been manipulated in vitro or that is a replication product of such a molecule.

[0134] The term “fragment,” with reference to an amino acid sequence (peptide or protein), relates to a part of an amino acid sequence, e.g., a sequence which represents the amino acid sequence shortened at the N-terminus and / or C-terminus. A fragment shortened at the C- terminus (N-terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 3′-end of the open reading frame. A fragment shortened at the N-terminus (C-terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 5′-end of the open reading frame, as long as the truncated open reading frame comprises a start codon that serves to initiate translation. A fragment of an amino acid sequence comprises, e.g., at least 50 %, at least 60 %, at least 70 %, at least 80%, at least 90%, or at least 99% of the amino acid residues from an amino acid sequence. In the present disclosure, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least, at most, exactly, or between (inclusive or202424720.3 34exclusive) any two of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived.

[0135] In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 70% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived. In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 80% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived. In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 85% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived. In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 90% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived. In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 95% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived. In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 97% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived. In one aspect, a fragment of a polypeptide, DNA nucleic acid or RNA nucleic acid sequence refers to a sequence having sequence identity of at least 99% with a polypeptide, DNA nucleic acid or RNA nucleic acid sequence, from which it is derived.

[0136] As used herein in the context of molecules, e.g., nucleic acids, proteins, or small molecules, the term “variant” refers to a molecule that shows significant structural identity with a reference molecule but differs structurally from the reference molecule, e.g., in the presence or absence or in the level of one or more chemical moieties as compared to the reference entity. In some aspects, a variant also differs functionally from its reference molecule. In general, whether a particular molecule is properly considered to be a “variant” of a reference molecule is based on its degree of structural identity with the reference molecule. As will be appreciated by those skilled in the art, any biological or chemical reference molecule has certain characteristic structural elements. A variant, by definition, is a distinct molecule that shares one or more such characteristic structural elements but differs in at least one aspect from the reference molecule. In some aspects, a variant polypeptide or nucleic acid may differ from a202424720.3 35reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalent components of the polypeptide or nucleic acid (e.g., that are attached to the polypeptide or nucleic acid backbone).

[0137] Changes can be introduced by mutation into a nucleic acid, thereby leading to changes in the amino acid sequence of a polypeptide (e.g., an antibody or antibody derivative) that it encodes. Mutations can be introduced using any technique known in the art. In one aspect, one or more particular amino acid residues are changed using, for example, a site- directed mutagenesis protocol. In another aspect, one or more randomly selected residues are changed using, for example, a random mutagenesis protocol. However it is made, a mutant polypeptide can be expressed and screened for a desired property.

[0138] Mutations can be introduced into a nucleic acid without significantly altering the biological activity of a polypeptide that it encodes. For example, one can make nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues. Alternatively, one or more mutations can be introduced into a nucleic acid that selectively changes the biological activity of a polypeptide that it encodes. See, e.g., Romain Studer et al., Biochem. J.449:581-594 (2013), incorporated herein by reference. For example, the mutation can quantitatively or qualitatively change the biological activity. Examples of quantitative changes include increasing, reducing or eliminating the activity. Examples of qualitative changes include altering the antigen specificity of an antibody.

[0139] Variant polypeptides encoded by nucleic acids of the disclosure may contain amino acid changes that confer any of a number of desirable properties. Variant polypeptides can be made using routine mutagenesis techniques and assayed as appropriate to determine whether they possess the desired property. The stability of protein(s) encoded by a variant nucleic acid may be measured by assaying thermal stability or stability upon urea denaturation or may be measured using in silico prediction. Methods for such experiments and in silico determinations are known in the art.

[0140] In some aspects, a variant polypeptide or nucleic acid shows an overall sequence identity with a reference polypeptide or nucleic acid that is at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some aspects, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid. In some aspects, a reference polypeptide or nucleic acid has one or more biological activities. In some aspects, a variant polypeptide or nucleic acid shares one or more of the biological202424720.3 36activities of the reference polypeptide or nucleic acid. In some aspects, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some aspects, a variant polypeptide or nucleic acid shows a reduced level of one or more biological activities as compared to the reference polypeptide or nucleic acid.

[0141] In some aspects, a polypeptide or nucleic acid of interest is considered to be a “variant” of a reference polypeptide or nucleic acid if it has an amino acid or nucleotide sequence that is identical to that of the reference but for a small number of sequence alterations at particular positions. Certain amino acids may be substituted for other amino acids in a protein or polypeptide sequence inserted, or deleted, as compared to the reference, with or without appreciable loss of interactive binding capacity with structures such as, for example, antigen- binding regions of antibodies or binding sites on substrate molecules. Since it is the interactive capacity and nature of a protein that defines its functional activity, certain amino acid substitutions can be made in a protein sequence and in its corresponding DNA coding sequence, and nevertheless produce a protein with similar or desirable properties.

[0142] Amino acid sequence variants of the disclosure can be substitutional, insertional, or deletion variants. The variant polypeptide or nucleic acid sequence has at least one modification compared to the reference polypeptide or nucleic acid sequence, e.g., from 1 to about 50 modifications. A variation in a polypeptide of the disclosure may affect 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more non-contiguous or contiguous amino acids of the protein or polypeptide, as compared to wild-type. In one aspect, the variant polypeptide or nucleic acid sequence has from 1 to about 50 modifications compared to the reference polypeptide or nucleic acid sequence. In one aspect, the variant polypeptide or nucleic acid sequence has from 1 to about 40 modifications compared to the reference polypeptide or nucleic acid sequence. In one aspect, the variant polypeptide or nucleic acid sequence has from 1 to about 30 modifications compared to the reference polypeptide or nucleic acid sequence. In one aspect, the variant polypeptide or nucleic acid sequence has from 1 to about 20 modifications compared to the reference polypeptide or nucleic acid sequence. In one aspect, the variant polypeptide or nucleic acid sequence has from 1 to about 10 modifications compared to the reference polypeptide or nucleic acid sequence. In one aspect, the variant polypeptide or nucleic acid sequence has from 1 to about 5 modifications compared to the reference polypeptide or nucleic acid sequence. Typically, fewer than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in a variant are substituted, inserted, or202424720.3 37deleted, as compared to the reference. A variant can comprise an amino acid sequence that is at least 50%, 60%, 70%, 80%, or 90%, including all values and ranges there between, identical to any sequence provided or referenced herein.

[0143] It also will be understood that amino acid and nucleic acid sequences may include additional residues, such as additional N- or C-terminal amino acids, or 5’ or 3’ nucleic acid sequences, respectively, and yet still be essentially identical as set forth in one of the sequences disclosed herein, so long as the sequence meets the criteria set forth above, including the maintenance of biological protein activity where protein expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences that may, for example, include various non-coding sequences flanking either of the 5’ or 3’ portions of the coding region.

[0144] The term “functionally equivalent codon” is used herein to refer to codons that encode the same amino acid, such as the six different codons for arginine. Also considered are “neutral substitutions” or “neutral mutations” which refers to a change in the codon or codons that encode biologically equivalent amino acids.

[0145] Deletion variants typically lack one or more residues of the native or wild type protein. Individual residues can be deleted or a number of contiguous amino acids can be deleted. A stop codon may be introduced (by substitution or insertion) into an encoding nucleic acid sequence to generate a truncated protein.

[0146] Insertional mutants typically involve the addition of amino acid residues at a non- terminal point in the polypeptide. This may include the insertion of one or more amino acid residues. Terminal additions may also be generated and can include fusion proteins which are multimers or concatemers of one or more peptides or polypeptides described or referenced herein.

[0147] Substitutional variants typically contain the exchange of one amino acid for another at one or more sites within the protein or polypeptide and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, that is, one amino acid is replaced with one of similar chemical properties.

[0148] “Conservative amino acid substitutions” may involve exchange of a member of one amino acid class with another member of the same class. Conservative replacements (also “conservative substitutions” or “conservative amino acid substitutions”) are those that take place within a family of amino acids that possess similar biochemical properties, including charge, hydrophobicity, and size. Genetically encoded amino acids are generally divided into202424720.3 38families based on the chemical nature of the side chain, e.g., acidic (aspartate, glutamate), basic (lysine, arginine, histidine), nonpolar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine). Thus, a conservative replacement may comprise replacement of an amino acid in one family for an amino acid in the same family (e.g., replacement of a lysine with an arginine, replacement of an aspartate for a glutamate, etc.). Alternatively, or in addition, amino acid similarity may be determined using a Blocks Substitution Matrix (BLOSUM), such as BLOSUM62 (Henikoff S and Henikoff JG, Proc. Natl. Acad. Sci. U.S.A 89(22): 10915-9 (1992)). In this case, a conservative replacement may be a substitution of amino acids having a non-negative value on a BLOSUM62 matrix. Whether an amino acid change results in a functional peptide can readily be determined by assaying the specific activity of the polypeptide derivative. Standard ELISA, Surface Plasmon Resonance (SPR), or other antibody binding assays can be performed by one skilled in the art to make a quantitative comparison of antigen binging affinity between the unmodified antibody and any polypeptide derivatives with conservative substitutions generated through any of several methods available to one skilled in the art. Conservative amino acid substitutions may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics or other reversed or inverted forms of amino acid moieties.

[0149] Alternatively, substitutions may be “non-conservative” (also “nonconservative”). In some aspects, a non-conservative substitution affects a function or activity of the polypeptide. In some aspects, a non-conservative substitution does not affect a function or activity of the polypeptide. Non-conservative changes typically involve substituting an amino acid residue with one that is chemically dissimilar, such as a polar or charged amino acid for a nonpolar or uncharged amino acid, and vice versa. Non-conservative substitutions may involve the exchange of a member of one of the amino acid classes for a member from another class.

[0150] In some aspects, a reference polypeptide or nucleic acid is a “wild type” or “WT” or “native” sequence found in nature, including allelic variations. A wild type polypeptide or nucleic acid sequence has a sequence that has not been intentionally modified. For the purposes of the present disclosure, “variants” of an amino acid sequence (peptide, protein, or polypeptide) comprise amino acid insertion variants, amino acid addition variants, amino acid deletion variants and / or amino acid substitution variants. “Variants” of a nucleotide sequence comprise nucleotide insertion variants, nucleotide addition variants, nucleotide deletion variants and / or nucleotide substitution variants. The term “variant” includes all mutants, splice202424720.3 39variants, post-translationally modified variants, conformations, isoforms, allelic variants, species variants, and species homologs, in particular, those which are naturally occurring. The term “variant” includes, in particular, fragments of an amino acid or nucleic acid sequence.

[0151] A fragment or variant of an amino acid sequence (peptide or protein) may be a “functional fragment” or “functional variant.” The term “functional fragment” or “functional variant” of an amino acid sequence relates to any fragment or variant exhibiting one or more functional properties identical or similar to those of the amino acid sequence from which it is derived, e.g., it is functionally equivalent. With respect to antigens or antigenic sequences, one particular function is one or more immunogenic activities displayed by the amino acid sequence from which the fragment or variant is derived. The term “functional fragment” or “functional variant,” as used herein, in particular refers to a variant molecule or sequence that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequence of the parent molecule or sequence and that is still capable of fulfilling one or more of the functions of the parent molecule or sequence. In one aspect, the modifications in the amino acid sequence of the parent molecule or sequence do not significantly affect or alter the characteristics of the molecule or sequence.

[0152] An amino acid sequence (peptide, protein, or polypeptide) “derived from” a designated amino acid sequence (peptide, protein, or polypeptide) refers to the origin of the first amino acid sequence. Preferably, the amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentially identical, or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a particular amino acid sequence may be variants of that particular sequence or a fragment thereof. For example, it will be understood by one of ordinary skill in the art that the antigens suitable for use herein may be altered such that they vary in sequence from the naturally occurring or native sequences from which they were derived, while retaining the desirable activity of the native sequences.

[0153] Changes may be introduced by mutation into a nucleic acid, thereby leading to changes in the amino acid sequence of a polypeptide (e.g., an antigen or antibody or antibody derivative) that it encodes. Mutations may be introduced using any technique known in the art. In one aspect, one or more particular amino acid residues are changed using, for example, a site-directed mutagenesis protocol. In another aspect, one or more randomly selected residues are changed using, for example, a random mutagenesis protocol. In some aspects, however it is made, a mutant polypeptide may be expressed and screened for a desired property.202424720.3 40

[0154] Mutations may be introduced into a nucleic acid without significantly altering the biological activity of a polypeptide that it encodes. For example, one may make nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues. Alternatively, one or more mutations may be introduced into a nucleic acid that selectively changes the biological activity of a polypeptide that it encodes. For example, the mutation may quantitatively or qualitatively change the biological activity. Examples of quantitative changes include increasing, reducing or eliminating the activity. Examples of qualitative changes include altering the antigen specificity of an antibody.

[0155] “Sequence similarity” indicates the percentage of amino acids that either are identical or that represent conservative amino acid substitutions. “Sequence identity” between two amino acid sequences indicates the percentage of amino acids that are identical between the sequences. The terms “% identical,” “% identity,” or similar terms are intended to refer, in particular, to the percentage of nucleotides or amino acids which are identical in an optimal alignment between the sequences to be compared. Said percentage is purely statistical, and the differences between the two sequences may be but are not necessarily randomly distributed over the entire length of the sequences to be compared. Comparisons of two sequences are usually carried out by comparing the sequences, after optimal alignment, with respect to a segment or “window of comparison,” in order to identify local regions of corresponding sequences. The optimal alignment for a comparison may be carried out manually or with the aid of the local homology algorithm by Smith and Waterman, 1981, Ads. App. Math. 2, 482, with the aid of the local homology algorithm by Neddleman and Wunsch, 1970, J. Mol. Biol. 48, 443, with the aid of the similarity search algorithm by Pearson and Lipman, 1988, Proc. Natl Acad. Sci. USA 88, 2444, or with the aid of computer programs using said algorithms (FOGSAA, GAP, BESTFIT, FASTA, BLAST P, BLAST N, and TFASTA in Wisconsin Genetics Software Package, Genetics Computer Group). In some aspects, percent identity of two sequences is determined using the BLASTN or BLASTP algorithm, as available on the United States National Center for Biotechnology Information (NCBI) website.

[0156] Percentage identity is obtained by determining the number of identical positions at which the sequences to be compared correspond, dividing this number by the number of positions compared (e.g., the number of positions in the reference sequence), and multiplying this result by 100.

[0157] In some aspects, the degree of similarity or identity is given for a region that is at least, at most, exactly, or between (inclusive or exclusive) any two of about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the entire length of the reference202424720.3 41sequence. For example, if the reference nucleic acid sequence consists of 200 nucleotides, the degree of identity is given for at least, at most, exactly, or between any two of about 100, about 120, about 140, about 160, about 180, or about 200 nucleotides, in some aspects, continuous nucleotides. In some aspects, the degree of similarity or identity is given for the entire length of the reference sequence.

[0158] Homologous amino acid sequences may exhibit at least, at most, exactly, or between (inclusive or exclusive) any two of 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% identity of the amino acid residues. In one aspect, homologous amino acid sequences exhibit at least 95% identity of the amino acid residues. In one aspect, homologous amino acid sequences exhibit at least 98% identity of the amino acid residues. In one aspect, homologous amino acid sequences exhibit at least 99% identity of the amino acid residues.

[0159] In the present disclosure, a vector refers to a nucleic acid molecule, such as an artificial nucleic acid molecule. A vector may be used to incorporate a nucleic acid sequence, such as a nucleic acid sequence comprising an open reading frame. Vectors include, but are not limited to, storage vectors, expression vectors, cloning vectors, and transfer vectors. A vector may be an RNA vector or a DNA vector. In some aspects the vector is a DNA molecule. In some aspects, the vector is a plasmid vector. In some aspects, the vector is a viral vector. Typically, an expression vector will contain a desired coding sequence and appropriate other sequences necessary for the expression of the operably linked coding sequence in a particular host organism (e.g., bacteria, yeast, plant, insect, or mammal) or in in vitro expression systems. Cloning vectors are generally used to engineer and amplify a certain desired fragment (typically a DNA fragment) and may lack functional sequences needed for expression of the desired fragment(s).

[0160] “Treating” or “treatment,” as used herein when used in connection with the occurrence of a disease, disorder, and / or condition, refers to the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition. As used herein, the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore202424720.3 42not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.

[0161] “Prevent” or “prevention,” as used herein when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder, or condition has been delayed for a predefined period of time.

[0162] As will be understood from context, “risk” of a disease, disorder, and / or condition refers to a likelihood that a particular individual will develop the disease, disorder, and / or condition. In some aspects, risk is expressed as a percentage. In some aspects, risk is at least, at most, exactly, or between (inclusive or exclusive) any two of from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 up to 100%. In some aspects risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples. In some aspects, a reference sample or group of reference samples have a known risk of a disease, disorder, condition and / or event. In some aspects a reference sample or group of reference samples are from individuals comparable to a particular individual. In some aspects, risk may reflect one or more genetic attributes, e.g., which may predispose an individual toward development (or not) of a particular disease, disorder and / or condition. In some aspects, risk may reflect one or more epigenetic events or attributes and / or one or more lifestyle or environmental events or attributes.

[0163] An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some aspects, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some aspects, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some aspects, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some aspects, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some aspects, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0164] As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers approved by the202424720.3 43United States Food and Drug Administration as being acceptable for use in humans or domestic animals. Pharmaceutical compositions may be immunogenic compositions. In some aspects, active agent is present in a unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some aspects, pharmaceutical compositions may be specially formulated for parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation. II. BMP-7

[0165] Bone morphogenic protein 7 (BMP-7), also known as osteogenic protein-1 (OP-1), is a secreted protein that belongs to the transforming growth factor beta (TGFB) superfamily and regulates proliferation, differentiation, and apoptosis in many different cell types by altering target gene transcription. The complete mRNA sequence of human BMP-7 has the GENBANK® Accession Number NM_001719, incorporated by reference herein in its entirety.

[0166] BMPs can act as either tumor suppressors or oncogenes depending on the cellular context and tumor type. Secreted BMP-7 impinges on effector T-cell functions, favoring the generation of immunosuppressive cells, and precluding response to immunotherapy. As shown herein, BMP-7 is upregulated in mouse and human tumors resistant to anti-PD1 therapy, and BMP-7 levels are higher not only in blood from mice bearing resistant tumors but also in pretreatment blood from patients exhibiting disease progression while on anti-PD1 and radiotherapy. BMP-7 has also been reported in a wide range of human cancers and is associated with metastasis and poor prognosis. In lung cancer, BMP-7 overexpression is associated with lymph node involvement and an indicator of bone metastasis. BMPs regulate immune cell responses and are immunosuppressive in cancer. For example, BMPs have been shown to regulate activation, growth, and cytokine secretion in macrophages and to promote PDL1 and PDL2 upregulation in dendritic cells. Treatment with BMP-7 in vitro and in vivo significantly enhanced monocyte polarization into M2 macrophages.

[0167] BMP ligands bind to and form heteromeric complexes with two types of serine / threonine kinase receptors on the cell surface, which then activate the “small mothers against decapentaplegic” (SMAD) proteins 1 and 5 in cells. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. In response to BMP ligands, SMAD proteins can be phosphorylated and activated by the BMP202424720.3 44receptor kinase. Phosphorylated SMAD proteins form oligomeric complexes, which are important for their function in the transcription regulation. Specifically, binding of BMP to its receptor leads to the phosphorylation of intracellular SMADs, which then bind to co-SMAD4 and translocate into the nucleus to regulate gene expression.

[0168] Secreted BMP-7 promotes resistance to immunotherapy by repressing macrophage- mediated inflammatory responses and Th1-associated cytokines in the tumor microenvironment. BMP-7 downregulates MAPK14 and MAPK14-regulated cytokines and chemokines including IL1A, IL1B, TNF, and CCL5 via SMAD1 activation. At the same time, BMP-7 decreases CD4+T-cell activation by downregulating IFNG and IL2 expression via SMAD1 / MAPK14 signaling.

[0169] BMP-7 can specifically downregulate MAPK14 at the mRNA and protein levels. MAPK14 can act as a tumor suppressor by regulating cell cycle progression and induction of apoptosis or as an oncogene by promoting invasion, inflammation, and angiogenesis. MAPK14 is a member of the p38 MAPK family. It is downregulated not only in tumors but also in TILs from anti-PD1-resistant tumors. P38 proteins are important participants in inflammatory signaling pathways and are activated in response to a variety of cellular stresses, including osmotic shock, lipopolysaccharides, and inflammatory cytokines. MAPK14 is the critical isoform in inflammatory responses and is involved in the expression of proinflammatory mediators in macrophages such as IL1B, TNF, and IL12 as well as CCL5, COX-2, IL8, IL6, IL3, IL2, and IL1, all of which contain AU-rich elements in their 3′-untranslated regions to which MAPK14 binds. MAPK14 participates in the regulation of IFNG expression and its mRNA stabilization in immune cells.

[0170] MAPK14 is known to be regulated by BMP-7 via SMAD activation. BMP-7 can either promote or inhibit MAPK14 activation depending on the cellular context and BMP-7 dose. MAPK14-regulated inflammatory cytokines IL1A, IL1B, and TNF are downregulated in tumor-infiltrating leukocytes (TILs) collected from 344SQR tumors treated with anti-PD1 versus 344SQP. Cytokines and chemokines regulated by MAPK14 including IL1A, IL1B, TNF, CCL5, IFNG, and IL2 are also downregulated in blood from mice bearing 344SQR tumors compared with parental tumors. Thus, BMP-7 regulates MAPK14 expression not only in tumors resistant to anti-PD1 but also in TILs in the tumor microenvironment, and BMP-7 also regulates expression of proinflammatory cytokines and chemokines in TILs via MAPK14 regulation.

[0171] Similar to results observed in tumors, BMP-7 regulates MAPK14 via SMAD1 activation in immune cells. Previous studies in macrophages isolated from a vivo model of202424720.3 45atherosclerosis treated with intravenous injections of BMP-7 or liposomal clodronate demonstrated that BMP-7 significantly reduced the number of proinflammatory macrophages and decreased MAPK14 activation while increasing SMAD1 / 5 / 8 phosphorylation in macrophages. Other studies have shown that BMP-7 promotes M2 polarization in human and mouse macrophages in vitro and in vivo models.

[0172] MAPK14 signaling promotes not only M2 monocytes polarization into M1-type cells in response to lipopolysaccharides but also is central in the activation of proinflammatory gene transcription. In macrophages, MAPK14 is activated by lipopolysaccharide and Toll-like receptor-4, which subsequently activates proinflammatory cytokines, including IL1 and TNF. Murine macrophages co-cultured with 344SQR cells have lower expression of MAPK14, IL1A, IL1B, TNF, and CCL5 compared with cells co-cultured with 344SQP cells. That these findings depend on BMP-7 has been confirmed by co-culturing macrophages with BMP-7-knockdown 344SQR cells, which results in higher expression levels of MAPK14, IL1A, IL1B, TNF, and CCL5 compared with control cells. Thus, BMP-7 suppresses the proinflammatory cytokine expression regulated by MAPK14 in macrophages.

[0173] P38 signaling is known to be activated in T cells stimulated via TCR signaling and reduced in anergic T cells. MAPK14 also participates in the regulation of IFNG expression in CD4+ T cells and promotes the 3′-untranslated region stabilization of IFNG mRNA in NK cells. Further, the inhibition of MAPK14 in Th1 cells differentiated in vitro blocked the IFNG expression induced by IL12 / IL18 and CD3 / CD28 stimulation. Previous studies showed that treating cells with SB203580, a specific inhibitor of MAPK14, suppressed the transcriptional activation of the IL2 promoter in T lymphocytes. SMAD regulatory pathways regulate different aspects of immune activation and immune suppression in T cells. For example, TGFB promotes the differentiation of CD4+ T cells into suppressive FOXP3+ T regulatory cells via SMAD activation. BMP-7 regulates MAPK14 expression via SMAD1 signaling not only in tumors and macrophages but also in CD4+ T cells. Activated CD4+ T cells incubated with BMP-7 had lower MAPK14, IFNG, and IL2 expression compared with untreated cells and cells treated with BMP-7 plus follistatin, a natural inhibitor of BMP-7. In agreement with these findings, other studies have also correlated IL2 activation with MAPK14 signaling in T cells. Thus, BMP-7 decreases IFNG and IL2 expression in CD4+ T cells via SMAD1 / MAPK14 signaling.

[0174] Impacts of BMP-7 expression on cancer and immunotherapy resistance are described in, for example, Cortez, M.A., et al. Nat Commun 11, 4840 (2020), incorporated by reference herein in its entirety.202424720.3 46III. Antibodies

[0175] Aspects of the disclosure relate to BMP-7-binding proteins. The terms “polypeptide that specifically binds BMP-7” and “BMP-7-binding protein” are used interchangeably herein. In some aspects, the BMP-7-binding protein specifically binds to human BMP-7.

[0176] In some aspects, the BMP-7-binding protein is an antibody, an antibody-like molecule, or an antigen-binding fragment thereof. In some aspects, the BMP-7-binding protein is an antibody, a nanobody, a minibody, an scFv fragment, or a Fab fragment. In some aspects, the BMP-7-binding protein is a human antibody, humanized antibody, recombinant antibody, chimeric antibody, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody. In some aspects, the BMP-7-binding protein is a monoclonal antibody. In some aspects, the BMP-7-binding protein is a murine antibody. In some aspects, the BMP-7-binding protein is a chimeric antibody. In some aspects, the BMP-7- binding protein is a humanized antibody.

[0177] In some aspects, the disclosed BMP-7-binding proteins include antibodies comprising a light chain variable region (VL) having 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and a heavy chain variable region (VH) having 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VLhas at least 85% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VH has at least 85% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 90% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VH has at least 90% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VHhas at least 95% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL comprises SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VHcomprises SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81.

[0178] In some aspects, the disclosure relates to a monoclonal antibody or antigen-binding fragment thereof, wherein the VL comprises an amino acid sequence having 85%, 86%, 87%,202424720.3 4788%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VH comprises an amino acid sequence having 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 85% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VHhas at least 85% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 90% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VHhas at least 90% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VLhas at least 95% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VH has at least 95% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VLcomprises SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79, and the VH comprises SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the disclosed monoclonal antibody or antigen-binding fragment thereof is a BMP-7-binding protein (i.e., are capable of binding to BMP-7).

[0179] Some aspects are directed to an antibody comprising a VL comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71. Some aspects are directed to an antibody comprising a VL comprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6. Some aspects are directed to an antibody comprising a VL comprising a CDR-L1 comprising SEQ ID NO:20, a CDR-L2 comprising SEQ ID NO:22, and a CDR-L3 comprising SEQ ID NO:24. Some aspects are directed to an antibody comprising a VLcomprising a CDR-L1 comprising SEQ ID NO:50, a CDR-L2 comprising SEQ ID NO:53, and a CDR-L3 comprising SEQ ID NO:57. Some aspects are directed to an antibody comprising a VL comprising a CDR-L1 comprising SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:71.

[0180] Some aspects are directed to an antibody comprising a VH comprising a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-202424720.3 48H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some aspects are directed to an antibody comprising a VH comprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:12. Some aspects are directed to an antibody comprising a VHcomprising a CDR- H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:32. Some aspects are directed to an antibody comprising a VH comprising a CDR-H1 comprising SEQ ID NO:26, a CDR-H2 comprising SEQ ID NO:28, and a CDR-H3 comprising SEQ ID NO:30. Some aspects are directed to an antibody comprising a VH comprising a CDR-H1 comprising SEQ ID NO:59, a CDR-H2 comprising SEQ ID NO:62, and a CDR-H3 comprising SEQ ID NO:65. Some aspects are directed to an antibody comprising a VHcomprising a CDR-H1 comprising SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:77.

[0181] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VH comprising a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0182] Some aspects are directed to an antibody comprising: a VLcomprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6; and a VH comprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:12. Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6; and a VH comprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:32. Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:20, a CDR-L2 comprising SEQ ID NO:22, and a CDR-L3 comprising SEQ ID NO:24; and a VHcomprising a CDR-H1 comprising SEQ ID NO:26, a CDR-H2 comprising SEQ ID NO:28, and a CDR-H3 comprising SEQ ID NO:30. In some aspects, the VL comprises SEQ ID NO:14. In some aspects, the VH comprises SEQ ID NO:16.202424720.3 49

[0183] Some aspects are directed to an antibody comprising: a VLcomprising a CDR-L1 comprising SEQ ID NO:50, a CDR-L2 comprising SEQ ID NO:53, and a CDR-L3 comprising SEQ ID NO:57; and a VH comprising a CDR-H1 comprising SEQ ID NO:59, a CDR-H2 comprising SEQ ID NO:62, and a CDR-H3 comprising SEQ ID NO:65. In some aspects, the VL comprises SEQ ID NO:34. In some aspects, the VH comprises SEQ ID NO:40. In some aspects, the VL comprises SEQ ID NO:36. In some aspects, the VH comprises SEQ ID NO:42. In some aspects, the VLcomprises SEQ ID NO:38. In some aspects, the VHcomprises SEQ ID NO:42.

[0184] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:71; and a VHcomprising a CDR-H1 comprising SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:77. In some aspects, the VL comprises SEQ ID NO:79. In some aspects, the VH comprises SEQ ID NO:81.

[0185] As used herein, the term “antibody” refers to an intact immunoglobulin of any class or isotype, or a fragment thereof that can compete with the intact antibody for specific binding to the target antigen. An isotype refers to the genetic variations or differences in the constant regions of the heavy and light chains of an antibody. In humans, there are five heavy chain isotypes: IgA, IgD, IgG, IgE, and IgM and two light chain isotypes: kappa and lambda. The IgG class is divided into four isotypes: IgG1, IgG2, IgG3 and IgG4 in humans, and IgG1, IgG2a, IgG2b and IgG3 in mice. They share more than 95% homology in the amino acid sequences of the Fc regions but show major differences in the amino acid composition and structure of the hinge region.

[0186] The term “antibody” includes a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a human antibody, a veneered antibody, a diabody, a humanized antibody, an antibody derivative, a recombinant antibody, a recombinant humanized antibody, an engineered antibody, a multi-specific antibody, a DARPin, or a derivative or fragment of each thereof. Also contemplated are antibodies having specificity for more than one antigen or target, including bispecific antibodies, trispecific antibodies, tetraspecific antibodies, and other multispecific antibodies.

[0187] As used herein, an “antibody” includes whole antibodies and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule. As used herein, the terms “antibody” or “immunoglobulin” are used interchangeably and refer to any of several classes of structurally related proteins that function as part of the immune response202424720.3 50of an animal, including IgM, IgD, IgG, IgA, IgE, and related proteins, as well as polypeptides comprising antibody CDR domains that retain antigen-binding activity. Examples of such include but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region or any portion thereof or at least one portion of a binding protein. In certain aspects, the antibody or antigen binding fragment specifically binds human BMP-7.

[0188] In one aspect, the anti-BMP-7 antibody or antigen binding fragment thereof is a neutralizing antibody or antigen-binding fragment thereof. The term “neutralizing” in the context of a BMP-7 neutralizing antibody refers to an antibody that may do one or more of: interfere with the BMP-7 receptor / BMP-7 interaction; reduce the concentration of BMP-7 receptor / BMP-7 interacted species in a subject or a cell; prevent the BMP-7 receptor / BMP-7 interaction in a subject or a cell; and / or reduce the biological function of BMP-7, which may include, but is not limited to, one or more of: promoting tumorigenesis or tumor progression; promoting cell growth and metastases; promoting inflammation, cell differentiation, adhesion, tumorigenesis, migration, invasion, and angiogenesis; inducing phosphorylation and activation of SMAD proteins; or downregulating MAPK14.

[0189] The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody. An antigen may possess one or more epitopes that can interact with different antibodies.

[0190] The term “epitope” refers to a moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. Epitope determinants may include a plurality of chemical atoms or groups on an antigen surface, such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In some aspects, such chemical atoms or groups are surface-exposed when the antigen adopts a relevant three-dimensional conformation. In some aspects, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some aspects, at least some such chemical atoms or groups are physically separated from one another when the antigen adopts an alternative conformation (e.g., is linearized). Generally, antibodies specific for a particular target antigen would recognize an epitope on the target antigen within a complex mixture.

[0191] The epitope regions of a given polypeptide can be identified using many different epitope mapping techniques well known in the art, including: x-ray crystallography, nuclear magnetic resonance spectroscopy, site-directed mutagenesis mapping, protein display arrays, and hydrogen-deuterium exchange see, e.g., Epitope Mapping Protocols, (Johan Rockberg and202424720.3 51Johan Nilvebrant, Ed., 2018) Humana Press, New York, N.Y. Such techniques are known in the art and described in, e.g., U.S. Pat. No.4,708,871; Geysen et al. Proc. Natl. Acad. Sci. USA 81:3998-4002 (1984); Geysen et al. Proc. Natl. Acad. Sci. USA 82:178-182 (1985); Geysen et al. Molec. Immunol.23:709-715 (1986), each of which is incorporated by reference herein in their entirety. Additionally, antigenic regions of proteins can also be predicted and identified using standard antigenicity and hydropathy plots.

[0192] The term “immunogenic sequence” means a molecule that includes an amino acid sequence of at least one epitope such that the molecule can stimulate the production of antibodies in an appropriate host. The term “immunogenic composition” means a composition that comprises at least one immunogenic molecule (e.g., an antigen or carbohydrate).

[0193] An intact antibody is generally composed of two full-length heavy chains and two full-length light chains, but in some instances may include fewer chains, such as antibodies naturally occurring in camelids that may comprise only heavy chains. Antibodies as disclosed herein may be derived solely from a single source or may be “chimeric,” that is, different portions of the antibody may be derived from two different antibodies. For example, for chimeric antibodies, the variable regions may be derived from a rat or murine source, while the constant region is derived from a different animal source, such as a human. The antibodies or binding fragments may be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term “antibody” includes derivatives, variants, fragments, and muteins thereof, examples of which are described below (Sela-Culang et al., Front Immunol.2013; 4: 302; 2013).

[0194] The term “variable region” refers to a portion of the antibody that gives the antibody its specificity for binding antigen. The variable region is typically located at the ends of the heavy and light chains. Variable loops of β-strands, three each on the light (VL) and heavy (VH) chains are responsible for binding to the antigen. These loops are referred to as the “complementarity determining regions” (CDRs). In general, the CDR residues are directly and most substantially involved in influencing antigen binding.

[0195] The term “constant region” refers to a portion of the antibody that is identical in all antibodies of the same isotype. The constant region differs in antibodies of different isotypes.

[0196] The term “light chain” may describe a full-length light chain or fragments thereof. A full-length light chain has a molecular weight of around 25,000 Daltons and includes a variable region domain (abbreviated herein as VL), and a constant region domain (abbreviated herein as CL). There are two classifications of light chains, identified as kappa (κ) and lambda (λ). The term “VLfragment” means a fragment of the light chain of a monoclonal antibody that202424720.3 52includes all or part of the light chain variable region, including CDRs. A VLfragment can further include light chain constant region sequences. The variable region domain of the light chain is at the amino-terminus of the polypeptide.

[0197] The term “heavy chain” may describe a full-length heavy chain or fragments thereof. For example, a full-length heavy chain for human IgG1 has a molecular weight of around 50,000 Daltons and includes a variable region domain (abbreviated herein as VH), and three constant region domains (abbreviated herein as CH1, CH2, and CH3). The term “VHfragment” means a fragment of the heavy chain of a monoclonal antibody that includes all or part of the heavy chain variable region, including CDRs. A VH fragment can further include heavy chain constant region sequences. The number of heavy chain constant region domains will depend on the isotype. The isotype of an antibody can be IgM, IgD, IgG, IgA, or IgE and is defined by the heavy chains present of which there are five classifications: mu (µ), delta (d), gamma (γ), alpha (α), or epsilon (ε) chains, respectively. Human IgG has several subtypes, including, IgG1, IgG2, IgG3, and IgG4. A. Types of Antibodies

[0198] Antibodies can be whole immunoglobulins of any isotype or classification, chimeric antibodies, or hybrid antibodies with specificity to two or more antigens. They may also be fragments (e.g., F(ab’)2, Fab’, Fab, Fv, and the like), including hybrid fragments. An immunoglobulin also includes natural, synthetic, or genetically engineered proteins that act like an antibody by binding to specific antigens to form a complex. The term antibody includes genetically engineered or otherwise modified forms of immunoglobulins.

[0199] The term “monomer” means an antibody containing only one immunoglobulin unit. Monomers are the basic functional units of antibodies. The term “dimer” means an antibody containing two immunoglobulin units attached to one another via constant domains of the antibody heavy chains (the Fc, or fragment crystallizable, region). The complex may be stabilized by a joining (J) chain protein. The term “multimer” means an antibody containing more than two immunoglobulin units attached to one another via constant domains of the antibody heavy chains (the Fc region). The complex may be stabilized by a joining (J) chain protein.

[0200] The term “bivalent antibody” means an antibody that comprises two antigen- binding sites. The two binding sites may have the same antigen specificities, or they may be bi-specific, meaning the two antigen-binding sites have different antigen specificities.202424720.3 53

[0201] Bispecific antibodies are a class of antibodies that have paratopes (i.e., antigen- binding sites) for two or more distinct epitopes. Bispecific antibodies can be biparatopic, wherein a bispecific antibody may specifically recognize a different epitope from the same antigen. Bispecific antibodies can be constructed from a pair of different single domain antibodies termed “nanobodies.” Single domain antibodies may be sourced and modified from cartilaginous fish and camelids. Nanobodies can be joined together by a linker using techniques typical to a person skilled in the art; such methods for selection and joining of nanobodies are described in PCT Publication No. WO2015044386A1, No. WO2010037838A2, and Bever et al., Anal Chem. 86:7875–7882 (2014), each of which are specifically incorporated herein by reference in their entirety.

[0202] Bispecific antibodies can be constructed as: a whole IgG, Fab’2, Fab’PEG, a diabody, or alternatively as a single chain variable fragment (scFv). Diabodies and scFvs can be constructed without an Fc region, using only variable domains. Bispecific antibodies may be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab’ fragments. See, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol.79:315- 321 (1990); Kostelny et al., J. Immunol.148:1547-1553 (1992), each of which are specifically incorporated by reference in their entirety.

[0203] In certain aspects, the antigen-binding domain may be multispecific or heterospecific by multimerizing with VH and VL region pairs that bind a different antigen. For example, the antibody may bind to, or interact with, (a) a cell surface antigen, (b) an Fc receptor on the surface of an effector cell, or (c) at least one other component. Accordingly, aspects may include, but are not limited to, bispecific, trispecific, tetraspecific, and other multispecific antibodies or antigen-binding fragments thereof that are directed to epitopes and to other targets, such as Fc receptors on effector cells.

[0204] Multispecific antibodies can be used and directly linked via a short flexible polypeptide chain, using routine methods known in the art. One such example is diabodies that are bivalent, bispecific antibodies with two antigen-binding sites in which the VHand VLdomains are expressed on a single polypeptide chain and utilize a linker that is too short to allow for pairing between domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain creating two antigen binding sites. The linker functionality is applicable for aspects of triabodies, tetrabodies, and higher order antibody multimers. (see, e.g., Hollinger et al., Proc Natl. Acad. Sci. USA 90:6444-6448 (1993); Polijak et al., Structure 2:1121-1123 (1994); Todorovska et al., J. Immunol. Methods 248:47-66 (2001), each of which is incorporated herein by reference in their entirety).202424720.3 54

[0205] The part of the Fv fragment of an antibody molecule that binds with high specificity to the epitope of the antigen is referred to herein as the “paratope.” The paratope consists of the amino acid residues that contact the epitope of an antigen to facilitate antigen recognition. Each of the two Fv fragments of an antibody is composed of the two variable domains, VHand VL, in dimerized configuration. The primary structure of each of the variable domains includes three hypervariable loops separated by, and flanked by, framework regions (FRs). The hypervariable loops are the regions of highest primary sequences variability among the antibody molecules from any mammal. The term hypervariable loop is sometimes used interchangeably with the term “complementarity determining region” (CDR). The length of the hypervariable loops (or CDRs) varies between antibody molecules. The framework regions of all antibody molecules from a given mammal have high primary sequence similarity / consensus. The consensus of framework regions can be used by one skilled in the art to identify both the framework regions and the hypervariable loops (or CDRs) which are interspersed among the framework regions. The hypervariable loops are given identifying names which distinguish their position within the polypeptide, and on which domain they occur. CDRs in the VL domain are identified as L1, L2, and L3, with L1 occurring at the most distal end and L3 occurring closest to the CLdomain. The CDRs may also be given the names CDR-L1, CDR-L2, and CDR-L3. The L3 (CDR-L3) is generally the region of highest variability among all antibody molecules produced by a given organism. The CDRs are regions of the polypeptide chain arranged linearly in the primary structure and separated from each other by FRs. The amino terminal (N-terminal) end of the VLchain is named FR1. The region identified as FR2 occurs between L1 and L2 hypervariable loops. FR3 occurs between L2 and L3 hypervariable loops, and the FR4 region is closest to the CL domain. This structure and nomenclature is repeated for the VHchain, which includes three CDRs identified as H1, H2, and H3, or CDR-H1, CDR-H2 and CDR-H3. The majority of amino acid residues in the variable domains, or Fv fragments (VH and VL), are part of the FRs (approximately 85%).

[0206] Several methods have been developed and can be used by one skilled in the art to identify the exact amino acids that constitute each of these regions. This can be done using any of a number of multiple sequence alignment methods and algorithms, which identify the conserved amino acid residues that make up the framework regions, therefore identifying the CDRs that may vary in length but are located between framework regions. Three commonly used methods have been developed for identification of the CDRs of antibodies: Kabat (as described in T. T. Wu and E. A. Kabat, J Exp Med, 132(2): 211–50 (1970)); Chothia (as described in C. Chothia et al., Nature, 342(6252): 877–83 (1989)); and IMGT (as described in202424720.3 55M.-P. Lefranc et al., Developmental & Comparative Immunology, 27(1): 55–77 (2003)). These methods each include unique numbering systems for the identification of the amino acid residues that constitute the variable regions. In most antibody molecules, the amino acid residues that actually contact the epitope of the antigen occur in the CDRs, although in some cases, residues within the framework regions contribute to antigen binding. Depending on the type and size of the antigen, different CDR residues may contact the antigen. See Almagro JC. J Mol Recognit.17(2):132-43 (2004), incorporated herein by reference.

[0207] One skilled in the art can use any of several methods to determine the paratope of an antibody. These methods include:

[0208] 1) Computational predictions of the tertiary structure of the antibody / epitope binding interactions based on the chemical nature of the amino acid sequence of the antibody variable region and composition of the epitope.

[0209] 2) Hydrogen-deuterium exchange and mass spectroscopy.

[0210] 3) Polypeptide fragmentation and peptide mapping approaches in which one generates multiple overlapping peptide fragments from the full length of the polypeptide and evaluates the binding affinity of these peptides for the epitope.

[0211] 4) Antibody Phage Display Library analysis in which the antibody Fab fragment encoding genes of the mammal are expressed by bacteriophage in such a way as to be incorporated into the coat of the phage. This population of Fab expressing phage are then allowed to interact with the antigen which has been immobilized or may be expressed in by a different exogenous expression system. Non-binding Fab fragments are washed away, thereby leaving only the specific binding Fab fragments attached to the antigen. The binding Fab fragments can be readily isolated and the genes which encode them determined. This approach can also be used for smaller regions of the Fab fragment including Fv fragments or specific VHand VL domains as appropriate.

[0212] In certain aspects, affinity matured antibodies are enhanced with one or more modifications in one or more CDRs thereof (and / or one or more FRs thereof) that result in an improvement in the affinity of the antibody for a target antigen as compared to a parent antibody that does not possess those alteration(s). Certain affinity matured antibodies will have nanomolar or picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art, e.g., Marks et al., Bio / Technology 10:779 (1992) describes affinity maturation by VH and VL domain shuffling, random mutagenesis of CDR and / or framework residues employed in phage display is described by Rajpal et al., PNAS.24: 8466-8471 (2005) and Thie et al., Methods Mol Biol.525:309-22 (2009) in conjugation with202424720.3 56computation methods as demonstrated in Tiller et al., Front. Immunol.8:986 (2017), each of which references are incorporated herein by reference in their entirety.

[0213] Chimeric immunoglobulins are the products of fused genes derived from different species (the various domains of the antibodies’ heavy and light chains are coded for by DNA from more than one species; see, e.g., U.S. Pat. No. 4,816,567); “humanized” antibodies generally have the FRs from human immunoglobulins and one or more CDRs are from a non- human source (e.g., murine).

[0214] As used herein, the term “humanized antibody” or “humanized immunoglobulin” refers to a human / non-human chimeric antibody that contains a minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a variable region of the recipient are replaced by residues from a variable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity. Humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. The humanized antibody can optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, a non-human antibody containing one or more amino acids in a framework region, a constant region or a CDR, that have been substituted with a correspondingly positioned amino acid from a human antibody. In general, humanized antibodies are expected to produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody. The humanized antibodies may have conservative amino acid substitutions which have substantially no effect on antigen binding or other antibody functions. Conservative substitutions groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, serine-threonine and asparagine- glutamine. Humanization or engineering of antibodies can be performed using any known method such as, but not limited to, those described in U.S. Pat. Nos. 5,723,323; 5,976,862; 5,824,514; 5,817,483; 5,814,476; 5,763,192; 5,723,323; 5,766,886; 5,714,352; 6,204,023; 6,180,370; 5,693,762; 5,530,101; 5,585,089; 5,225,539; and 4,816,567; each incorporated by reference herein in its entirety.

[0215] Minimizing the antibody polypeptide sequence from the non-human species can optimize chimeric antibody function and reduces immunogenicity. Specific amino acid residues of the non-human antibody are modified to be homologous to corresponding residues in a human antibody. One example is the “CDR-grafted” antibody, in which an antibody comprises one or more CDRs from a particular species or belonging to a specific antibody class202424720.3 57or subclass, while the remainder of the antibody chain(s) is identical or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. In some instances, corresponding non-human (e.g., murine) residues replace framework region residues of the human immunoglobulin. Replacement of human framework region residues with non-human framework region residues may serve to improve and / or restore antigen binding. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody to further refine performance. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region, typically that of a human immunoglobulin. See, e.g., Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Presta, Curr. Op. Struct. Biol.2:593 (1992); Vaswani and Hamilton, Ann. Allergy, Asthma and Immunol. 1:105 (1998); Harris, Biochem. Soc. Transactions 23; 1035 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428 (1994); Verhoeyen et al., Science 239:1534-36 (1988); Almagro et al., Front Immunol 8; 1751 (2018); and Payes et al., “Genetic Engineering of Antibody Molecules,” In: Reviews in Cell Biology and Molecular Medicine. John Wiley & Sons, Inc., Hoboken, New Jersey, USA. 1(3): 1-52 (2015), each of which is incorporated by reference herein in its entirety.

[0216] Intrabodies are intracellularly localized immunoglobulins that bind to intracellular antigens as opposed to secreted antibodies, which bind antigens in the extracellular space.

[0217] Antibodies also include “linear antibodies.” The procedure for making linear antibodies is known in the art and described in Zapata et al., 1995. Briefly, these antibodies comprise a pair of tandem Ed segments (VH-CH1-VH-CH1) which form a pair of antigen binding regions. Linear antibodies can be bispecific or monospecific.

[0218] The terms “polyclonal antibody” or “polyclonal antibody composition” as used herein refer to a preparation of antibodies that are derived from different B-cell lines. They are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope. Thus, polyclonal antibody preparations typically include different antibodies against different determinants (epitopes). In order to produce polyclonal antibodies, a host, such as a rabbit or goat, is immunized with the antigen or antigen fragment, generally with an adjuvant and, if necessary, coupled to a carrier. Antibodies to the antigen are subsequently collected from the sera of the host. The polyclonal antibody can be affinity purified against the antigen rendering it monospecific.

[0219] A monoclonal antibody or “mAb” refers to an antibody obtained from a population of substantially homogeneous antibodies from an exclusive parental cell, e.g., the population is identical except for naturally occurring mutations that may be present in minor amounts.202424720.3 58Each monoclonal antibody is directed against a single antigenic determinant (epitope). Monoclonal antibodies are highly specific, as each monoclonal antibody is directed against a single determinant on the antigen. B. Functional Antibody Fragments and Antigen-Binding Fragments 1. Antigen-Binding Fragments

[0220] Certain aspects relate to antibody fragments, such as antibody fragments that bind to antigen. The term functional antibody fragment includes antigen-binding fragments of an antibody that retain the ability to specifically bind to an antigen. These fragments are constituted of various arrangements of the variable region heavy chain (VH) and / or light chain (VL) and can include constant region heavy chain 1 (CH1) and light chain (CL). In some aspects, they lack the Fc region constituted of heavy chain 2 (CH2) and 3 (CH3) domains. Aspects of antigen binding fragments and the modifications thereof may include: (i) the Fab fragment type constituted with the VL, VH, CL, and CH1 domains; (ii) the Fd fragment type constituted with the VHand CH1 domains; (iii) the Fv fragment type constituted with the VHand VLdomains; (iv) the single domain fragment type, dAb, (Holt et al. Trends Biotechnol. 21(11):484-90 (2003)) constituted with a single VH or VL domain; (v) isolated complementarity determining region (CDR) regions. Such terms are described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, NY (1989); Molec. Biology and Biotechnology: A Comprehensive Desk Reference (Myers, R. A. (ed.), New York: VCH Publisher, Inc.); Huston et al., Cell Biophysics, 22:189-224 (1993); Pluckthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E. D., Advanced Immunochemistry, 2d ed., Wiley-Liss, Inc. New York, N.Y. (1990); Antibodies, 4:259-277 (2015), each of which are incorporated by reference in their entirety.

[0221] Antigen-binding fragments also include fragments of an antibody that retain exactly, at least, or at most 1, 2, or 3 CDRs from a light chain variable region. Fusions of CDR- containing sequences to an Fc region (or a CH2 or CH3 region thereof) are included within the scope of this definition including, for example, scFv fused, directly or indirectly, to an Fc region are included herein.

[0222] The term Fab fragment means a monovalent antigen-binding fragment of an antibody containing the variable (VLand VH) and the constant (CLand CH1) domains. The term Fab’ fragment means a monovalent antigen-binding fragment of a monoclonal antibody that is larger than a Fab fragment. For example, a Fab’ fragment includes the VL, VH, CL and CH1202424720.3 59domains and all or part of the hinge region. The term F(ab’)2 fragment means a bivalent antigen-binding fragment of a monoclonal antibody comprising two Fab’ fragments linked by a disulfide bridge at the hinge region. An F(ab’)2 fragment includes, for example, all or part of the two VHand VLdomains and can further include all or part of the two CLand CH1 domains.

[0223] The term Fd fragment means a fragment of the heavy chain of a monoclonal antibody, which includes all or part of the VH, including the CDRs. An Fd fragment can further include CH1 region sequences.

[0224] The term Fv fragment means a monovalent antigen-binding fragment of a monoclonal antibody, including all or part of the VL and VH, and absent of the CL and CH1 domains. The VLand VHinclude, for example, the CDRs. Single-chain antibodies (sFv or scFv) are Fv molecules in which the VLand VHregions have been connected by a flexible linker to form a single polypeptide chain, which forms an antigen-binding fragment. Single chain antibodies are discussed in detail in International Patent Application Publication No. WO 88 / 01649 and U.S. Pat. Nos. 4,946,778 and 5,260,203, the disclosures of which are herein incorporated by reference. The term (scFv)2 means bivalent or bispecific sFv polypeptide chains that include oligomerization domains at their C-termini, separated from the sFv by a hinge region. The oligomerization domain comprises self-associating α-helices, e.g., leucine zippers, which can be further stabilized by additional disulfide bonds. (scFv)2 fragments are also known as “miniantibodies” or “minibodies.”

[0225] A single domain antibody is an antigen-binding fragment containing only a VHor the VLdomain. In some instances, two or more VHregions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens. 2. Fragment Crystallizable (Fc) Region

[0226] An Fc region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains. The term “Fc polypeptide” as used herein includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing a hinge region that promotes dimerization are included. 3. Cell Surface Receptors202424720.3 60

[0227] Antigen-binding proteins of the present disclosure may be expressed on the surface of a cell. In some aspects, antigen-binding proteins are cell surface receptors comprising antigen binding domains (e.g., BMP-7-binding domains) disclosed herein. In some aspects, described herein are cell surface receptors comprising a BMP-7-binding domain and one or more additional components or domains. Examples of cell surface receptors of the present disclosure include chimeric antigen receptor (CARs) and T-cell receptors (TCRs). A BMP-7- specific cell surface receptor may comprise one or more of an antigen binding domain, a signal peptide, an extracellular spacer, a transmembrane domain, a cytoplasmic region, and a linker. In some aspects, a cell surface receptor of the present disclosure comprises an antigen binding domain having or comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity with one or more of SEQ ID NOs:1-16 and 19-81. Cells expressing a BMP-7-specific cell surface receptor may be useful in treating one or more BMP-7-associated conditions, as described elsewhere herein. C. Polypeptides with Antibody CDRs & Scaffolding Domains that Display the CDRs

[0228] Antigen-binding peptide scaffolds, such as CDRs, are used to generate protein- binding molecules in accordance with the aspects. Generally, a person skilled in the art can determine the type of protein scaffold on which to graft at least one of the CDRs. It is known that scaffolds, optimally, must meet a number of criteria such as: good phylogenetic conservation; known three-dimensional structure; small size; few or no post-transcriptional modifications; and / or be easy to produce, express, and purify. Skerra, J Mol Recognit, 13:167- 87 (2000).

[0229] The protein scaffolds can be sourced from but are not limited to fibronectin type III FN3 domain (known as “monobodies”), fibronectin type III domain 10, lipocalin, anticalin, Z- domain of protein A of Staphylococcus aureus, thioredoxin A or proteins with a repeated motif such as the “ankyrin repeat”, the “armadillo repeat”, the “leucine-rich repeat” and the “tetratricopeptide repeat”. Such proteins are described in US Patent Publication Nos. 2010 / 0285564, 2006 / 0058510, 2006 / 0088908, 2005 / 0106660, and PCT Publication No. WO2006 / 056464, each of which are specifically incorporated herein by reference in their entirety. Scaffolds derived from toxins from scorpions, insects, plants, mollusks, etc., and the protein inhibiters of neuronal nitric oxide synthase (PIN) may also be used. D. Antibody Binding202424720.3 61

[0230] The term “selective-binding agent”, “antigen-binding agent”, or “antigen-binding protein” refers to a molecule that binds to an antigen. Non-limiting examples include antibodies, antigen-binding fragments, scFv, Fab, Fab’, F(ab’)2, single chain antibodies, peptides, peptide fragments and proteins.

[0231] The term “binding” refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and / or hydrogen-bond interactions, including interactions such as salt bridges and water bridges. “Immunologically reactive” means that the selective binding agent or antibody of interest will bind with antigens present in a biological sample. The term “immune complex” refers the combination formed when an antibody or selective binding agent binds to an epitope on an antigen. 1. Affinity / Avidity

[0232] The term “affinity” refers the strength with which an antibody or selective binding agent binds an epitope. In antibody binding reactions, this is expressed as the affinity constant (Kaor kasometimes referred to as the association constant) for any given antibody or selective binding agent. Affinity is measured as a comparison of the binding strength of the antibody to its antigen relative to the binding strength of the antibody to an unrelated amino acid sequence. The terms “immunoreactive” and “preferentially binds” are used interchangeably herein with respect to antibodies and / or selective binding agent.

[0233] There are several experimental methods that can be used by one skilled in the art to evaluate the binding affinity of any given antibody or selective binding agent for its antigen. This is generally done by measuring the equilibrium dissociation constant (KDor Kd), using the equation KD = koff / kon = [A][B] / [AB]. The term koff is the rate of dissociation between the antibody and antigen per unit time and is related to the concentration of antibody and antigen present in solution in the unbound form at equilibrium. The term konis the rate of antibody and antigen association per unit time and is related to the concentration of the bound antigen- antibody complex at equilibrium. The units used for measuring the KD are mol / L (molarity, or M), or concentration. The Kaof an antibody is the inverse of the KDand is determined by the equation Ka = 1 / KD. Examples of some experimental methods that can be used to determine the KD value are enzyme-linked immunosorbent assays (ELISA), isothermal titration calorimetry (ITC), fluorescence anisotropy, surface plasmon resonance (SPR), and affinity capillary electrophoresis (ACE).202424720.3 62

[0234] Antibodies deemed useful in certain aspects may have an equilibrium dissociation constant of at least, at most, exactly, or between (inclusive or exclusive) any two of about 10- 6, 10-7, 10-8, 10-9, 10-10M, 10-11M, 10-12M, or any range derivable therein. These values are reported for antibodies discussed herein and the same assay may be used to evaluate the binding properties of such antibodies. An antibody of the disclosure is said to “specifically bind” its target antigen when the dissociation constant (KD) is about 10-8M. The antibody specifically binds antigen with “high affinity” when the KDis about 5×10-9M, and with “very high affinity” when the KDis about 5×10-12M. 2. Epitope Specificity

[0235] The epitope of an antigen is the specific region of the antigen for which an antibody has binding affinity. In the case of protein or polypeptide antigens, the epitope is the specific residues (or specified amino acids or protein segment) that the antibody binds with high affinity. An antibody does not necessarily contact every residue within the protein. Nor does every single amino acid substitution or deletion within a protein necessarily affect binding affinity. For purposes of this specification and the accompanying claims, the terms “epitope” and “antigenic determinant” are used interchangeably to refer to the site on an antigen to which B and / or T cell receptors respond or recognize. Polypeptide epitopes can be formed from both contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a polypeptide. In some aspects, an epitope includes at least 3, for example 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, in a unique spatial conformation.

[0236] Epitope specificity of an antibody can be determined in a variety of ways. One approach, for example, involves testing a collection of overlapping peptides of about 15 amino acids spanning the full sequence of the protein and differing in increments of a small number of amino acids (e.g., 3 to 30 amino acids). The peptides are immobilized in separate wells of a microtiter dish. Immobilization can be accomplished, for example, by biotinylating one terminus of the peptides. This process may affect the antibody affinity for the epitope, therefore different samples of the same peptide can be biotinylated at the N and C terminus and immobilized in separate wells for the purposes of comparison. This is useful for identifying end-specific antibodies. Optionally, additional peptides can be included terminating at a particular amino acid of interest. This approach is useful for identifying end-specific antibodies to internal fragments. An antibody or antigen-binding fragment is screened for binding to each202424720.3 63of the various peptides. The epitope is defined as a segment of amino acids that is common to all peptides to which the antibody shows high affinity binding.

[0237] It also is possible to determine without undue experimentation, whether an antibody has the same specificity as the antibody of this disclosure by determining whether the antibody being tested prevents an antibody of this disclosure from binding the protein or polypeptide with which the antibody is normally reactive. If the antibody being tested competes with the antibody of the disclosure as shown by a decrease in binding by the monoclonal antibody of this disclosure, then it is likely that the two antibodies bind to the same or a closely related epitope. Alternatively, one can pre-incubate the antibody of this disclosure with a protein with which it is normally reactive, and determine if the antibody being tested is inhibited in its ability to bind the antigen. If the antibody being tested is inhibited then, likely, it has the same, or a closely related, epitopic specificity as the antibody of this disclosure. 3. Modification of Antigen-Binding Domains

[0238] It is understood that the antibodies of the present disclosure may be modified to yield variant antibodies. Variant antibodies are substantially identical to the antibody polypeptide sequences, or fragments thereof, and still bind the epitopes of the present disclosure. Polypeptide sequences are “substantially identical” when optimally aligned using such programs as Clustal Omega, IGBLAST, GAP, or BESTFIT using default gap weights, they share at least 80% sequence identity, at least 90% sequence identity, at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, or at least 99% sequence identity or any range therein.

[0239] As discussed herein, minor variations in the amino acid sequences of antibodies or antigen-binding regions thereof are contemplated as being encompassed by the present disclosure, providing that the variations in the amino acid sequence maintain at least 75%, more preferably at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% and most preferably at least 99% sequence identity. In some aspects, conservative amino acid replacements are contemplated.

[0240] The variable region of the antibodies of the present disclosure can be modified by mutating amino acid residues within the VH and / or VL CDR 1, CDR 2 and / or CDR 3 regions to improve one or more binding properties (e.g., affinity) of the antibody. Mutations may be introduced by site-directed mutagenesis or PCR-mediated mutagenesis and the effect on antibody binding, or other functional property of interest, can be evaluated in appropriate in202424720.3 64vitro or in vivo assays. Preferably conservative modifications are introduced and typically no more than one, two, three, four or five residues within a CDR region are altered. The mutations may be amino acid substitutions, additions or deletions.

[0241] Framework modifications can be made to the antibodies to decrease immunogenicity, for example, by “backmutating” one or more framework residues to the corresponding germline sequence.

[0242] In addition, the antibodies of the disclosure may be engineered to include modifications within the Fc region to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cellular cytotoxicity. Such modifications include, but are not limited to, alterations of the number of cysteine residues in the hinge region to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody (U.S. Pat. No. 5,677,425) and amino acid mutations in the Fc hinge region to decrease the biological half-life of the antibody (U.S. Pat. No.6,165,745).

[0243] Fragments or analogs of antibodies or immunoglobulin molecules can be readily prepared by those skilled in the art. Certain preferred amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and / or amino acid sequence data to public or proprietary sequence databases. Preferably, computerized comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and / or function. Standard methods to identify protein sequences that fold into a known three-dimensional structure are available to those skilled in the art; Dill and McCallum., Science 338:1042-1046 (2012). Several algorithms for predicting protein structures and the gene sequences that encode these have been developed, and many of these algorithms can be found at the National Center for Biotechnology Information (on the World Wide Web at ncbi.nlm.nih.gov / guide / proteins / ) and at the Bioinformatics Resource Portal (on the World Wide Web at expasy.org / proteomics). Thus, the foregoing examples demonstrate that those of skill in the art can recognize sequence motifs and structural conformations that may be used to define structural and functional domains in accordance with the disclosure.

[0244] It is also contemplated that the antigen-binding domain may be multi-specific or multivalent by multimerizing the antigen-binding domain with VHand VLregion pairs that bind either the same antigen (multi-valent) or a different antigen (multi-specific). E. Enzymatic or Chemical Modification of Antibodies202424720.3 65

[0245] Additionally, the antibodies of the disclosure may be enzymatically or chemically modified to produce further derivatives of the antibodies and antigen binding fragments that are described herein. The term “antibody derivative” can include post-translational modification to the linear polypeptide sequence of the antibody or fragment. The derivatized antibody or fragment thereof may comprise any molecule or substance that imparts a desired property to the antibody or fragment.

[0246] The derivatized antibody can comprise, for example, a chemical post-translational modification, a detectable (or labeling) moiety (e.g., a radioactive, colorimetric, antigenic, or enzymatic molecule, or a detectable bead), a molecule that binds to another molecule (e.g., biotin or streptavidin), a therapeutic or diagnostic moiety (e.g., a radioactive, cytotoxic, or pharmaceutically active moiety), or a molecule that increases the suitability of the antibody for a particular use (e.g., administration to a subject, such as a human subject, or other in vivo or in vitro uses). An antibody or fragment thereof can be covalently attached to a molecule or substance, such as a labeling moiety or a therapeutic moiety; covalent attachment does not prevent the antibody from generating an anti-idiotypic response. An antibody or fragment thereof can be non-covalently attached to a molecule or substance, such as a labeling moiety or a therapeutic moiety.

[0247] Optionally, an antibody or an antigen-binding fragment can be chemically conjugated to, or expressed as, a fusion protein with other proteins. In some aspects, polypeptides may be chemically modified by conjugating or fusing the polypeptide to serum protein, such as human serum albumin, to increase half-life of the resulting molecule. See, e.g., EP 0322094 and EP 0486525. In some aspects, the polypeptides may be conjugated to a diagnostic agent and used diagnostically, for example, to monitor the development or progression of a disease and determine the efficacy of a given treatment regimen. In some aspects, the polypeptides may also be conjugated to a therapeutic agent to provide a therapy in combination with the therapeutic effect of the polypeptide.

[0248] In some aspects, disclosed are antibodies and antibody-like molecules that are linked to at least one agent to form an antibody conjugate or payload. To increase the efficacy of antibody molecules as diagnostic or therapeutic agents, it is conventional to link or covalently bind or complex at least one desired molecule or moiety. Such a molecule or moiety may be, but is not limited to, at least one effector or reporter molecule. Effector molecules comprise molecules having a desired activity, e.g., cytotoxic activity. Non-limiting examples of effector molecules include toxins, therapeutic enzymes, antibiotics, radiolabeled nucleotides and the like. By contrast, a reporter molecule is defined as any moiety that may be detected202424720.3 66using an assay. Non-limiting examples of reporter molecules that have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, luminescent molecules, photoaffinity molecules, colored particles, or ligands. 1. Post-Translational Modifications

[0249] The antigen-binding protein can have or lack one or more post-translational modifications such as myristoylation, palmitoylation, isoprenylation or prenylation, farnesylation, geranylgeranylation, glypiation, acylation, acetylation, formylation, alkylation, methylation, amide bond formation, amidation at C-terminus, arginylation, polyglutamylation, polyglycylation, butyrylation, glycosylation, glycation, polysialylation, malonylation, hydroxylation, iodination, phosphorylation, adenylylation, propionylation, S- glutathionylation, S-nitrosylation, S-sulfenylation (aka S-sulphenylation), succinylation, sulfation, biotinylation, pegylation, SUMOylation, ubiquitination, neddylation, pupylation, disulfide bridges, or racemization. The antigen-binding protein can have reduced or increased amounts of one or more post-translational modifications as compared to the same antigen- binding protein expressed in the cell that is native to the encoded gene. The reduction or increase may be by at least or at most 25, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500% or more (or any range derivable therein).

[0250] In some aspects, contemplated are glycosylation variants of antibodies, wherein the number and / or type of glycosylation site(s) has been altered compared to the amino acid sequences of the parent polypeptide. Glycosylation of the polypeptides can be altered, for example, by modifying one or more sites of glycosylation within the polypeptide sequence to increase the affinity of the polypeptide for antigen (U.S. Pat. Nos. 5,714,350 and 6,350,861, incorporated herein by reference). Antibody protein variants comprise a greater or a lesser number of N-linked glycosylation sites than the native antibody. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate or alter this sequence will prevent addition of an N-linked carbohydrate chain present in the native polypeptide. For example, the glycosylation can be reduced by the deletion of an Asn or by substituting the Asn202424720.3 67with a different amino acid. In other aspects, one or more new N-linked glycosylation sites are created.

[0251] Additional antibody variants include cysteine variants, wherein one or more cysteine residues in the parent or native amino acid sequence are deleted from or substituted with another amino acid (e.g., serine). Cysteine variants are useful, inter alia, when antibodies must be refolded into a biologically active conformation. Cysteine variants may have fewer cysteine residues than the native antibody and typically have an even number to minimize interactions resulting from unpaired cysteines.

[0252] In some aspects, the polypeptides can be pegylated to increase biological half-life by reacting the polypeptide with polyethylene glycol (PEG) or a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the polypeptide. Polypeptide pegylation may be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). Methods for pegylating proteins are known in the art and can be applied to the polypeptides of the disclosure to obtain PEGylated derivatives of antibodies. See, e.g., EP 0154316 and EP 0401384, incorporated herein by reference. In some aspects, the antibody is conjugated or otherwise linked to transthyretin (TTR) or a TTR variant. The TTR or TTR variant can be chemically modified with, for example, a chemical selected from the group consisting of dextran, poly(n-vinyl pyrrolidone), polyethylene glycols, propropylene glycol homopolymers, polypropylene oxide / ethylene oxide co-polymers, polyoxyethylated polyols, and polyvinyl alcohols. As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins. 2. Conjugates

[0253] Certain examples of antibody conjugates are those conjugates in which the antibody is linked to a detectable label. “Detectable labels” are compounds and / or elements that can be detected due to their specific functional properties, and / or chemical characteristics, the use of which allows the antibody to be detected, and / or further quantified if desired. The term also includes sequences conjugated to the polynucleotide that will provide a signal upon expression of the inserted sequences, such as green fluorescent protein (GFP) and the like. The label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable. The labels can be suitable for small scale detection or more suitable for202424720.3 68high-throughput screening. The label may be simply detected, or it may be quantified. A response that is simply detected generally comprises a response whose existence merely is confirmed, whereas a response that is quantified generally comprises a response having a quantifiable (e.g., numerically reportable) value such as an intensity, polarization, and / or other property. Examples of detectable labels include, but not limited to, radioactive isotopes, fluorescers, semiconductor nanocrystals, chemiluminescers, chromophores, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, dyes, metal ions, metal sols, ligands (e.g., biotin, streptavidin or haptens) and the like. Examples of labels are, but not limited to, horseradish peroxidase (HRP), fluorescein, fluorescein isothiocyanate (FITC), rhodamine, dansyl, umbelliferone, dimethyl acridinium ester (DMAE), Texas red, luminol, nicotinamide adenine dinucleotide phosphate (NADPH), and α- or ß-galactosidase.

[0254] In luminescence or fluorescence assays, the detectable response may be generated directly using a luminophore or fluorophore associated with an assay component involved in binding, or indirectly using a luminophore or fluorophore associated with another (e.g., reporter or indicator) component. Examples of luminescent labels that produce signals include but are not limited to bioluminescence and chemiluminescence. Detectable luminescence response generally comprises a change in, or an occurrence of, a luminescence signal. Suitable methods and luminophores for luminescently labeling assay components are known in the art and described for example in Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6.sup.th ed.). Examples of luminescent probes include, but are not limited to, aequorin and luciferases. Examples of suitable fluorescent labels include, but are not limited to, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosin, coumarin, methyl- coumarins, pyrene, Malacite green, stilbene, Lucifer Yellow, Cascade Blue.TM., and Texas Red. Other suitable optical dyes are described in the Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6.sup.th ed.).

[0255] In another aspect, the fluorescent label is functionalized to facilitate covalent attachment to a cellular component present in or on the surface of the cell or tissue such as a cell surface marker. Suitable functional groups, including, but not are limited to, isothiocyanate groups, amino groups, haloacetyl groups, maleimides, succinimidyl esters, and sulfonyl halides, all of which may be used to attach the fluorescent label to a second molecule. The choice of the functional group of the fluorescent label will depend on the site of attachment to either a linker, the agent, the marker, or the second labeling agent.

[0256] Attachment of the fluorescent label may be either directly to the cellular component or compound or alternatively, can by via a linker. Suitable binding pairs for use in indirectly202424720.3 69linking the fluorescent label to the intermediate include, but are not limited to, antigens / antibodies, e.g., rhodamine / anti-rhodamine, biotin / avidin and biotin / streptavidin.

[0257] Antibodies may also be coupled to low molecular weight haptens to increase the sensitivity of the antibody in an assay. The haptens can then be specifically detected by means of a second reaction. For example, it is common to use haptens such as biotin, which reacts avidin, or dinitrophenol, pyridoxal, and fluorescein, which can react with specific anti-hapten antibodies. See, Harlow and Lane (1988) supra.

[0258] Antibody conjugates also include those intended primarily for use in vitro, where the antibody is linked to a secondary binding ligand and / or to an enzyme to generate a colored product upon contact with a chromogenic substrate. Examples of suitable enzymes include, but are not limited to, urease, alkaline phosphatase, (horseradish) hydrogen peroxidase, or glucose oxidase. Preferred secondary binding ligands are biotin and / or avidin and streptavidin compounds. The uses of such labels are well known to those of skill in the art and are described, for example, in U.S. Patents 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241; each incorporated herein by reference. Molecules containing azido groups may also be used to form covalent bonds to proteins through reactive nitrene intermediates that are generated by low intensity ultraviolet light.

[0259] Additional suitable conjugated molecules include ribonuclease (RNase), DNase I, an antisense oligonucleotide, an inhibitory RNA molecule such as a siRNA molecule, an immunostimulatory nucleic acid, aptamers, ribozymes, triplex forming molecules, and external guide sequences (e.g., guide RNAs). Aptamers are small nucleic acids ranging from 15-50 bases in length that fold into defined secondary and tertiary structures, such as stem-loops or G-quartets, and can bind small molecules, such as ATP (U.S. Pat. No. 5,631,146) and theophiline (U.S. Pat. No.5,580,737), as well as large molecules, such as reverse transcriptase (U.S. Pat. No.5,786,462) and thrombin (U.S. Pat. No.5,543,293). Ribozymes are nucleic acid molecules that can catalyze a chemical reaction, either intramolecularly or intermolecularly. Ribozymes typically cleave nucleic acid substrates through recognition and binding of the target substrate with subsequent cleavage. Triplex forming function nucleic acid molecules can interact with double-stranded or single-stranded nucleic acid by forming a triplex, in which three strands of DNA form a complex dependent on both Watson-Crick and Hoogsteen base- pairing. Triplex molecules can bind target regions with high affinity and specificity. The functional nucleic acid molecules may act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional nucleic acid molecules may possess a de novo activity independent of any other molecules.202424720.3 70

[0260] The antibodies of the disclosure or antigen-binding regions thereof can also be linked to another functional molecule such as another antibody or ligand for a receptor to generate a bi-specific or multi-specific molecule that binds to at least two or more different binding sites or target molecules. Linking of the antibody to one or more other binding molecules, such as another antibody, antibody fragment, peptide, or binding mimetic, can be done, for example, by chemical coupling, genetic fusion, or noncovalent association. Multi- specific molecules can further include a third binding specificity, in addition to the first and second target epitope.

[0261] The antibodies or fragments thereof of the present disclosure may be linked to a moiety that is toxic to a cell to which the antibody is bound to form “depleting” antibodies.

[0262] The antibodies of the disclosure may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.

[0263] The antibodies also can be bound to many different carriers. Thus, this disclosure also provides compositions containing the antibodies and another substance, active or inert. Examples of well-known carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylase, natural and modified cellulose, polyacrylamide, agarose, and magnetite. The nature of the carrier can be either soluble or insoluble for purposes of the disclosure. Those skilled in the art will know of other suitable carriers for binding monoclonal antibodies, or will be able to ascertain such, using routine experimentation.

[0264] In some aspects, contemplated are immunoconjugates comprising an antibody or antigen-binding fragment thereof conjugated (e.g., covalently attached) to a cytotoxic agent such as a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). In this way, the agent of interest can be targeted directly to cells bearing the targeted cell surface antigen. The antibody and agent may be associated through non-covalent interactions such as through electrostatic forces, or by covalent bonds. Various linkers, known in the art, can be employed to form the immunoconjugate. Additionally, the immunoconjugate can be provided in the form of a genetic fusion protein. In one aspect, an antibody may be conjugated to various therapeutic substances to target the cell surface antigen. Examples of conjugated agents include, but are not limited to, metal chelate complexes, drugs, toxins, and other effector molecules, such as cytokines,202424720.3 71lymphokines, chemokines, immunomodulators, radiosensitizers, asparaginase, carboranes, and radioactive halogens.

[0265] In antibody drug conjugates (ADC), an antibody is conjugated to one or more drug moieties through a linker. The ADC may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group of an antibody with a bivalent linker reagent, to form antibody- L, via a covalent bond, followed by reaction with a drug moiety D; and (2) reaction of a nucleophilic group of a drug moiety with a bivalent linker reagent, to form D-L, via a covalent bond, followed by reaction with the nucleophilic group of an antibody. ADC may also be produced by modification of the antibody to introduce electrophilic moieties, which can react with nucleophilic substituents on the linker reagent or drug. Alternatively, a fusion protein comprising the antibody and cytotoxic agent may be made, e.g., by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.

[0266] Examples of ADC known to a person skilled in the art are pro-drugs useful for the local delivery of cytotoxic or cytostatic agents, i.e. drugs to kill or inhibit tumor cells in the treatment of cancer (Syrigos and Epenetos, Anticancer Res. 19:605-614 (1999); Niculescu- Duvaz and Springer, Adv. Drg. Del. Rev. 26:151-172 (1997); U.S. Pat. No. 4,975,278). In contrast, systematic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the target tumor cells (Baldwin et al., Lancet 1:603-5 (1986); Thorpe, “Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review,” In: Monoclonal Antibodies ‘84: Biological and Clinical Applications, A. Pincera et al., (eds.) pp. 475-506) (1985). Both polyclonal antibodies and monoclonal antibodies have been reported as useful in these strategies (Rowland et al., Cancer Immunol. Immunother. 21:183-87 (1986)).

[0267] In certain aspects, ADCs include covalent or aggregative conjugates of antibodies, or antigen-binding fragments thereof, with other proteins or peptides, such as by expression of recombinant fusion proteins comprising heterologous polypeptides fused to the N-terminus or C-terminus of an antibody polypeptide. For example, the conjugated peptide may be a heterologous signal (or leader) polypeptide, e.g., the yeast alpha-factor leader, or a peptide such as an epitope tag (e.g., V5-His). Antibody-containing fusion proteins may comprise peptides added to facilitate purification or identification of the antibody (e.g., poly-His). An antibody202424720.3 72polypeptide also can be linked to the FLAG® (Sigma-Aldrich, St. Louis, Mo.) peptide as described in Hopp et al., Bio / Technology 6:1204 (1988), and U.S. Pat. No.5,011,912.

[0268] The conjugated agents can be linked to the antibody directly or indirectly, using any of a large number of available methods. Several methods are known in the art for the attachment or conjugation of an antibody to its conjugate moiety (Amon et al., 1985; Hellstrom et al., 1987; Thorpe, 1985; Baldwin et al., 1985; Thorpe et al., 1982).

[0269] Some attachment methods involve the use of a metal chelate complex employing, for example, an organic chelating agent such a diethylenetriaminepentaacetic acid anhydride (DTPA); ethylenetriaminetetraacetic acid; N-chloro-p-toluenesulfonamide; and / or tetrachloro- 3-6-diphenylglycouril-3 attached to the antibody (U.S. Patent Nos.4,472,509 and 4,938,948, each incorporated herein by reference).

[0270] Monoclonal antibodies may also be reacted with an enzyme in the presence of a coupling agent such as glutaraldehyde or periodate.

[0271] Conjugates may also be made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).

[0272] In some aspects, derivatization of immunoglobulins by selectively introducing sulfhydryl groups in the Fc region of an immunoglobulin, using reaction conditions that do not alter the antibody combining site, are contemplated. Antibody conjugates produced according to this methodology are disclosed to exhibit improved longevity, specificity, and sensitivity (U.S. Pat. No.5,196,066, incorporated herein by reference).

[0273] Site-specific attachment of effector or reporter molecules, wherein the reporter or effector molecule is conjugated to a carbohydrate residue in the Fc region has also been disclosed in the literature (O’Shannessy et al., J. Immunol. Methods 99(2):153-61 (1987)).

[0274] Bi-specific and multi-specific molecules can be prepared using methods known in the art. For example, each binding unit of the hi-specific molecule can be generated separately and then conjugated to one another. When the binding molecules are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation. Examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5’-dithiobis(2-nitroberizoic acid) (DTNB), o-phenylenedimaleimide (oRDM), N-202424720.3 73succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N- maleimidomethyl)cyclohaxane-I-carboxylate (sulfo-SMCC) (Karpovsky et al., 1984; Liu et al., 1985). When the binding molecules are antibodies, they can be conjugated by sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains. F. Proteins

[0275] In certain aspects the size of a protein or polypeptide (wild-type or modified) may comprise, but is not limited to, at least, at most, exactly, or between (inclusive or exclusive) any two of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 1500, 1750, 2000, 2250, 2500 amino acid residues or greater, and any range derivable therein, or derivative of a corresponding amino sequence described or referenced herein. It is contemplated that polypeptides may be mutated by truncation, rendering them shorter than their corresponding wild-type form, also, they might be altered by fusing or conjugating a heterologous protein or polypeptide sequence with a particular function (e.g., for targeting or localization, for enhanced immunogenicity, for purification purposes, etc.). As used herein, the term “domain” refers to any distinct functional or structural unit of a protein or polypeptide, and generally refers to a sequence of amino acids with a structure or function recognizable by one skilled in the art.

[0276] The polypeptides or proteins of the disclosure may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (or any derivable range therein) or more variant amino acids (e.g., amino acid substitutions) or be at least, at most, exactly, or between (inclusive or exclusive) any two of 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with at least, at most, exactly, or between (inclusive or exclusive) any two of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,202424720.3 7439, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, or more contiguous amino acids or nucleic acids, or any range derivable therein, of any of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 50, 53, 57, 59, 62, 65, 67, 69, 71, 73, 75, 77, 79, or 81.

[0277] In some aspects, the protein or polypeptide may comprise amino acids 1 to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110 (or any derivable range therein) of any of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 50, 53, 57, 59, 62, 65, 67, 69, 71, 73, 75, 77, 79, or 81.

[0278] In some aspects, the protein or polypeptide may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 (or any derivable range therein) contiguous amino acids of any of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 50, 53, 57, 59, 62, 65, 67, 69, 71, 73, 75, 77, 79, or 81.

[0279] In some aspects, the polypeptide or protein may comprise at least, at most, exactly, or between (inclusive or exclusive) any two of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 (or any derivable range therein) contiguous amino acids that are at least, at most, exactly, or between (inclusive or exclusive) any two of 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with one of any of SEQ ID202424720.3 75NOs:2, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 50, 53, 57, 59, 62, 65, 67, 69, 71, 73, 75, 77, 79, or 81.

[0280] In some aspects there is a polypeptide starting at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110 of any of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 50, 53, 57, 59, 62, 65, 67, 69, 71, 73, 75, 77, 79, or 81 and comprising at least, at most, exactly, or between (inclusive or exclusive) any two of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110 (or any derivable range therein) contiguous amino acids or nucleotides of any of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 50, 53, 57, 59, 62, 65, 67, 69, 71, 73, 75, 77, 79, or 81.

[0281] Nucleotide as well as protein, polypeptide, and peptide sequences for various genes have been previously disclosed and may be found in the recognized computerized databases. Two commonly used databases are the National Center for Biotechnology Information’s GENBANK® and GENPEPT® databases (on the World Wide Web at ncbi.nlm.nih.gov) and The Universal Protein Resource (UNIPROT®; on the World Wide Web at uniprot.org). The coding regions for these genes may be amplified and / or expressed using the techniques disclosed herein or as would be known to those of ordinary skill in the art.

[0282] It is contemplated that in compositions of the disclosure, there is between about 0.001 mg and about 10 mg of total polypeptide per ml. The concentration of polypeptide in a composition can be at least, at most, exactly, or between (inclusive or exclusive) any two of about 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 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, 10.0 mg / ml or more (or any range derivable therein). 1. Sequences

[0283] Amino acid sequences from 12 light chain variable region CDRs from the BMP-7- binding proteins (e.g., antibodies) of the present disclosure are provided in SEQ ID NOs:2, 4,202424720.3 766, 20, 22, 24, 50, 53, 57, 67, 69, and 71 as follows and in Table 1: CDR-L1 (SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67), CDR-L2 (SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69), CDR-L3 (SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71). Table 1

[0284] Amino acid sequences from 13 heavy chain variable region CDRs from the BMP- 7-binding proteins (e.g., antibodies) of the present disclosure are provided in SEQ ID NOs:8, 10, 12, 26, 28, 30, 32, 59, 62, 65, 73, 75, and 77 as follows and in Table 2: CDR-H1 (SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73), CDR-H2 (SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75), and CDR-H3 (SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77). Table 2202424720.3 77

[0285] The amino acid sequence for a first full light chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:14 as follows:

[0286] DIVMTQSPSSMYASLGERVTITCKASQDITGYLGWFQQKPGKSPKTLIYRA DRLVDGVPSRFSGSGSGQDYSLTISSLEYEDMGIYYCLQYDEFPLTFGAGTKLELK (SEQ ID NO:14).

[0287] The amino acid sequence for a second full light chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:34 as follows:

[0288] DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYY TSNRFTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYSSPPTFGGGTKLEIK (SEQ ID NO:34).

[0289] The amino acid sequence for a third full light chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:36 as follows:

[0290] DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGQAPKLLIYY TSNRFTGVPDRFSGSGSGTDFTLTISSLQPEDFATYYCQQDYSSPPTFGGGTKLEIK (SEQ ID NO:36).

[0291] The amino acid sequence for a fourth full light chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:38 as follows:

[0292] DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGQAPKLLIYY TSNRFTGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQDYSSPPTFGGGTKLEIK (SEQ ID NO:38).

[0293] The amino acid sequence for a fifth full light chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:79 as follows:

[0294] SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYY TSNRFTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYSSPPTFGGGTKLEIK (SEQ ID NO:79).

[0295] The amino acid sequence for a first full heavy chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:16 as follows:

[0296] SGPELKKPGETVKISCKASGYTFTDSSMHWVKQAPGKGLKWMGWINTET GEPTYVDDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCSRDYDWFAYWGQGTL VTVSA (SEQ ID NO:16).202424720.3 78

[0297] The amino acid sequence for a second full heavy chain variable region of a BMP- 7-binding protein disclosed herein is provided in SEQ ID NO:40 as follows:

[0298] QVQLVQSGSELKKPGASVKVSCKASGYTFTDSSMHWVRQAPGQGLKWM GWINTETGEPTYVDDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARDYDWFAY WGQGTLVTVSS (SEQ ID NO:40).

[0299] The amino acid sequence for a third full heavy chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:42 as follows:

[0300] QVQLVQSGSELKKPGASVKVSCKASGYTFTDSSMHWVRQAPGQGLEWM GWINTETGEPTYVDDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARDYDWFAY WGQGTLVTVSS (SEQ ID NO:42).

[0301] The amino acid sequence for a fourth full heavy chain variable region of a BMP-7- binding protein disclosed herein is provided in SEQ ID NO:81 as follows:

[0302] IQLVQSGPELKKPGETVKISCKASGYTFTDSSMHWVKQAPGKGLKWMG WINTETGEPTYVDDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCSRDYDWFAY WGQGTLVTVSA (SEQ ID NO:81).

[0303] In some aspects, the VH and the VL are on the same polypeptide. In some aspects, the VHand the VLare on different polypeptides.

[0304] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79. Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody- like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VLhas at least 85% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79. In some aspects, the VH has at least 85% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VLhas at least 90% identity202424720.3 79to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79. In some aspects, the VH has at least 90% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79. In some aspects, the VHhas at least 95% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL comprises SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79. In some aspects, the VHcomprises SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81.

[0305] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79; and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 85% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79; and the VHhas at least 85% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 90% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79; and the VH has at least 90% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79; and the VH has at least 95% identity to SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81. In some aspects, the VLcomprises SEQ ID NO:14, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:79; and the VH comprises SEQ ID NO:16, SEQ ID NO:40, SEQ ID NO:42, or SEQ ID NO:81.

[0306] Some aspects are directed to antigen-binding proteins (e.g., antibodies, antibody- like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%,202424720.3 8096%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:14; and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:16. In some aspects, the VL has at least 85% identity to SEQ ID NO:14, and the VH has at least 85% identity to SEQ ID NO:16. In some aspects, the VL has at least 90% identity to SEQ ID NO:14, and the VHhas at least 90% identity to SEQ ID NO:16. In some aspects, the VL has at least 95% identity to SEQ ID NO:14, and the VH has at least 95% identity to SEQ ID NO:16. In some aspects, the VL comprises SEQ ID NO:14, and the VH comprises SEQ ID NO:16.

[0307] Some aspects are directed to antigen-binding proteins (e.g., antibodies, antibody- like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:34; and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:40. In some aspects, the VLhas at least 85% identity to SEQ ID NO:34, and the VHhas at least 85% identity to SEQ ID NO:40. In some aspects, the VLhas at least 90% identity to SEQ ID NO:34, and the VH has at least 90% identity to SEQ ID NO:40. In some aspects, the VL has at least 95% identity to SEQ ID NO:34, and the VH has at least 95% identity to SEQ ID NO:40. In some aspects, the VLcomprises SEQ ID NO:34, and the VHcomprises SEQ ID NO:40.

[0308] Some aspects are directed to antigen-binding proteins (e.g., antibodies, antibody- like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:36; and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable202424720.3 81therein, to SEQ ID NO:42. In some aspects, the VLhas at least 85% identity to SEQ ID NO:36, and the VH has at least 85% identity to SEQ ID NO:42. In some aspects, the VL has at least 90% identity to SEQ ID NO:36, and the VH has at least 90% identity to SEQ ID NO:42. In some aspects, the VLhas at least 95% identity to SEQ ID NO:36, and the VHhas at least 95% identity to SEQ ID NO:42. In some aspects, the VL comprises SEQ ID NO:36, and the VH comprises SEQ ID NO:42.

[0309] Some aspects are directed to antigen-binding proteins (e.g., antibodies, antibody- like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:38; and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:42. In some aspects, the VL has at least 85% identity to SEQ ID NO:38, and the VHhas at least 85% identity to SEQ ID NO:42. In some aspects, the VLhas at least 90% identity to SEQ ID NO:38, and the VH has at least 90% identity to SEQ ID NO:42. In some aspects, the VL has at least 95% identity to SEQ ID NO:38, and the VH has at least 95% identity to SEQ ID NO:42. In some aspects, the VLcomprises SEQ ID NO:38, and the VHcomprises SEQ ID NO:42.

[0310] The amino acid sequence for a full light chain constant region of a BMP-7-binding protein disclosed herein is provided in SEQ ID NO:44 as follows:

[0311] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:44).

[0312] The amino acid sequence for a full heavy chain constant region of a BMP-7-binding protein disclosed herein is provided in SEQ ID NO:46 as follows:

[0313] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP202424720.3 82PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:46).

[0314] In some aspects, the CH and the CL are on the same polypeptide. In some aspects, the CHand the CLare on different polypeptides.

[0315] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain constant region (CL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:44. Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen- binding fragment thereof) comprising a heavy chain constant region (CH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:46. In some aspects, the CLhas at least 85% identity to SEQ ID NO:44. In some aspects, the CH has at least 85% identity to SEQ ID NO:46. In some aspects, the CL has at least 90% identity to SEQ ID NO:44. In some aspects, the CH has at least 90% identity to SEQ ID NO:46. In some aspects, the CLhas at least 95% identity to SEQ ID NO:44. In some aspects, the CHhas at least 95% identity to SEQ ID NO:46. In some aspects, the CLcomprises SEQ ID NO:44. In some aspects, the CH comprises SEQ ID NO:46.

[0316] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain constant region (CL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:44; and a heavy chain constant region (CH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:46. In some aspects, the CL has at least 85% identity to SEQ ID NO:44; and the CH has at least 85% identity to SEQ ID NO:46. In some aspects, the CL has at least 90% identity to SEQ ID NO:44; and the CHhas at least 90% identity to SEQ ID NO:46.202424720.3 83In some aspects, the CLhas at least 95% identity to SEQ ID NO:44; and the CHhas at least 95% identity to SEQ ID NO:46. In some aspects, the CL comprises SEQ ID NO:44; and the CH comprises SEQ ID NO:46.

[0317] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; and a light chain constant region (CL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:44. Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:40 or SEQ ID NO:42; and a heavy chain constant region (CH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:46. In some aspects, the VL has at least 85% identity to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; and the CLhas at least 85% identity to SEQ ID NO:44. In some aspects, the VH has at least 85% identity to SEQ ID NO:40 or SEQ ID NO:42; and the CH has at least 85% identity to SEQ ID NO:46. In some aspects, the VL has at least 90% identity to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; and the CLhas at least 90% identity to SEQ ID NO:44. In some aspects, the VH has at least 90% identity to SEQ ID NO:40 or SEQ ID NO:42; and the CH has at least 90% identity to SEQ ID NO:46. In some aspects, the VLhas at least 95% identity to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; and the CLhas at least 95% identity to SEQ ID NO:44. In some aspects, the VHhas at least 95% identity to SEQ ID NO:40 or SEQ ID NO:42; and the CH has at least 95% identity to SEQ ID NO:46. In some aspects, the VL comprises SEQ ID NO:34, SEQ ID NO:36, or SEQ ID202424720.3 84NO:38; and the CLcomprises SEQ ID NO:44. In some aspects, the VHcomprises SEQ ID NO:40 or SEQ ID NO:42; and the CH comprises SEQ ID NO:46.

[0318] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; a light chain constant region (CL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:44; a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:40 or SEQ ID NO:42; and a heavy chain constant region (CH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:46. In some aspects, the VL has at least 85% identity to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; the CLhas at least 85% identity to SEQ ID NO:44; the VHhas at least 85% identity to SEQ ID NO:40 or SEQ ID NO:42; and the CHhas at least 85% identity to SEQ ID NO:46. In some aspects, the VL has at least 90% identity to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; the CL has at least 90% identity to SEQ ID NO:44; the VH has at least 90% identity to SEQ ID NO:40 or SEQ ID NO:42; and the CHhas at least 90% identity to SEQ ID NO:46. In some aspects, the VL has at least 95% identity to SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; the CL has at least 95% identity to SEQ ID NO:44; the VH has at least 95% identity to SEQ ID NO:40 or SEQ ID NO:42; and the CHhas at least 95% identity to SEQ ID NO:46. In some aspects, the VL comprises SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:38; the CL comprises SEQ ID NO:44; the VH comprises SEQ ID NO:40 or SEQ ID NO:42; and the CHcomprises SEQ ID NO:46.

[0319] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or202424720.3 85between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID SEQ ID NO:79. Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:81. In some aspects, the VL has at least 85% identity to SEQ ID NO:79. In some aspects, the VHhas at least 85% identity to SEQ ID NO:81. In some aspects, the VLhas at least 90% identity to SEQ ID NO:79. In some aspects, the VH has at least 90% identity to SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:79. In some aspects, the VH has at least 95% identity to SEQ ID NO:81. In some aspects, the VLcomprises SEQ ID NO:79. In some aspects, the VHcomprises SEQ ID NO:81.

[0320] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a light chain variable region (VL) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:79; and a heavy chain variable region (VH) having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:81. In some aspects, the VL has at least 85% identity to SEQ ID NO:79; and the VH has at least 85% identity to SEQ ID NO:81. In some aspects, the VL has at least 90% identity to SEQ ID NO:79; and the VHhas at least 90% identity to SEQ ID NO:81. In some aspects, the VL has at least 95% identity to SEQ ID NO:79; and the VH has at least 95% identity to SEQ ID NO:81. In some aspects, the VL comprises SEQ ID NO:79; and the VHcomprises SEQ ID NO:81.

[0321] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a CDR-L1 having at least, at most, exactly, or between (inclusive or202424720.3 86exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0322] Some aspects are directed to antigen-binding proteins (e.g., antibodies, antibody- like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP-7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having 85% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having 85% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having 95% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having 90% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having 95% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having 95% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0323] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:2; a CDR-L2 having 85% sequence identity to SEQ ID NO:4; and a CDR-L3 having 85% sequence identity to SEQ ID NO:6. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to202424720.3 87SEQ ID NO:2; a CDR-L2 having 90% sequence identity to SEQ ID NO:4; and a CDR-L3 having 90% sequence identity to SEQ ID NO:6. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:2; a CDR-L2 having 95% sequence identity to SEQ ID NO:4; and a CDR-L3 having 95% sequence identity to SEQ ID NO:6. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:2; a CDR-L2 comprising SEQ ID NO:4; and a CDR-L3 comprising SEQ ID NO:6.

[0324] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:20; a CDR-L2 having 85% sequence identity to SEQ ID NO:22; and a CDR-L3 having 85% sequence identity to SEQ ID NO:24. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:20; a CDR-L2 having 90% sequence identity to SEQ ID NO:22; and a CDR-L3 having 90% sequence identity to SEQ ID NO:24. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:20; a CDR-L2 having 95% sequence identity to SEQ ID NO:22; and a CDR-L3 having 95% sequence identity to SEQ ID NO:24. Some aspects are directed to antigen-binding proteins comprising a CDR- L1 comprising SEQ ID NO:20; a CDR-L2 comprising SEQ ID NO:22; and a CDR-L3 comprising SEQ ID NO:24.

[0325] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:50; a CDR-L2 having 85% sequence identity to SEQ ID NO:53; and a CDR-L3 having 85% sequence identity to SEQ ID NO:57. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:50; a CDR-L2 having 90% sequence identity to SEQ ID NO:53; and a CDR-L3 having 90% sequence identity to SEQ ID NO:57. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:50; a CDR-L2 having 95% sequence identity to SEQ ID NO:53; and a CDR-L3 having 95% sequence identity to SEQ ID NO:57. Some aspects are directed to antigen-binding proteins comprising a CDR- L1 comprising SEQ ID NO:50; a CDR-L2 comprising SEQ ID NO:53; and a CDR-L3 comprising SEQ ID NO:57.

[0326] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:67; a CDR-L2 having 85% sequence identity to SEQ ID NO:69; and a CDR-L3 having 85% sequence identity to SEQ ID NO:71. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:67; a CDR-L2 having 90% sequence identity to SEQ ID NO:69; and a CDR-L3202424720.3 88having 90% sequence identity to SEQ ID NO:71. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:67; a CDR-L2 having 95% sequence identity to SEQ ID NO:69; and a CDR-L3 having 95% sequence identity to SEQ ID NO:71. Some aspects are directed to antigen-binding proteins comprising a CDR- L1 comprising SEQ ID NO:67; a CDR-L2 comprising SEQ ID NO:69; and a CDR-L3 comprising SEQ ID NO:71.

[0327] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a CDR-H1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0328] Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 85% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having 85% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having 85% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 90% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having 90% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR- H3 having 90% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 95% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having 95% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having 95% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some202424720.3 89aspects are directed to antigen-binding proteins comprising a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0329] Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 85% sequence identity to SEQ ID NO:8; a CDR-H2 having 85% sequence identity to SEQ ID NO:10; and a CDR-H3 having 85% sequence identity to SEQ ID NO:12. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 90% sequence identity to SEQ ID NO:8; a CDR-H2 having 90% sequence identity to SEQ ID NO:10; and a CDR-H3 having 90% sequence identity to SEQ ID NO:12. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 95% sequence identity to SEQ ID NO:8; a CDR-H2 having 95% sequence identity to SEQ ID NO:10; and a CDR-H3 having 95% sequence identity to SEQ ID NO:12. Some aspects are directed to antigen-binding proteins comprising a CDR- H1 comprising SEQ ID NO:8; a CDR-H2 having 85% comprising SEQ ID NO:10; and a CDR- H3 comprising SEQ ID NO:12.

[0330] Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 85% sequence identity to SEQ ID NO:26; a CDR-H2 having 85% sequence identity to SEQ ID NO:28; and a CDR-H3 having 85% sequence identity to SEQ ID NO:30. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 90% sequence identity to SEQ ID NO:26; a CDR-H2 having 90% sequence identity to SEQ ID NO:28; and a CDR-H3 having 90% sequence identity to SEQ ID NO:30. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 95% sequence identity to SEQ ID NO:26; a CDR-H2 having 95% sequence identity to SEQ ID NO:28; and a CDR-H3 having 95% sequence identity to SEQ ID NO:30. Some aspects are directed to antigen-binding proteins comprising a CDR- H1 comprising SEQ ID NO:26; a CDR-H2 comprising SEQ ID NO:28; and a CDR-H3 comprising SEQ ID NO:30.

[0331] Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 85% sequence identity to SEQ ID NO:26; a CDR-H2 having 85% sequence identity to SEQ ID NO:28; and a CDR-H3 having 85% sequence identity to SEQ ID NO:32. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 90% sequence identity to SEQ ID NO:26; a CDR-H2 having 90% sequence identity to SEQ ID NO:28; and a CDR-H3 having 90% sequence identity to SEQ ID NO:32. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 95% sequence identity to SEQ ID NO:26; a CDR-H2 having 95% sequence identity to SEQ ID NO:28; and a CDR-H3 having 95% sequence identity202424720.3 90to SEQ ID NO:32. Some aspects are directed to antigen-binding proteins comprising a CDR- H1 comprising SEQ ID NO:26; a CDR-H2 comprising SEQ ID NO:28; and a CDR-H3 comprising SEQ ID NO:32.

[0332] Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 85% sequence identity to SEQ ID NO:59; a CDR-H2 having 85% sequence identity to SEQ ID NO:62; and a CDR-H3 having 85% sequence identity to SEQ ID NO:65. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 90% sequence identity to SEQ ID NO:59; a CDR-H2 having 90% sequence identity to SEQ ID NO:62; and a CDR-H3 having 90% sequence identity to SEQ ID NO:65. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 95% sequence identity to SEQ ID NO:59; a CDR-H2 having 95% sequence identity to SEQ ID NO:62; and a CDR-H3 having 95% sequence identity to SEQ ID NO:65. Some aspects are directed to antigen-binding proteins comprising a CDR- H1 comprising SEQ ID NO:59; a CDR-H2 comprising SEQ ID NO:62; and a CDR-H3 comprising SEQ ID NO:65.

[0333] Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 85% sequence identity to SEQ ID NO:73; a CDR-H2 having 85% sequence identity to SEQ ID NO:75; and a CDR-H3 having 85% sequence identity to SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 90% sequence identity to SEQ ID NO:73; a CDR-H2 having 90% sequence identity to SEQ ID NO:75; and a CDR-H3 having 90% sequence identity to SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-H1 having 95% sequence identity to SEQ ID NO:73; a CDR-H2 having 95% sequence identity to SEQ ID NO:75; and a CDR-H3 having 95% sequence identity to SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR- H1 comprising SEQ ID NO:73; a CDR-H2 comprising SEQ ID NO:75; and a CDR-H3 comprising SEQ ID NO:77.

[0334] Aspects of the present disclosure include antigen-binding proteins (e.g., antibodies, antibody-like molecules, or fragments thereof) (e.g., a bone morphogenetic protein-7 (BMP- 7)-binding protein, or a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof) comprising a CDR-L1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value202424720.3 91derivable therein, to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a CDR-H1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0335] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having 85% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having 85% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a CDR-H1 having 85% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having 85% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having 85% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having 90% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having 90% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a CDR-H1 having 90% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having 90% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having 90% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having 95% sequence202424720.3 92identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having 95% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a CDR-H1 having 95% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having 95% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having 95% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0336] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:2; a CDR-L2 having 85% sequence identity to SEQ ID NO:4; and a CDR-L3 having 85% sequence identity to SEQ ID NO:6; and a CDR-H1 having 85% sequence identity to SEQ ID NO:8; a CDR-H2 having 85% sequence identity to SEQ ID NO:10; and a CDR-H3 having 85% sequence identity to SEQ ID NO:12. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:2; a CDR-L2 having 90% sequence identity to SEQ ID NO:4; and a CDR-L3 having 90% sequence identity to SEQ ID NO:6; and a CDR-H1 having 90% sequence identity to SEQ ID NO:8; a CDR-H2 having 90% sequence identity to SEQ ID NO:10; and a CDR-H3 having 90% sequence identity to SEQ ID NO:12. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:2; a CDR-L2 having 95% sequence identity to SEQ ID NO:4; and a CDR-L3 having 95% sequence identity to SEQ ID NO:6; and a CDR-H1 having 95% sequence identity to SEQ ID NO:8; a CDR-H2 having 95% sequence identity to SEQ ID NO:10; and a CDR-H3 having 95% sequence identity to SEQ ID NO:12. Some aspects are directed to antigen-binding proteins comprising a CDR- L1 comprising SEQ ID NO:2; a CDR-L2 comprising SEQ ID NO:4; and a CDR-L3 comprising SEQ ID NO:6; and a CDR-H1 comprising SEQ ID NO:8; a CDR-H2 comprising SEQ ID NO:10; and a CDR-H3 comprising SEQ ID NO:12.

[0337] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:20; a CDR-L2 having 85% sequence identity to SEQ ID NO:22; and a CDR-L3 having 85% sequence identity to SEQ ID NO:24; and a CDR-H1 having202424720.3 9385% sequence identity to SEQ ID NO:26; a CDR-H2 having 85% sequence identity to SEQ ID NO:28; and a CDR-H3 having 85% sequence identity to SEQ ID NO:30. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:20; a CDR-L2 having 90% sequence identity to SEQ ID NO:22; and a CDR-L3 having 90% sequence identity to SEQ ID NO:24; and a CDR-H1 having 90% sequence identity to SEQ ID NO:26; a CDR-H2 having 90% sequence identity to SEQ ID NO:28; and a CDR- H3 having 90% sequence identity to SEQ ID NO:30. Some aspects are directed to antigen- binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:20; a CDR-L2 having 95% sequence identity to SEQ ID NO:22; and a CDR-L3 having 95% sequence identity to SEQ ID NO:24; and a CDR-H1 having 95% sequence identity to SEQ ID NO:26; a CDR-H2 having 95% sequence identity to SEQ ID NO:28; and a CDR-H3 having 95% sequence identity to SEQ ID NO:30. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:20; a CDR-L2 comprising SEQ ID NO:22; and a CDR-L3 comprising SEQ ID NO:24; and a CDR-H1 comprising SEQ ID NO:26; a CDR-H2 comprising SEQ ID NO:28; and a CDR-H3 comprising SEQ ID NO:30.

[0338] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:20; a CDR-L2 having 85% sequence identity to SEQ ID NO:22; and a CDR-L3 having 85% sequence identity to SEQ ID NO:24; and a CDR-H1 having 85% sequence identity to SEQ ID NO:26; a CDR-H2 having 85% sequence identity to SEQ ID NO:28; and a CDR-H3 having 85% sequence identity to SEQ ID NO:32. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:20; a CDR-L2 having 90% sequence identity to SEQ ID NO:22; and a CDR-L3 having 90% sequence identity to SEQ ID NO:24; and a CDR-H1 having 90% sequence identity to SEQ ID NO:26; a CDR-H2 having 90% sequence identity to SEQ ID NO:28; and a CDR- H3 having 90% sequence identity to SEQ ID NO:32. Some aspects are directed to antigen- binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:20; a CDR-L2 having 95% sequence identity to SEQ ID NO:22; and a CDR-L3 having 95% sequence identity to SEQ ID NO:24; and a CDR-H1 having 95% sequence identity to SEQ ID NO:26; a CDR-H2 having 95% sequence identity to SEQ ID NO:28; and a CDR-H3 having 95% sequence identity to SEQ ID NO:32. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:20; a CDR-L2 comprising SEQ ID NO:22; and a CDR-L3 comprising SEQ ID NO:24; and a CDR-H1 comprising SEQ ID NO:26; a CDR-H2 comprising SEQ ID NO:28; and a CDR-H3 comprising SEQ ID NO:32.202424720.3 94

[0339] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:50; a CDR-L2 having 85% sequence identity to SEQ ID NO:53; and a CDR-L3 having 85% sequence identity to SEQ ID NO:57; and a CDR-H1 having 85% sequence identity to SEQ ID NO:59; a CDR-H2 having 85% sequence identity to SEQ ID NO:62; and a CDR-H3 having 85% sequence identity to SEQ ID NO:65. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:50; a CDR-L2 having 90% sequence identity to SEQ ID NO:53; and a CDR-L3 having 90% sequence identity to SEQ ID NO:57; and a CDR-H1 having 90% sequence identity to SEQ ID NO:59; a CDR-H2 having 90% sequence identity to SEQ ID NO:62; and a CDR- H3 having 90% sequence identity to SEQ ID NO:65. Some aspects are directed to antigen- binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:50; a CDR-L2 having 95% sequence identity to SEQ ID NO:53; and a CDR-L3 having 95% sequence identity to SEQ ID NO:57; and a CDR-H1 having 95% sequence identity to SEQ ID NO:59; a CDR-H2 having 95% sequence identity to SEQ ID NO:62; and a CDR-H3 having 95% sequence identity to SEQ ID NO:65. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:50; a CDR-L2 comprising SEQ ID NO:53; and a CDR-L3 comprising SEQ ID NO:57; and a CDR-H1 comprising SEQ ID NO:59; a CDR-H2 comprising SEQ ID NO:62; and a CDR-H3 comprising SEQ ID NO:65.

[0340] Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 85% sequence identity to SEQ ID NO:67; a CDR-L2 having 85% sequence identity to SEQ ID NO:69; and a CDR-L3 having 85% sequence identity to SEQ ID NO:71; and a CDR-H1 having 85% sequence identity to SEQ ID NO:73; a CDR-H2 having 85% sequence identity to SEQ ID NO:75; and a CDR-H3 having 85% sequence identity to SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 having 90% sequence identity to SEQ ID NO:67; a CDR-L2 having 90% sequence identity to SEQ ID NO:69; and a CDR-L3 having 90% sequence identity to SEQ ID NO:71; and a CDR-H1 having 90% sequence identity to SEQ ID NO:73; a CDR-H2 having 90% sequence identity to SEQ ID NO:75; and a CDR- H3 having 90% sequence identity to SEQ ID NO:77. Some aspects are directed to antigen- binding proteins comprising a CDR-L1 having 95% sequence identity to SEQ ID NO:67; a CDR-L2 having 95% sequence identity to SEQ ID NO:69; and a CDR-L3 having 95% sequence identity to SEQ ID NO:71; and a CDR-H1 having 95% sequence identity to SEQ ID NO:73; a CDR-H2 having 95% sequence identity to SEQ ID NO:75; and a CDR-H3 having 95% sequence identity to SEQ ID NO:77. Some aspects are directed to antigen-binding proteins comprising a CDR-L1 comprising SEQ ID NO:67; a CDR-L2 comprising SEQ ID202424720.3 95NO:69; and a CDR-L3 comprising SEQ ID NO:71; and a CDR-H1 comprising SEQ ID NO:73; a CDR-H2 comprising SEQ ID NO:75; and a CDR-H3 comprising SEQ ID NO:77.

[0341] In some aspects, the disclosure relates to a bone morphogenetic protein-7 (BMP-7)- binding protein comprising: a light chain variable region (VL) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a bone morphogenetic protein-7 (BMP-7)-binding protein comprising: a heavy chain variable region (VH) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0342] In some aspects, the disclosure relates to a bone morphogenetic protein-7 (BMP-7)- binding protein comprising: a light chain variable region (VL) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a heavy chain variable region (VH) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.202424720.3 96

[0343] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0344] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0345] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0346] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some202424720.3 97aspects, the disclosure relates to a BMP-7-binding protein comprising: a VHcomprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0347] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0348] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0349] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0350] In some aspects, the disclosure relates to a BMP-7-binding protein comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50,202424720.3 98SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0351] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VL comprises a CDR-L1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0352] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VLcomprises a CDR-L1 having at least 85% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 85% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 85% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0353] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VL comprises a CDR-L1 having at least 90% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 90% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 90% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0354] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VLcomprises a CDR-L1 having at least 95% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 95% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 95% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0355] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VL comprises a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID202424720.3 99NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0356] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VH comprises a CDR-H1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0357] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VH comprises a CDR-H1 having at least 85% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 85% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 85% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0358] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VHcomprises a CDR-H1 having at least 90% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 90% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 90% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0359] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VHcomprises a CDR-H1 having at least 95% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 95% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 95% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0360] In some aspects, the disclosure relates to a BMP-7-binding protein, wherein the VH comprises a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID202424720.3 100NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0361] Some aspects are directed to a monoclonal (e.g., humanized) antibody or antigen- binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. Some aspects are directed to a monoclonal (e.g., humanized) antibody or antigen- binding fragment thereof comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0362] Some aspects are directed to a monoclonal (e.g., humanized) antibody or antigen- binding fragment thereof comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0363] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID202424720.3 101NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0364] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0365] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0366] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID202424720.3 102NO:67, SEQ ID NO:69, or SEQ ID NO:71. In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VH comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0367] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0368] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VLcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 90% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0369] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VHcomprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 95% identity to SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.202424720.3 103

[0370] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof comprising: a VL comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and a VH comprising three CDRs, wherein one or more of the CDRs comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.

[0371] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VLcomprises a CDR-L1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0372] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VL comprises a CDR-L1 having at least 85% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 85% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 85% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0373] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VL comprises a CDR-L1 having at least 90% sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 90% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 90% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0374] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VLcomprises a CDR-L1 having at least 95%202424720.3 104sequence identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 having at least 95% sequence identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 having at least 95% sequence identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0375] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VL comprises a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71.

[0376] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VHcomprises a CDR-H1 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range derivable therein, to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%,88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, or any range or value derivable therein, to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0377] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VH comprises a CDR-H1 having at least 85% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 85% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 85% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0378] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VH comprises a CDR-H1 having at least 90% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 90% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 90% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.202424720.3 105

[0379] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VH comprises a CDR-H1 having at least 95% sequence identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 having at least 95% sequence identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 having at least 95% sequence identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0380] In some aspects, the disclosure relates to a monoclonal (e.g., humanized) antibody or antigen-binding fragment thereof, wherein the VH comprises a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0381] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity, or any range derivable therein, with SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity, or any range derivable therein, with SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity, or any range derivable therein, with SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VH comprising a CDR- H1 comprising an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity, or any range derivable therein, with SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity, or any range derivable therein, with SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising an amino acid sequence having at least, at most, exactly, or between (inclusive or exclusive) any two of 85%, 86%, 87%, 88%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity, or any range derivable therein, with SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.202424720.3 106

[0382] Some aspects are directed to an antibody comprising: a VLcomprising a CDR-L1 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VH comprising a CDR-H1 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0383] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VH comprising a CDR-H1 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0384] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VHcomprising a CDR-H1 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising an amino acid sequence having at least 95%202424720.3 107identity with SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0385] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67, a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69, and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:71; and a VH comprising a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73, a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75, and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:77.

[0386] Some aspects are directed to an antibody comprising: a VLcomprising a CDR-L1 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:2, a CDR- L2 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:4, and a CDR-L3 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:6; and a VH comprising a CDR-H1 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:8, a CDR-H2 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:10, and a CDR-H3 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:12. Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:2, a CDR-L2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:4, and a CDR-L3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:6; and a VH comprising a CDR-H1 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:8, a CDR-H2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:10, and a CDR-H3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:12. Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:2, a CDR-L2 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:4, and a CDR-L3 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:6; and a VH comprising a CDR-H1 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:8, a CDR-H2 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:10, and a CDR-H3 comprising an amino acid sequence having at least 95% identity with SEQ ID NO:12. Some aspects are directed to an antibody comprising: a VL comprising a CDR- L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising202424720.3 108SEQ ID NO:6; and a VHcomprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:12.

[0387] Some aspects are directed to an antibody comprising: a VL comprising a CDR-L1 comprising an amino acid sequence having at least 85% identity with SEQ ID NO:2, a CDR- L2 comprising an ...

Claims

CLAIMS What is claimed is:

1. A bone morphogenetic protein-7 (BMP-7)-binding protein comprising: a) a light chain variable region (VL) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity with SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and b) a heavy chain variable region (VH) comprising three complementarity determining regions (CDRs), wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identical identity with SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:

77.

2. The BMP-7 binding protein of claim 1, wherein one or more of the CDRs of the VL comprise an amino acid sequence having at least 90% identity with SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71, and one or more of the CDRs of the VH comprise an amino acid sequence having at least 90% identity with SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:

77.

3. The BMP-7 binding protein of claim 1 or claim 2, wherein one or more of the CDRs of the VL comprise an amino acid sequence having at least 95% identity with SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71, and one or more of the CDRs of the VHcomprise an amino acid sequence having at least 95% identity with SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.202424720.3 1854. The BMP-7 binding protein of any one of claims 1-3, wherein one or more of the CDRs of the VL comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71, and one or more of the CDRs of the VHcomprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:

77.

5. The BMP-7 binding protein of any one of claims 1-4, wherein the VL comprises a CDR- L1 having at least 85% identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having at least 85% identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having at least 85% identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:

71.

6. The BMP-7 binding protein of claim 5, wherein the CDR-L1 comprises SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; the CDR-L2 comprises SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and the CDR-L3 comprises SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, or SEQ ID NO:

71.

7. The BMP-7 binding protein of any one of claims 1-6, wherein the VHcomprises a CDR- H1 having at least 85% identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having at least 85% identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having at least 85% identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:

77.

8. The BMP-7 binding protein of claim 7, wherein the CDR-H1 comprises SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; the CDR-H2 comprises SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and the CDR-H3 comprises SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:

77.

9. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 85% identity with SEQ ID NO:14 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:16.202424720.3 18610. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:14 and the VH comprises an amino acid sequence with at least 90% identity with SEQ ID NO:

16.

11. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:14 and the VH comprises an amino acid sequence with at least 95% identity with SEQ ID NO:

16.

12. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises SEQ ID NO:14 and the VH comprises SEQ ID NO:

16.

13. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 85% identity with SEQ ID NO:34 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

40.

14. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 90% identity with SEQ ID NO:34 and the VH comprises an amino acid sequence with at least 90% identity with SEQ ID NO:

40.

15. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 95% identity with SEQ ID NO:34 and the VH comprises an amino acid sequence with at least 95% identity with SEQ ID NO:

40.

16. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises SEQ ID NO:34 and the VH comprises SEQ ID NO:

40.

17. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:36 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

42.

18. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 90% identity with SEQ ID NO:36 and the VHcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:

42.

19. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 95% identity with SEQ ID NO:36 and the VHcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:42.202424720.3 18720. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises SEQ ID NO:36 and the VH comprises SEQ ID NO:

42.

21. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 85% identity with SEQ ID NO:38 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

42.

22. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 90% identity with SEQ ID NO:38 and the VHcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:

42.

23. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises an amino acid sequence with at least 95% identity with SEQ ID NO:38 and the VHcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:

42.

24. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises SEQ ID NO:38 and the VH comprises SEQ ID NO:

42.

25. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:79 and the VH comprises an amino acid sequence with at least 85% identity with SEQ ID NO:

81.

26. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:79 and the VH comprises an amino acid sequence with at least 90% identity with SEQ ID NO:

81.

27. The BMP-7 binding protein of any one of claims 1-8, wherein the VLcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:79 and the VHcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:

81.

28. The BMP-7 binding protein of any one of claims 1-8, wherein the VL comprises SEQ ID NO:79 and the VHcomprises SEQ ID NO:

81.

29. The BMP-7 binding protein of any of claims 1-28, wherein the VH and the VL are on the same polypeptide.

30. The BMP-7 binding protein of any of claims 1-28, wherein the VHand the VLare on different polypeptides.202424720.3 18831. The BMP-7 binding protein of any one of claims 1-30, wherein the BMP-7 binding protein binds to human BMP-7.

32. The BMP-7 binding protein of any one of claims 1-31, wherein the BMP-7 binding protein is a human antibody, humanized antibody, recombinant antibody, chimeric antibody, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody.

33. The BMP-7 binding protein of claim 32, wherein the antibody is a monoclonal antibody.

34. The BMP-7 binding protein of claim 32, wherein the antibody is a chimeric antibody.

35. The BMP-7 binding protein of claim 32, wherein the antibody is a humanized antibody.

36. A composition comprising the BMP-7 binding protein of any of claims 1-35 and one or more additional therapeutics.

37. The composition of claim 36, wherein the one or more additional therapeutics comprise one or more immunotherapies.

38. The composition of claim 37, wherein the one or more immunotherapies comprise a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, a programmed death-ligand 1 (PDL-1) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, or a T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.

39. The composition of claim 38, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

40. The composition of claim 38, wherein the PD1 inhibitor is an anti-PD1 antibody.

41. The composition of claim 38, wherein the PDL-1 inhibitor is an anti-PDL-1 antibody.

42. The composition of claim 38, wherein the LAG3 inhibitor is an anti-LAG3 antibody.

43. The composition of claim 38, wherein the TIM-3 inhibitor is an anti-TIM-3 antibody.

44. The composition of claim 37, wherein the one or more immunotherapies comprise a CAR-T cell therapy.202424720.3 18945. The composition of claim 44, wherein the CAR-T cell therapy comprises EGFR- targeted CAR-T cells.

46. The composition of claim 44 or 45, wherein the CAR-T cell therapy comprises CAR-T cells that are genetically modified to have disrupted or reduced expression of one or more Bone Morphogenetic Protein (BMP) receptors.

47. The composition of claim 46, wherein the one or more BMP receptors comprise Bone Morphogenetic Protein Receptor Type 1A (BMPR1A), Bone Morphogenetic Protein Receptor Type 1B (BMPR1B), Activin A receptor type I (ACVR1), Activin receptor type 2A (ACVR2A), Activin receptor type 2B (ACVR2B), Bone morphogenetic protein receptor type 2 (BMPR2), or any combination thereof.

48. A pharmaceutical composition comprising (i) the BMP-7-binding protein of any of claims 1-35 or the composition of any of claims 36-47 and (ii) a pharmaceutically acceptable excipient.

49. The pharmaceutical composition of claim 48, further comprising an additional therapeutic.

50. The pharmaceutical composition of claim 49, wherein the additional therapeutic is a chemotherapeutic.

51. A nucleic acid comprising a nucleotide sequence encoding for the BMP-7-binding protein of any of claims 1-35 or a fragment thereof.

52. The nucleic acid of claim 51, wherein the nucleic acid encodes the heavy chain variable region and the light chain variable region of the BMP-7-binding protein.

53. The nucleic acid of claim 51, wherein the nucleic acid encodes the heavy chain variable region of the BMP-7-binding protein.

54. The nucleic acid of claim 51, wherein the nucleic acid encodes the light chain variable region of the BMP-7-binding protein.

55. An expression vector comprising the nucleic acid of any one of claims 51-54.202424720.3 19056. The expression vector of claim 55, wherein the nucleic acid is operably linked to an expression control sequence.

57. The expression vector of claim 55 or claim 56, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:

78.

58. The expression vector of claim 55 or claim 56, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:

78.

59. The expression vector of claim 55 or claim 56, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:

78.

60. The expression vector of claim 55 or claim 56, wherein the expression vector comprises SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, or SEQ ID NO:

78.

61. The expression vector of any of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:

80.

62. The expression vector of any of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:

80.

63. The expression vector of any of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:

80.

64. The expression vector of any of claims 55-60, wherein the expression vector comprises SEQ ID NO:15, SEQ ID NO:39, SEQ ID NO:41, or SEQ ID NO:

80.

65. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:13 and a nucleotide sequence with at least 85% identity to SEQ ID NO:15.202424720.3 19166. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:33 and a nucleotide sequence with at least 85% identity to SEQ ID NO:

39.

67. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:35 and a nucleotide sequence with at least 85% identity to SEQ ID NO:

41.

68. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:37 and a nucleotide sequence with at least 85% identity to SEQ ID NO:

41.

69. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 85% identity to SEQ ID NO:78 and a nucleotide sequence with at least 85% identity to SEQ ID NO:

80.

70. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:13 and a nucleotide sequence with at least 90% identity to SEQ ID NO:

15.

71. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:33 and a nucleotide sequence with at least 90% identity to SEQ ID NO:

39.

72. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:35 and a nucleotide sequence with at least 90% identity to SEQ ID NO:

41.

73. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:37 and a nucleotide sequence with at least 90% identity to SEQ ID NO:

41.

74. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 90% identity to SEQ ID NO:78 and a nucleotide sequence with at least 90% identity to SEQ ID NO:80.202424720.3 19275. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:13 and a nucleotide sequence with at least 95% identity to SEQ ID NO:

15.

76. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:33 and a nucleotide sequence with at least 95% identity to SEQ ID NO:

39.

77. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:35 and a nucleotide sequence with at least 95% identity to SEQ ID NO:

41.

78. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:37 and a nucleotide sequence with at least 95% identity to SEQ ID NO:

41.

79. The expression vector of any one of claims 55-60, wherein the expression vector comprises a nucleotide sequence with at least 95% identity to SEQ ID NO:78 and a nucleotide sequence with at least 95% identity to SEQ ID NO:

80.

80. The expression vector of any one of claims 55-60, wherein the expression vector comprises SEQ ID NO:13 and SEQ ID NO:

15.

81. The expression vector of any one of claims 55-60, wherein the expression vector comprises SEQ ID NO:33 and SEQ ID NO:

39.

82. The expression vector of any one of claims 55-60, wherein the expression vector comprises SEQ ID NO:35 and SEQ ID NO:

41.

83. The expression vector of any one of claims 55-60, wherein the expression vector comprises SEQ ID NO:37 and SEQ ID NO:

41.

84. The expression vector of any one of claims 55-60, wherein the expression vector comprises SEQ ID NO:78 and SEQ ID NO:

80.

85. A cell comprising (i) the BMP-7-binding protein of any of claims 1-35, (ii) the nucleic acid of any one of claim 51-54, or (iii) the expression vector of any one of claims 55-84.202424720.3 19386. The cell of claim 85, wherein the cell is an immune cell.

87. The cell of claim 85 or claim 86, wherein the cell comprises the BMP-7-binding protein and wherein the cell is capable of secreting the BMP-7-binding protein outside the cell.

88. The cell of claim 87, wherein the cell is a B cell.

89. The cell of claim 85 or claim 86, wherein the cell comprises the BMP-7-binding protein and wherein the BMP-7-binding protein is attached to a surface of the cell.

90. The cell of claim 89, wherein the BMP-7-binding protein is a chimeric antigen receptor.

91. The cell of claim 89, wherein the BMP-7-binding protein is a T cell receptor.

92. The cell of any of claims 89-91, wherein the cell is a T cell.

93. The cell of any one of claims 85-92, wherein the cell is genetically modified to have disrupted or reduced expression of one or more bone morphogenetic protein (BMP) receptors.

94. The cell of claim 93, wherein the one or more BMP receptors comprise Bone Morphogenetic Protein Receptor Type 1A (BMPR1A), Bone Morphogenetic Protein Receptor Type 1B (BMPR1B), Activin A receptor type I (ACVR1), Activin receptor type 2A (ACVR2A), Activin receptor type 2B (ACVR2B), Bone morphogenetic protein receptor type 2 (BMPR2), or any combination thereof.

95. A method for generating a BMP-7-binding protein, the method comprising culturing the cell of any one of claims 85-94 under conditions sufficient to express the BMP-7-binding protein in the cell.

96. A method for generating the BMP-7-binding protein of any of claims 1-35 comprising: (a) providing to a cell a nucleic acid encoding for the BMP-7-binding protein; and (b) subjecting the cell to conditions sufficient to express the nucleic acid in the cell.

97. A method of treating a subject for cancer comprising administering to the subject a therapeutically effective amount of the BMP-7-binding protein of any of claims 1-35, the composition of any of claims 36-47, the pharmaceutical composition of any of claims 48-50, the nucleic acid of any of claims 51-54, the expression vector of any of claims 55-84, or the cell of any of claims 85-94.202424720.3 19498. The method of claim 97, wherein the subject was previously treated with a cancer therapy.

99. The method of claim 97 or claim 98, wherein the cancer therapy comprises one or more immunotherapies.

100. The method of claim 99, wherein the one or more immunotherapies comprise a cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor, a programmed cell death protein 1 (PD1) inhibitor, a programmed death-ligand 1 (PDL-1) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, or a T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.

101. The method of any one of claims 98-100, wherein the subject was determined to be resistant to the cancer therapy.

102. The method of any one of claims 97-101, wherein the cancer is a solid tumor.

103. The method of claim any one of claims 97-101, wherein the cancer is lung cancer.

104. The method of claim 97, wherein cancer cells in the subject overexpress BMP-7 compared to non-cancerous cells.

105. The method of claim 104, wherein the cancer is pancreatic cancer, osteosarcoma, prostate cancer, colorectal cancer, malignant melanoma, breast cancer, ovarian cancer, esophageal cancer, gastric cancer, or renal cell cancer.

106. The method of claim 104 or 105, wherein the cancer is pancreatic cancer.

107. The method of any one of claims 97-106, further comprising administering to the subject an additional therapy.

108. The method of claim 107, wherein the additional therapy is radiotherapy, chemotherapy, or immunotherapy.

109. A monoclonal antibody or antigen-binding fragment thereof comprising: a) a VL comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identity with SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ202424720.3 195ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71; and b) a VH comprising three CDRs, wherein one or more of the CDRs comprise an amino acid sequence having at least 85% identical identity with SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:

77.

110. The monoclonal antibody or antigen-binding fragment of claim 109, wherein one or more of the CDRs of the VL comprise an amino acid sequence having at least 90% identity with SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71, and one or more of the CDRs of the VH comprise an amino acid sequence having at least 90% identity with SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:

77.

111. The monoclonal antibody or antigen-binding fragment of claim 109 or claim 110, wherein one or more of the CDRs of the VLcomprise an amino acid sequence having at least 95% identity with SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71, and one or more of the CDRs of the VHcomprise an amino acid sequence having at least 95% identity with SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:

77.

112. The monoclonal antibody or antigen-binding fragment of any one of claims 109-111, wherein one or more of the CDRs of the VL comprise SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:69, or SEQ ID NO:71, and one or more of the CDRs of the VH comprise SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:

12. SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:59, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:73, SEQ ID NO:75, or SEQ ID NO:77.202424720.3 196113. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-112, wherein the VL comprises a CDR-L1 having at least 85% identity to SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 having at least 85% identity to SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 having at least 85% identity to SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, SEQ ID NO:

71.

114. The monoclonal antibody or antigen-binding fragment thereof of claim 113, wherein the CDR-L1 comprises SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; the CDR-L2 comprises SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and the CDR-L3 comprises SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, SEQ ID NO:

71.

115. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-114, wherein the VHcomprises a CDR-H1 having at least 85% identity to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 having at least 85% identity to SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 having at least 85% identity to SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:

77.

116. The monoclonal antibody or antigen-binding fragment thereof of claim 115, wherein the CDR-H1 comprises SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; the CDR-H2 comprises SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and the CDR-H3 comprises SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:

77.

117. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises an amino acid sequence with at least 85% identity with SEQ ID NO:14 and the VH comprises an amino acid sequence with at least 85% identity with SEQ ID NO:

16.

118. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises an amino acid sequence with at least 90% identity with SEQ ID NO:14 and the VHcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:

16.

119. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 95% identity with202424720.3 197SEQ ID NO:14 and the VHcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:

16.

120. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises SEQ ID NO:14 and the VHcomprises SEQ ID NO:

16.

121. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises an amino acid sequence with at least 85% identity with SEQ ID NO:34 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

40.

122. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:34 and the VHcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:

40.

123. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:34 and the VH comprises an amino acid sequence with at least 95% identity with SEQ ID NO:

40.

124. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises SEQ ID NO:34 and the VH comprises SEQ ID NO:

40.

125. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:36 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

42.

126. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:36 and the VH comprises an amino acid sequence with at least 90% identity with SEQ ID NO:

42.

127. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises an amino acid sequence with at least 95% identity with202424720.3 198SEQ ID NO:36 and the VHcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:

42.

128. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises SEQ ID NO:36 and the VHcomprises SEQ ID NO:

42.

129. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises an amino acid sequence with at least 85% identity with SEQ ID NO:38 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

42.

130. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:38 and the VHcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:

42.

131. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:38 and the VH comprises an amino acid sequence with at least 95% identity with SEQ ID NO:

42.

132. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises SEQ ID NO:38 and the VH comprises SEQ ID NO:

42.

133. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:79 and the VHcomprises an amino acid sequence with at least 85% identity with SEQ ID NO:

81.

134. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises an amino acid sequence with at least 90% identity with SEQ ID NO:79 and the VH comprises an amino acid sequence with at least 90% identity with SEQ ID NO:

81.

135. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VL comprises an amino acid sequence with at least 95% identity with202424720.3 199SEQ ID NO:79 and the VHcomprises an amino acid sequence with at least 95% identity with SEQ ID NO:

81.

136. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-116, wherein the VLcomprises SEQ ID NO:79 and the VHcomprises SEQ ID NO:

81.

137. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 109-136, wherein the monoclonal antibody or antigen-binding fragment thereof binds to human BMP-7.

138. An antibody comprising: a) a VL comprising a CDR-L1 comprising SEQ ID NO:2, SEQ ID NO:20, SEQ ID NO:50, or SEQ ID NO:67; a CDR-L2 comprising SEQ ID NO:4, SEQ ID NO:22, SEQ ID NO:53, or SEQ ID NO:69; and a CDR-L3 comprising SEQ ID NO:6, SEQ ID NO:24, SEQ ID NO:57, SEQ ID NO:71; and b) a VH comprising a CDR-H1 comprising SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:59, or SEQ ID NO:73; a CDR-H2 comprising SEQ ID NO:10, SEQ ID NO:28, SEQ ID NO:62, or SEQ ID NO:75; and a CDR-H3 comprising SEQ ID NO:12, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:65, or SEQ ID NO:

77.

139. An antibody comprising: a) a VL comprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6; and b) a VHcomprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:

12.

140. An antibody comprising: a) a VL comprising a CDR-L1 comprising SEQ ID NO:2, a CDR-L2 comprising SEQ ID NO:4, and a CDR-L3 comprising SEQ ID NO:6; and b) a VH comprising a CDR-H1 comprising SEQ ID NO:8, a CDR-H2 comprising SEQ ID NO:10, and a CDR-H3 comprising SEQ ID NO:

32.

141. An antibody comprising: c) a VL comprising a CDR-L1 comprising SEQ ID NO:20, a CDR-L2 comprising SEQ ID NO:22, and a CDR-L3 comprising SEQ ID NO:24; and202424720.3 200d) a VH comprising a CDR-H1 comprising SEQ ID NO:26, a CDR-H2 comprising SEQ ID NO:28, and a CDR-H3 comprising SEQ ID NO:

30.

142. The antibody of any one of claims 138-141, wherein the VL comprises SEQ ID NO:

14.

143. The antibody of any one of claims 138-141, wherein the VH comprises SEQ ID NO:

16.

144. An antibody comprising: e) a VL comprising a CDR-L1 comprising SEQ ID NO:50, a CDR-L2 comprising SEQ ID NO:53, and a CDR-L3 comprising SEQ ID NO:57; and f) a VH comprising a CDR-H1 comprising SEQ ID NO:59, a CDR-H2 comprising SEQ ID NO:62, and a CDR-H3 comprising SEQ ID NO:

65.

145. The antibody of claim 144, wherein the VLcomprises SEQ ID NO:34, SEQ ID NO:36, or SEQ ID NO:

38.

146. The antibody of claim 144 or 145, wherein the VH comprises SEQ ID NO:40 or SEQ ID NO:

42.

147. The antibody of any one of claims 144-146, wherein the VLcomprises SEQ ID NO:34 and the VH comprises SEQ ID NO:

40.

148. The antibody of any one of claims 144-146, wherein the VL comprises SEQ ID NO:36 and the VHcomprises SEQ ID NO:

42.

149. The antibody of any one of claims 144-146, wherein the VL comprises SEQ ID NO:38 and the VH comprises SEQ ID NO:

42.

150. A method of increasing the efficacy of a cancer therapy administered to a subject for treatment of cancer, the method comprising administering to the subject a therapeutically effective amount of the cancer therapy and the BMP-7-binding protein of any of claims 1-35, the nucleic acid of any of claims 51-54, the expression vector of any of claims 55-84, or the cell of any of claims 85-94.

151. The method of claim 150, wherein the cancer therapy and the BMP-7-binding protein of any of claims 1-35, the nucleic acid of any of claims 51-54, the expression vector of any of claims 55-84, or the cell of any of claims 85-94 are comprised in the same composition.202424720.3 201152. The method of claim 150, wherein the cancer therapy and the BMP-7-binding protein of any of claims 1-35, the nucleic acid of any of claims 51-54, the expression vector of any of claims 55-84, or the cell of any of claims 85-94 are comprised in the different compositions.

153. The method of any one of claims 150-152, wherein the cancer therapy comprises an immunotherapy.

154. The method of claim 153, wherein the immunotherapy comprises a CAR-T cell therapy.

155. The method of claim 153 or 154, wherein the immunotherapy comprises EGFR- targeted CAR-T cells.

156. The method of claim 153 or 154, wherein the immunotherapy comprises CAR-T cells genetically modified to have disrupted or reduced expression of one or more Bone Morphogenetic Protein (BMP) receptors.

157. The method of any one of claims 150-156, wherein the cancer cells overexpress BMP- 7 compared to non-cancerous cells.

158. The method of any one of claims 150-157, wherein the cancer is pancreatic cancer, osteosarcoma, prostate cancer, colorectal cancer, malignant melanoma, breast cancer, ovarian cancer, esophageal cancer, gastric cancer, or renal cell cancer.

159. The method of any one of claims 150-158, wherein the cancer is pancreatic cancer.202424720.3 202

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