Human Anti-α5β1 antibodies and uses thereof

Abstract

The present invention provides, among other things, an integrin α5β1 antibodies and therapeutic uses of such antibodies in effectively treating diseases or disorders associated with integrin α5β1, such as pulmonary arterial hypertension (PAH). The human integrin α5β1 antibodies disclosed herein are characterized with a high affinity to α5β1 integrin, ability to specifically inhibit interaction with fibronectin, and / or binding to α5 β-propeller domain.

Description

HUMAN ANTI-a5pi ANTIBODIES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. provisional application No. 63 / 599,271, filed November 15, 2023, the content of which is hereby incorporated by reference in its entirety.INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING

[0002] The present specification refers to and includes a Sequence Listing filed herewith (submitted electronically as an XML file named MORF-019WOl_SL.xml on November 14, 2024). The .xml file was generated on October 28, 2024, and is 188,416 bytes in size. The entire content of the sequence listing is herein incorporated by reference in its entirety.BACKGROUND

[0003] Fibronectin (Fn) is an extracellular matrix protein that orchestrates complex cell adhesion and signaling through cell surface integrin receptors (Fibronectin-binding integrins (e.g., a5pi)) during tissue development, remodeling, and disease, such as hypertension and heart failure. Heart failure (HF) is a debilitating disease in which abnormal function of the heart leads to inadequately low perfusion of tissues and organs of the body. Hypertension is a responsible for various deleterious effects and with high morbidity and mortality including heart failure. One form of hypertension is pulmonary arterial hypertension (PAH). PAH is a rare but devastating disease, in which the normally low pulmonary arterial pressure becomes elevated due to vasoconstriction and remodeling of pulmonary vessels. Vasoconstriction and vascular remodeling increases workload on the right side of the heart, causing right heart hypertrophy, fibrosis and ultimately heart failure.

[0004] Current treatments include vasodilators targeting Ca2+ channels or endothelin receptors. There is a need for new approaches in the treatment of pulmonary hypertension, PAH, heart failure and related diseases.SUMMARY OF INVENTION

[0005] The present invention provides, among other things, integrin a5pi antibodies and therapeutic uses of such antibodies in effectively treating diseases or disorders associatedwith integrin a5pi, such as pulmonary arterial hypertension (PAH). As described herein, the present disclosure is, in part, based on identification of human integrin a5pi antibodies that are effective in preventing integrin signaling that promotes cell proliferation and resistance to apoptosis contributing to vascular remodeling of pulmonary arterioles and arteries (PAs). In particular, anti-a5pi antibodies of the present invention are characterized with (1) a high affinity to a5pi integrin, (2) ability to specifically inhibit interaction with fibronectin, and / or (3) binding to a5 P-propeller domain. As a result, anti-a5pi antibodies of the present disclosure are highly effective in reversing the PAs vascular remodeling prevalent in PAH.

[0006] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to integrin a5pi comprising a heavy chain complementarity-determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity-determining region 1 (LCDR1), LCDR2, and LCDR3 shown in Table A.

[0007] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to integrin a5pi comprising a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence of ARGRGYSSGWFDY (SEQ ID NO: 54); a LCDR1 comprising an amino acid sequence of QSVLHNSHNENY (SEQ ID NO: 83), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYYSTPWT (SEQ ID NO: 105).

[0008] In some embodiments, the antibody or antigen binding fragment thereof comprises a variable heavy chain (VH) comprising a sequence at least 85% identical to SEQ ID NO: 130. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a sequence at least 90% identical to SEQ ID NO: 130. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a sequence at least 95% identical to SEQ ID NO: 130. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a sequence at least 95% identical to SEQ ID NO: 130. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH identical to SEQ ID NO: 130.

[0009] In some embodiments, the antibody or antigen binding fragment thereof comprises a variable light chain (VL) comprising an amino acid sequence at least 85% identical to SEQ ID NO: 173. In some embodiments, the antibody or antigen bindingfragment thereof comprises a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 173. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO:173. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 99% identical to SEQ ID NO: 173. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence identical to SEQ ID NO: 173.

[0010] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to integrin a5pi comprising a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence of ARGRGYTSGWFDY (SEQ ID NO: 55), a LCDR1 comprising an amino acid sequence of QSVLHTSHNENY (SEQ ID NO: 84), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYFSTPWT (SEQ ID NO: 106).

[0011] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO: 131. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 131. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 131. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 99% identical to SEQ ID NO: 131. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence identical to SEQ ID NO: 131.

[0012] In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO:174. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 174. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 174. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 99% identical to SEQ ID NO: 174. In some embodiments, the antibody orantigen binding fragment thereof comprises a VL comprising an amino acid sequence identical to SEQ ID NO: 174.

[0013] In some embodiments, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 131, wherein the HCDR1 comprises an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), the HCDR2 comprises an amino acid sequence of INPNSGGT (SEQ ID NO: 31), and the HCDR3 comprises an amino acid sequence that is identical or differs by 1 amino acid from ARGRGYTSGWFDY (SEQ ID NO: 55). In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 174, wherein the LCDR1 comprises an amino acid sequence that is identical or differs by 1 amino acid from QSVLHTSHNENY (SEQ ID NO: 84), the LCDR2 comprises an amino acid sequence of WAS (SEQ ID NO: 97), and the LCDR3 comprises an amino acid sequence that is identical or differs by 1 amino acid from QQYFSTPWT (SEQ ID NO: 106).

[0014] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to integrin a5pi comprising a HCDR1 comprising an amino acid sequence of GFSFSYDS (SEQ ID NO: 8), a HCDR2 comprising an amino acid sequence of ISGSSSTI (SEQ ID NO: 39), a HCDR3 comprising an amino acid sequence of ARGAGTGVFDY (SEQ ID NO: 59), a LCDR1 comprising an amino acid sequence of QDISSF (SEQ ID NO: 87), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPWT (SEQ ID NO: 111).

[0015] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO: 140. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 140. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 140. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 99% identical to SEQ ID NO: 140. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence identical to SEQ ID NO: 140.

[0016] In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO: 183. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 183. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 183. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 99% identical to SEQ ID NO: 183. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence identical to SEQ ID NO: 183.

[0017] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to integrin a5pi comprising a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO: 40), a HCDR3 comprising an amino acid sequence of ARGFAL (SEQ ID NO: 61), a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of QQYISYPIT (SEQ ID NO: 114).

[0018] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO: 144. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 144. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 144. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 99% identical to SEQ ID NO: 144. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence identical to SEQ ID NO: 144.

[0019] In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO: 187. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 187. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprisingan amino acid sequence at least 95% identical to SEQ ID NO: 187. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 99% identical to SEQ ID NO: 187. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence identical to SEQ ID NO: 187.

[0020] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to integrin a5pi comprising a HCDR1 comprising an amino acid sequence of GFTFSNYG (SEQ ID NO: 25), a HCDR2 comprising an amino acid sequence of IWYDGSNK (SEQ ID NO: 48), a HCDR3 comprising an amino acid sequence of ARGEGPGILDY (SEQ ID NO: 76), a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPFT (SEQ ID NO: 119).

[0021] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO: 163. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 163. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 163. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence at least 99% identical to SEQ ID NO: 163. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising an amino acid sequence identical to SEQ ID NO: 163.

[0022] In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO: 206. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 206. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 206. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence at least 99% identical to SEQ ID NO: 206. In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising an amino acid sequence identical to SEQ ID NO: 206.

[0023] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that competes for binding to integrin a5pi with a reference antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 shown in Table A.

[0024] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to the same epitope on integrin a5pi recognized by a reference antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 shown in Table A.

[0025] In one aspect, the present invention provides, among other things, an antibody or antigen binding fragment thereof that binds to the overlapping epitope on integrin a5pi recognized by a reference antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 shown in Table A.

[0026] In some embodiments, the reference antibody comprises a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence of ARGRGYSSGWFDY (SEQ ID NO: 54), a LCDR1 comprising an amino acid sequence of QSVLHNSHNENY (SEQ ID NO: 83), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYYSTPWT (SEQ ID NO: 105).

[0027] In some embodiments, the reference antibody comprises a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence of ARGRGYTSGWFDY (SEQ ID NO: 55), a LCDR1 comprising an amino acid sequence of QSVLHTSHNENY (SEQ ID NO: 84), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYFSTPWT (SEQ ID NO: 106).

[0028] In some embodiments, the reference antibody comprises a HCDR1 comprising an amino acid sequence of GFSFSYDS (SEQ ID NO: 8), a HCDR2 comprising an amino acid sequence of ISGSSSTI (SEQ ID NO: 39), a HCDR3 comprising an amino acid sequence of ARGAGTGVFDY (SEQ ID NO: 59), a LCDR1 comprising an amino acid sequence of QDISSF (SEQ ID NO: 87), a LCDR2 comprising an amino acid sequence of AAS (SEQ IDNO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPWT (SEQ ID NO: 111).

[0029] In some embodiments, the reference antibody comprises a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO: 40), a HCDR3 comprising an amino acid sequence of ARGFAL (SEQ ID NO: 61), a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of QQYISYPIT (SEQ ID NO: 114).

[0030] In some embodiments, the reference antibody comprises a HCDR1 comprising an amino acid sequence of GFTFSNYG (SEQ ID NO: 25), a HCDR2 comprising an amino acid sequence of IWYDGSNK (SEQ ID NO: 48), a HCDR3 comprising an amino acid sequence of ARGEGPGILDY (SEQ ID NO: 76), a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPFT (SEQ ID NO: 119).

[0031] In some embodiments, the antibody or antigen binding fragment thereof comprises a means for inhibiting binding of fibronectin to integrin a5pi. In some embodiments, the antibody or antigen binding fragment thereof comprises a means for inhibiting binding for fibronectin to integrin a5pi and an Fc domain.

[0032] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from GFTGSNYG (SEQ ID NO: 25), a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from IWYDGSNK (SEQ ID NO: 48), and a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 5 amino acids ARGEGPGILDY (SEQ ID NO: 76). In some embodiments, the antibody or antigen binding fragment comprises a VL comprising a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 4 amino acids from LQHNSYPFT (SEQ ID NO: 119).

[0033] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence that is identical toor differs by no more than 4 amino acids from GFSFSYDS (SEQ ID NO: 8), a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 6 amino acids from ISGSSSTI (SEQ ID NO: 39), and a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 5 amino acids ARGAGTGVFDY (SEQ ID NO: 59). In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 3 amino acids from QDISSF (SEQ ID NO: 87), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from LQHNSYPWT (SEQ ID NO: 111).

[0034] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO: 40), and a HCDR3 comprising an amino acid sequence of ARGFQH (SEQ ID NO: 60). In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from SSNIGSNT (SEQ ID NO: 88), a LCDR2 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from SNN (SEQ ID NO: 98), and a LCDR3 comprising an amino acid sequence of AAWDDSLNGPGV (SEQ ID NO: 112).

[0035] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from INHSGST (SEQ ID NO: 40), and a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from ARGFAL (SEQ ID NO: 61). In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from QQYISYPIT (SEQ ID NO: 114).

[0036] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from GGTFSSNA (SEQ ID NO: 27), a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from IIPIFGTV (SEQ ID NO: 50), and a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 6 amino acids from ARGSGSGAFDI (SEQ ID NO: 78). In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from LQHNSYPWT (SEQ ID NO: 111).

[0037] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from INPHSGGT (SEQ ID NO: 29), and a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 3 amino acids from ARGGWKLGISLAFDI (SEQ ID NO: 52). In some embodiments, the antibody or antigen binding fragment comprises a VL comprising a LCDR1 comprising an amino acid sequence of QGISSY (SEQ ID NO: 79), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from QQLKSYLYT (SEQ ID NO: 104).

[0038] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), and a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from ARGRGYTSGWFDY (SEQ ID NO: 55). In some embodiments, the antibody or antigen binding fragment thereof comprises a VL comprising a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 4 amino acids from QSVLHTSHNENY (SEQ ID NO: 84), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from QQYFSTPWT (SEQ ID NO:

[0039] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 85% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 90% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 95% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 99% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences identical to sequences shown in Table B.

[0040] In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 85% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 90% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 95% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences at least 99% identical to sequences shown in Table B. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH and a VL comprising amino acid sequences identical to sequences shown in Table B.

[0041] In some embodiments, the antibody or antigen binding fragment thereof comprises a Fab, a single chain Fv (scFv), a single domain antibody (sdAb), a VHH, one or more CDRs, a VH, a VL, a Fab-like bispecific antibody (bsFab), a single-domain antibody- linked Fab (s-Fab), an antibody, or a combination thereof. In some embodiments, the antibody or antigen binding fragment thereof comprises a Fab. In some embodiments, the antibody or antigen binding fragment thereof comprises a single chain Fv (scFv). In some embodiments, the antibody or antigen binding fragment thereof comprises a single domain antibody (sdAb). In some embodiments, the antibody or antigen binding fragment thereof comprises a VHH. In some embodiments, the antibody or antigen binding fragment thereof comprises one or more CDRs. In some embodiments, the antibody or antigen binding fragment thereof comprises a VH. In some embodiments, the antibody or antigen bindingfragment thereof comprises a VL. In some embodiments, the antibody or antigen binding fragment thereof comprises a Fab-like bispecific antibody (bsFab). In some embodiments, the antibody or antigen binding fragment thereof comprises a single-domain antibody-linked Fab (s-Fab). In some embodiments, the antibody or antigen binding fragment thereof comprises an antibody.

[0042] In some embodiments, the antibody or antigen binding fragment thereof further comprises an Fc domain. In some embodiments, the Fc domain is derived from IgGl. In some embodiments, the Fc domain is derived from IgG2a. In some embodiments, the Fc domain is derived from IgG2b. In some embodiments, the Fc domain is derived from IgG3. In some embodiments, the Fc domain is derived from IgG4.

[0043] In some embodiments, the present invention comprises a nucleic acid encoding the antibody or antigen binding fragment thereof. In some embodiments, the present invention provides a vector comprising the nucleic acid. In some embodiments, the vector comprises a nucleic acid encoding the antibody or antigen binding fragment thereof. In some embodiments, the present invention comprises a host cell comprising the vector. In some embodiments, the host cell comprises the nucleic acid.

[0044] In some embodiments, the present invention comprises a method of making an antibody or antigen binding fragment thereof. In some embodiments, the method comprises culturing a host cell comprising a nucleic acid encoding the antibody or antigen binding fragment thereof under conditions that allow production of the antibody or antigen binding fragment thereof.

[0045] In some embodiments, the present invention provides a composition comprising the antibody or antigen binding fragment thereof, the nucleic acid, the vector, or the host cell. In some embodiments, the composition comprises the antibody or antigen binding fragment thereof. In some embodiments, the composition comprises the nucleic acid. In some embodiments, the composition comprises the vector. In some embodiments, the composition comprises the host cell.

[0046] In some embodiments, the present invention provides a pharmaceutical composition comprising the antibody or antigen binding fragment thereof, the nucleic acid, the vector, or the host cell, and a carrier. In some embodiments, the pharmaceutical composition comprises the antibody or antigen binding fragment thereof and a carrier. In some embodiments, the pharmaceutical composition comprises the nucleic acid and a carrier.In some embodiments, the pharmaceutical composition comprises the vector and a carrier. In some embodiments, the pharmaceutical composition comprises the host cell and a carrier.

[0047] In one aspect, the present invention provides, among other things, a method of treating pulmonary arterial hypertension (PAH) in a subject, comprising administering a pharmaceutical composition comprising an antibody means for inhibiting binding of fibronectin to a5pi integrin, and one or more physiologically acceptable carriers, excipients, or diluents.

[0048] In one aspect, the present invention provides, among other things, a method of treating pulmonary arterial hypertension (PAH) in a subject, comprising administering an antibody or antigen binding fragment thereof that binds to a5pi.

[0049] In one aspect, the present invention provides, among other things, a method of treating a heart or lung disease in a subject comprising administering a pharmaceutical composition comprises an antibody means for inhibiting binding of fibronectin to a5pi integrin, and one or more physiologically acceptable carriers, excipients, or diluents.

[0050] In some embodiments, the heart or lung disease comprises pulmonary hypertension WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, WHO Group 5 pulmonary hypertension, WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, or WHO Class IV pulmonary hypertension. In some embodiments, the disease comprises WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH). In some embodiments, the disease comprises WHO Group 2 pulmonary hypertension. In some embodiments, the disease comprises WHO Group 3 pulmonary hypertension. In some embodiments, the disease comprises WHO Group 4 pulmonary hypertension. In some embodiments, the disease comprises WHO Group 5 pulmonary hypertension. In some embodiments, the disease comprises WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH). In some embodiments, the disease comprises WHO Class II pulmonary hypertension. In some embodiments, the disease comprises WHO Class III pulmonary hypertension. In some embodiments, the disease comprises WHO Class IV pulmonary hypertension.

[0051] In some embodiments, the disease comprises cardiac fibrosis, heart failure, or right ventricle failure. In some embodiments, the disease comprises cardiac fibrosis. In someembodiments, the disease comprises heart failure. In some embodiments, the disease comprises right ventricle failure.BRIEF DESCRIPTION OF DRAWINGS

[0052] Drawings are for illustration purposes only, not for limitation.

[0053] FIG. 1 is a series of exemplary graphs showing % inhibition of cell adhesion assay in serum-condition and human serum (HS) condition.

[0054] FIG. 2 is an exemplary graph showing percent proliferation of PASMCs treated with exemplary integrin a5pi antibodies.

[0055] FIG. 3 is an exemplary graph showing results of competition ELISA assay.DEFINITIONS

[0056] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification.

[0057] “Active agent” and “therapeutic agent” means a molecule (e.g., a small molecule compound, peptides, an antibody or antibody fragment, etc.) that exerts a preventive or therapeutic effect on a disease or disease condition. Active agent may refer not only to a single active agent but also to a combination of two or more different active agents.

[0058] “Alleviate” and “ameliorate” means a process by which the severity of a sign or symptom of a disorder is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. Therapeutically effective dosages are expected to decrease the severity of, and so alleviate and ameliorate, a sign or symptom of disease.

[0059] As used herein, the term “affinity” refers to the characteristics of a binding interaction between a binding moiety (e.g., integrin a5pi antibody) and a target (e.g., a5pi) and that indicates the strength of the binding interaction. In some embodiments, the measure of affinity is expressed as a dissociation constant (KD).

[0060] As used herein, the term “antibody” refers to a polypeptide that includes at least one immunoglobulin variable region, e.g., an amino acid sequence that provides an immunoglobulin variable domain or immunoglobulin variable domain sequence. For example, an antibody can include a heavy (H) chain variable region (abbreviated herein as VH), and a light (L) chain variable region (abbreviated herein as VL). In another example,an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. An antibody typically includes three complementarity determining regions (abbr. CDRs) in the light chain of the immunoglobulin and three complementarity determining regions (CDRs) in the heavy chain of the immunoglobulin. The three CDRs in the light chain of the immunoglobulin are called, from the N-terminal side, CDR1, CDR2 and CDR3, respectively. The three CDRs in the heavy chain of the immunoglobulin are also called, from the N-terminal side, CDR1, CDR2 and CDR3, respectively. A “CDR” may be identified in accordance with the definitions of the Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, and / or conformational definitions or any method of CDR determination well known in the art. The term “antibody” encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab, F(ab')2, Fd, Fv, and dAb fragments) as well as complete antibodies, e.g., intact immunoglobulins of types IgA, IgG, IgE, IgD, IgM (as well as subtypes thereof). The light chains of the immunoglobulin can be of types kappa or lambda.

[0061] “Dosage form” means any form of a pharmaceutical composition for administration to a subject (typically a human or animal of veterinary interest suffering from a disease or condition to be treated). “Dose” refers to an amount of active agent. “Unit dosage form” refers to a dosage form that contains a fixed amount of active agent. A single tablet or capsule is a unit dosage form. Multiple unit dosage forms can be administered to provide a therapeutically effective dose. A dosage form can include a combination of dosage forms.

[0062] As used herein, the term “EC 50” refers to a half maximal effective concentration. The term EC50 refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after a specified exposure time. More simply, EC50 can be defined as the concentration required to obtain a 50% of the desired effect.

[0063] As used herein, the term “Fab” refers to an antibody fragment comprising a portion of an intact antibody, comprising the antigen-binding or variable region thereof.

[0064] As used herein, the term “Fc region” refers to a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not bepresent. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0065] As used herein, the term “IC50” refers to the concentration needed to inhibit half of the maximum biological response of the ligand binding, and can be determined by cell-adhesion assay (CAA) or ligand binding assay (LBA).

[0066] As used herein, the term “identity” refers a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules as known in the art, comparing the sequences of these molecules. The relationship determined by doing. In the art, “identity” also means the degree of sequence relatedness between nucleic acid molecules or polypeptides, and in some cases more than one nucleotide sequence or more than one. It may be determined by a match between amino acid sequence strings. “Identity” means between a gap alignment (if any) addressed by a particular mathematical model or computer program (i.e., an “algorithm”) and a smaller sequence of two or more sequences. Measure the percent identity match.

[0067] As used herein, the term “zzz vitro" refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0068] As used herein, the term “zzz vzvo” refers to events that occur within a multicellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).

[0069] “Integrin inhibitor” or “Integrin a5Bl inhibitor” or “VLA5 inhibitor” refers to a molecule that can bind to integrin alpha 5 (ITGA5) or integrin a5Bl heterodimer and has a5Bl integrin and / or ITGA5 inhibitory activity. In some embodiments, inhibiting activity comprises inhibition of binding of a5Bl integrin and / or ITGA5 to smooth muscle cells, fibroblasts, stellate cells, myofibroblasts, pericytes and / or other cells of mesenchymal origin. In some embodiments, inhibiting activity comprises inhibition of migration of smooth muscle cells, fibroblasts, stellate cells, myofibroblasts, pericytes and / or other cells of mesenchymal origin. In some embodiments, inhibiting activity comprises inhibition of differentiation of smooth muscle cells, fibroblasts, stellate cells, myofibroblasts, pericytes and / or other cells ofmesenchymal origin. In some embodiments, inhibiting activity comprises inhibition of extracellular matrix synthesis and / or deposition.

[0070] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0071] As used herein, “Pulmonary arterial hypertension (PAH)” refers to a rare disease, in which the normally low pulmonary artery pressure becomes elevated due to vasoconstriction and to the remodeling of pulmonary vessels. This in turn increases workload on the right side of the heart, causing right heart hypertrophy, fibrosis and ultimately heart failure.

[0072] As used herein a “peptide” refers to a peptide or polypeptide that comprise multiple amino acids. The terms “peptide” and “polypeptide” are used interchangeably. The amino acid sequence or variant thereof can be part of a larger peptide, i.e., of a peptide that has been N terminally and / or C-terminally extended by a one or more additional amino acids. The amino acid sequence or variant thereof of a peptide of the invention may also be N- terminally and / or C-terminally modified, preferably by comprising an N- and / or C-terminal elongating group. Alternatively, said amino acid sequence or a variant thereof is N- and / or C- terminally extended.

[0073] “Pharmaceutically acceptable” means not biologically undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0074] “Preventing” and “prevent” means avoiding the onset of a clinically evident disease progression altogether or slowing the onset of a pre-clinically evident stage of adisease in individuals at risk. Prevention includes prophylactic treatment of those at risk of developing a disease.

[0075] As used herein, the term “scFv” refers to a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of ten to about 25 amino acids.

[0076] As used herein, “selective binding”, “selectively binds” “specific binding”, or “specifically binds” refers, with respect to a binding moiety and a target, preferential association of a binding moiety to a target and not to an entity that is not the target. A certain degree of non-specific binding may occur between a binding moiety and a non-target. In some embodiments, a binding moiety selectively binds a target if binding between the binding moiety and the target is greater than 2-fold, greater than 5-fold, greater than 10-fold, or greater than 100-fold as compared with binding of the binding moiety and a non-target. In some embodiments, a binding moiety selectively binds a target if the binding affinity is less than about 10'5M, less than about 10'6M, less than about 10'7M, less than about 10'8M, or less than about 10'9M.

[0077] “Sign” means an indication of disease and includes conditions that can be observed by a doctor, nurse, or other health care professional.

[0078] As used herein, the term “similarity” is used in the art with respect to related concepts, but in contrast to “identity,” “similarity”, refers to both identity and conservative substitution matches. If two polypeptide sequences have, for example, 10 identical amino acids out of 20 amino acids and the rest are all non-conservative substitutions, the percent identity and percent similarity are both 50%. In the same example, if there are 5 more conservative substitutions, the percent identity remains 50%, but the percent similarity is 75%. Thus, if there are conservative substitutions, the percent similarity between the two polypeptides is higher than the percent identity between these two polypeptides.

[0079] As used herein, the term “subject”, means any subject for whom diagnosis, prognosis, or therapy is desired. For example, a subject can be a mammal, e.g., a human or non-human primate (such as an ape, monkey, orangutan, or chimpanzee), a dog, cat, guinea pig, rabbit, rat, mouse, horse, cattle, or cow.

[0080] “Subject in need thereof’ refers to a human or other mammal suitable for treatment with an active agent. A subject in need thereof may have a disease or be at an increased risk, relative to the general population, of developing a disease.

[0081] “Symptom” means a sign or other indication of disease, illness, or injury. Symptoms may be felt or noticed by the individual experiencing them or by others, including by non-health-care professionals.

[0082] As used herein, the term “therapeutically effective amount” refers to an amount of a therapeutic molecule (e.g., an integrin a5pi antibody described herein) which confers a therapeutic effect on a treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic molecule or composition effective to treat, ameliorate, or prevent a particular disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and / or also lessening the severity or frequency of symptoms of the disease. A therapeutically effective amount can be administered in a dosing regimen that may comprise multiple unit doses. For any particular therapeutic molecule, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific pharmaceutical agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the specific therapeutic molecule employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0083] As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and / or reduce incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and / or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.

[0084] “Pulmonary hypertension (PH)” includes diseases which share the defining element of a mean pulmonary arterial pressure ^25 mm Hg. PH has been classified and divided into 5 groups and 5 classes characterized by the World Health Organization (WHO).In some embodiments, pulmonary hypertension is WHO Functional Class I pulmonary hypertension, WHO Functional Class II pulmonary hypertension, WHO Functional Class III pulmonary hypertension, WHO Functional Class IV pulmonary hypertension or pulmonary arterial hypertension (PAH). In some embodiments, the disease is pulmonary hypertension, WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, and WHO Group 5 pulmonary hypertension.

[0085] The term "vector" refers to a polynucleotide (usually DNA) used to artificially carry foreign genetic material to another cell where it can be replicated or expressed. Nonlimiting exemplary vectors include plasmids, viral vectors, cosmids, and artificial chromosomes. Such vectors may be derived from a variety of sources, including bacterial and viral sources. A non-limiting exemplary viral source for a plasmid is adeno-associated virus.

[0086] Various aspects of the disclosure are described in detail in the following sections. The use of sections is not meant to limit the disclosure. Each section can apply to any aspect of the disclosure. In this application, the use of “or” means “and / or” unless stated otherwise. As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.DETAILED DESCRIPTION

[0087] The present invention provides, in part, integrin a5pi antibodies and therapeutic uses of such antibodies in effectively treating diseases or disorders associated with the increased expression or activity of integrin a5pi. In some embodiments, the present invention comprises integrin a5pi antibodies that act as integrin a5pi inhibitors, blocking the interaction with fibronectin. In some embodiments, the integrin a5pi antibodies of the present invention are administered as part of a method of treating a heart or lung disease in a subject.Integrin a5pi

[0088] Many normal physiological and disease processes require cells to contact other cells and / or extracellular matrix. Cell-matrix and cell-cell adhesion is mediated through several families of proteins including integrins, selectins, cadherins, and immunoglobulins, and facilitates a variety of normal cellular functions such as proliferation, migration, differentiation, or survival. Cell adhesion is also key to a range of pathologies, and so pharmacological disruption of cell adhesion interactions can provide a mechanism fortherapeutic intervention. Members of the integrin superfamily adhesion molecules play an important role in acute and chronic disease states such as cancer, inflammatory diseases, stroke, and neurodegenerative disorders. Thus, integrins represent a complex biological area.

[0089] The integrin superfamily of cell surface receptors is formed from a number of structurally and functionally related surface glycoproteins, with each receptor existing as a heterodimer of non-covalently linked a and P subunits. At least 18 different a and 8 p subunits have been identified in mammals, which are known to form 24 different heterodimeric receptors. Each integrin interacts selectively with defined extracellular ligands, including extracellular matrix proteins such as, fibronectin, vitronectin, collagen and cell surface adhesion molecules such as VCAM, ICAM and MAdCAM.

[0090] The integrin a5pi (a5pi or alpha5 betal) is composed of an a5 (ITGA5, a5, or alpha5) and pi (bl or betal) subunit. The a5 subunit forms a specific dimer with the betal subunit and is widely expressed. Although several integrins bind to fibronectin, integrin a5pi almost exclusively mediates cell adhesion through an interaction with fibronectin, binding via a short arginine-glycine-aspartate (RGD) adhesion motif in the 10thtype III repeat of fibronectin (FN10) as well as via the “synergistic site” (PHSRN) in the 9thtype III repeat (FN9). Endothelial cells and platelets can bind to fibrin via a5pi. The a5pi interaction with fibronectin plays important roles in physiopathological angiogenesis and vascular integrity. Although endothelial cells express a variety of integrins, a5pi is important for survival of endothelial cells on provisional matrix in vitro, suppressing apoptosis and promoting proliferation.

[0091] Expression of a5Bl integrin is mainly in the vasculature and connective tissue. It is further expressed to varying degrees in many cell types including fibroblasts, hematopoietic cell, immune cells, smooth muscle cells, and epithelial cells. However, overexpression or upregulation of integrin a5pi is associated with several diseases. Expression is significantly enhanced in tumor blood vessels and also in the tumor cells of many types of cancer, including colon, breast, ovarian, lung and brain tumors. High expression of a5Bl integrin has been observed in fibrotic tissue associated with, for example, pulmonary fibrosis. Additionally, integrin a5pi expression is upregulated in pulmonary hypertension patients.

[0092] In tissues, normal fibroblasts are present in low population of only 4-5%. However, during fibrosis they proliferate and can occupy up to 80-90% of the organ mass.Myofibroblasts in the fibrotic tissue produce large amounts of extracellular matrix proteins that make the tissue scarred and non-functional. Inhibition of myofibroblasts can counteract these processes. Integrins promote cell proliferation, survival, hypertrophic growth, and fibrosis. As described herein, integrin a5pi antibodies can modulate these key elements that can lead to the progression of pulmonary hypertension (e.g., PAH).Integrin a.50 l Domains and Conformations

[0093] Integrin a5pi is composed of several domains. For example, integrin a5 comprises the calf-2 domain, the calf-1 domain, the thigh domain, and the B-propeller. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to any one of the domains of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the B-propeller domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the thigh domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the calf-1 domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the calf-2 domain of integrin a5.

[0094] Integrin a5pi also has several conformations controlled by its binding to fibronectin. When bound to fibronectin, integrin a5pi exhibits an “open” conformation. When not bound, or when blocked, integrin a5pi maintains a “closed” or “bent” conformation. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the closed conformation of integrin a5pi . In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof maintains the closed conformation of the integrin a5pi antibody. In some embodiments, the integrin a5pi antibody in blocks the interaction between integrin a5pi and fibronectin. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof blocks the binding of fibronectin to integrin a5pi. In some embodiments, the integrin a5pi antibody or antigen binding fragment is an integrin a5pi inhibitor.Integrin a5pi Antibody

[0095] The present invention provides, among other things, an antibody or antigen binding fragment thereof that binds a5pi with high affinity and inhibits fibronectin from binding to a5pi. Furthermore, anti-a5pi antibodies of the present invention, among other things, bind to the a5 P-propeller domain and compete with fibronectin.

[0096] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to any one of the domains of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the P-propeller domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the thigh domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the calf-1 domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the calf-2 domain of integrin a5. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof binds to the interface between a5 and pi subunits.

[0097] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a Fab, a single chain Fv (scFv), a single domain antibody (VHH), one or more CDRs, a variable heavy chain (VH), a variable light chain (VL), a Fab-like bispecific antibody (bsFab), a single-domain antibody-linked Fab (s-Fab), an antibody, or a combination thereof.

[0098] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a Fab. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a single chain Fv (scFv). In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a single domain antibody (VHH). In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises one or more CDRs. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a variable heavy chain (VH). In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a variable light chain (VL). In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a Fab-like bispecific antibody (bsFab). In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a single-domain antibody-linked Fab (s-Fab). In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises an antibody.

[0099] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises an Fc domain. In some embodiments, the Fc domain is derived from IgGl, IgG2a, IgG2b, IgG3, or IgG4. In some embodiments, the Fc domain is derived from IgGl. In some embodiments, the Fc domain is derived from IgG2a. In some embodiments, the Fc domain is derived from IgG2b. In some embodiments, the Fc domain is derived from IgG3. In some embodiments, the Fc domain is derived from IgG4.

[0100] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof has been modified, or engineered, to enhance the stability of the antibody or antigen binding fragment thereof.Exemplary Integrin a5Bl Antibodies

[0101] In some embodiments, the integrin a5pi antibody or antigen binding fragment comprises at least one, two, or three complementary determining regions (CDRs) from a heavy chain variable region having an amino acid sequence as set forth in Table A, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In some embodiments, integrin a5pi antibody or antigen binding fragment thereof comprises at least one, two, or three CDRs from a light chain variable region having an amino acid sequence as set forth in Table A , or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In an embodiment, the integrin a5pi antibody or antigen binding fragment thereof comprises at least one, two, three, four, five, or six CDRs from heavy and light chain variable regions having an amino acid sequence as set forth in Table A , or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions).Table A. CDRs of Exemplary Integrin a5pi Antibodies.

[0102] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain CDR1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 31, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 54, a light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 83, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 97, and a LCDR3 comprising SEQ ID NO: 105.

[0103] In some embodiments, the integrin a5pi antibody or antigen binding fragment comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 31, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 55, a LCDR1 comprising an amino acid sequence of SEQ ID NO:84, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 97, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 106.

[0104] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 8, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 39, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 59, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 87, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0105] In some embodiments, the integrin a5pi antibody or antigen binding fragment comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 40, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 61, a LCDR1 comprising an amino acid sequence of SEQ ID NO:85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 114.

[0106] In some embodiments, the integrin a5pi antibody or antigen binding fragment comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 25, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 48, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 76, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 119.

[0107] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2comprising an amino acid sequence of SEQ ID NO: 28, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 51 a LCDR1 comprising an amino acid sequence of SEQ ID NO: 79, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 103.

[0108] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 29, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 52, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 79, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 103.

[0109] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 30, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 53, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 79, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 103.

[0110] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 29, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 52, a LCDR1 comprising an amino acid sequence of SEQ ID NO:79, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 104.[OHl] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 31, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 54, a LCDR1 comprising an amino acid sequence of SEQ ID NO:80, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 97, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 105.

[0112] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 31, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 54, a LCDR1 comprising an amino acid sequence of SEQ ID NO:81, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 97, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 105.

[0113] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 31, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 54, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 82, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 97, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 105.

[0114] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 2, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 32, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 56, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 107.

[0115] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 3, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 33, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 56, a LCDR1 comprising an amino acid sequence of SEQ ID NO:85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 108.

[0116] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 34, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 56, a LCDR1 comprising an amino acid sequence of SEQ ID NO:86, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 109.

[0117] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 35, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 57, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 108.

[0118] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 6, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 36, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 56, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 87, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 110.

[0119] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 37, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 58, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0120] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 38, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 58, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0121] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 37, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 59, a LCDR1 comprising an amino acid sequence of SEQ ID NO:87, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0122] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 40, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 60, a LCDR1 comprising an amino acid sequence of SEQ ID NO:88, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 98, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 112.

[0123] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, a HCDR2comprising an amino acid sequence of SEQ ID NO: 40, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 60, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 90, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 99, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 112.

[0124] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 40, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 61, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 113.

[0125] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 10, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 40, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 61, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 114.

[0126] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 11, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 41, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 61, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 114.

[0127] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 12, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 37, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 62, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 91, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0128] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 13, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 37, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 63, a LCDR1 comprising an amino acid sequence ofSEQ ID NO: 92, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 100, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 115.

[0129] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 40, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 60, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 93, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 116.

[0130] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 14, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 42, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 64, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0131] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 15, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 43, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 65, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 117.

[0132] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 5, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 32, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 66, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 87, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 118.

[0133] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 16, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 32, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 67, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 108.

[0134] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 17, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 44, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 68, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 119.

[0135] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 18, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 45, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 69, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 119.

[0136] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 19, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 46, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 70, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 119.

[0137] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 20, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 43, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 71, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 94, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 101, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 120.

[0138] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 21, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 29, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 72, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 79, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 121.

[0139] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 22, aHCDR2 comprising an amino acid sequence of SEQ ID NO: 32, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 73, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0140] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 23, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 34, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 74, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 119.

[0141] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 47, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 75, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 119.

[0142] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 26, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 49, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 77, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 95, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 102, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 122.

[0143] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence of SEQ ID NO: 27, a HCDR2 comprising an amino acid sequence of SEQ ID NO: 50, a HCDR3 comprising an amino acid sequence of SEQ ID NO: 78, a LCDR1 comprising an amino acid sequence of SEQ ID NO: 85, a LCDR2 comprising an amino acid sequence of SEQ ID NO: 96, and a LCDR3 comprising an amino acid sequence of SEQ ID NO: 111.

[0144] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises CDRs with one or more amino acid different from CDRs shown in Table A.

[0145] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence with no greater than 2 amino acids different from GFTGSNYG (SEQ ID NO: 25), a HCDR2 comprising an amino acid sequence with no greater than 1 amino acid different from IWYDGSNK (SEQ ID NO: 48), a HCDR3 comprising an amino acid sequence with no greater than 5 amino acids different from ARGEGPGILDY (SEQ ID NO: 76), a LCDR1 comprising QGISNY (SEQ ID NO: 85), a LCDR2 comprising AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence with no greater than 4 amino acids different from LQHNSYPFT (SEQ ID NO: 119).

[0146] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence with no greater than 4 amino acids different from GFSFSYDS (SEQ ID NO: 8), a HCDR2 comprising an amino acid sequence with no greater than 6 amino acids different from ISGSSSTI (SEQ ID NO: 39), a HCDR3 comprising an amino acid sequence with no greater than 5 amino acids different from ARGAGTGVFDY (SEQ ID NO: 59), a LCDR1 comprising an amino acid sequence with no greater than 3 amino acids different from QDISSF (SEQ ID NO: 87), a LCDR2 comprising AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence with no greater than 2 amino acids different from LQHNSYPWT (SEQ ID NO: 111).

[0147] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDRl comprising GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising INHSGST (SEQ ID NO: 40), a HCDR3 comprising ARGFQH (SEQ ID NO: 60), a LCDR1 comprising an amino acid sequence with no greater than 1 amino acid different from SSNIGSNT (SEQ ID NO: 88), a LCDR2 comprising an amino acid sequence with no greater than 1 amino acid different from SNN (SEQ ID NO: 98), a LCDR3 comprising AAWDDSLNGPGV (SEQ ID NO: 112).

[0148] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence with no greater than 1 amino acid different from GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence with no greater than 1 amino acid different from INHSGST (SEQ ID NO: 40), a HCDR3 comprising an amino acid sequence with no greater than 2 amino acids different from ARGFAL (SEQ ID NO: 61), a LCDR1 comprising an amino acid sequence with no greater than 1 amino acid different from QGISNY (SEQ ID NO: 85), a LCDR2 comprisingAAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence with no greater than 1 amino acid different from QQYISYPIT (SEQ ID NO: 114).

[0149] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence with no greater than 1 amino acid different from GGTFSSNA (SEQ ID NO: 27), a HCDR2 comprising an amino acid sequence with no greater than 2 amino acids different from IIPIFGTV (SEQ ID NO: 50), a HCDR3 comprising an amino acid sequence with no greater than 6 amino acids different from ARGSGSGAFDI ( SEQ ID NO: 78), a LCDR1 comprising QGISNY (SEQ ID NO: 85), a LCDR2 comprising AAS (SEQ ID NO: 96), a LCDR3 comprising an amino acid sequence with no greater than 1 amino acid different from LQHNSYPWT (SEQ ID NO: 111).

[0150] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising an amino acid sequence with no greater than 1 amino acid different from GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence with no greater than 2 amino acids different from INPHSGGT (SEQ ID NO: 29), a HCDR3 comprising an amino acid sequence with no greater than 3 amino acids different from ARGGWKLGISLAFDI (SEQ ID NO: 52), a LCDR1 comprising QGISSY (SEQ ID NO: 79), a LCDR2 comprising AAS (SEQ ID NO: 96), a LCDR3 comprising an amino acid sequence with no greater than 2 amino acids different from QQLKSYLYT (SEQ ID NO: 104).

[0151] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a HCDR1 comprising GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence with no greater than 1 amino acid different from ARGRGYTSGWFDY (SEQ ID NO: 55), a LCDR1 comprising an amino acid sequence with no greater than 4 amino acids different from QSVLHTSHNENY (SEQ ID NO: 84), a LCDR2 comprising WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence with no greater than 1 amino acid different from QQYFSTPWT (SEQ ID NO: 106).

[0152] In some embodiments, the integrin a5pi antibody or antigen binding fragment comprises a heavy chain (HC) comprising an amino acid sequence selected from Table B, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In some embodiments, the integrin a5pi antibody or antigen binding fragmentcomprises a light chain (LC) comprising an amino acid sequence selected from Table B, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In some embodiments, the integrin a5pi antibody or antigen binding fragment comprises a HC and a LC comprising amino acid sequences selected from Table B, or sequences substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions).Table B. Exemplary HC and LC of Integrin a5pi Antibodies.

[0153] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:123. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 123. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 123. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 123. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 123.

[0154] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:124. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 124. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 124. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 124. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 124.

[0155] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:125. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 125. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 125. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 125. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 125.

[0156] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:126. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 126. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 126. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 126. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 126.

[0157] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:127. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 127. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 127. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 127. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 127.

[0158] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:128. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 128. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 128. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 128. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 128.

[0159] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:129. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 129. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 129. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 129. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 129.

[0160] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:130. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 130. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 130. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 130. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 130.

[0161] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:131. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 131. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 131. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 131. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 131.

[0162] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:132. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 132. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 132. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 132. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 132.

[0163] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:133. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 133. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 133. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 133. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 133.

[0164] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:134. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 134. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 134. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 134. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 134.

[0165] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:135. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 135. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 135. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 135. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 135.

[0166] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:136. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 136. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 136. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 136. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 136.

[0167] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:137. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 137. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 137. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 137. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 137.

[0168] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:138. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 138. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 138. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 138. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 138.

[0169] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:139. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 139. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 139. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 139. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 139.

[0170] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:140. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 140. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 140. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 140. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 140.

[0171] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:141. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 141. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 141. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 141. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 141.

[0172] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:142. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 142. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 142. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 142. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 142.

[0173] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:143. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 143. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 143. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 143. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 143.

[0174] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:144. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 144. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 144. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 144. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 144.

[0175] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:145. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 145. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 145. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 145. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 145.

[0176] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO: 146. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 146. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 146. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 146. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 146.

[0177] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:148. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 148. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 148. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 148. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 148.

[0178] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:149. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 149. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 149. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 149. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 149.

[0179] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:150. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 150. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 150. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 150. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 150.

[0180] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:151. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 151. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 151. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 151. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 151.

[0181] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:152. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 152. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 152. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 152. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 152.

[0182] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:153. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 153. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 153. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 153. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 153.

[0183] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:154. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 154. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 154. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 154. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 154.

[0184] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:155. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 155. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 155. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 155. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 155.

[0185] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:156. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 156. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 156. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 156. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 156.

[0186] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:157. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 157. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 157. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 157. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 157.

[0187] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:158. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 158. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 158. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 158. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 158.

[0188] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:159. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 159. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 159. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 159. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 159.

[0189] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:160. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 160. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 160. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 160. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 160.

[0190] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:161. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 161. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 161. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 161. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 161.

[0191] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:162. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 162. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 162. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 162. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 162.

[0192] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:163. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 163. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 163. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 163. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 163.

[0193] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:164. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 164. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 164. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 164. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 164.

[0194] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence identical to SEQ ID NO:165. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 165. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 165. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 165. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 165.

[0195] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:166. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 166. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 166. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 166. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 166.

[0196] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:167. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 167. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 167. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 167. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 167.

[0197] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:168. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 168. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 168. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 168. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 168.

[0198] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:169. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 169. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 169. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 169. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 169.

[0199] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:170. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 170. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 170. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 170. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 170.

[0200] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:171. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 171. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 171. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 171. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 171.

[0201] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:172. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 172. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 172. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 172. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 172.

[0202] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:173. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 173. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 173. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 173. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 173.

[0203] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:174. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 174. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 174. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 174. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 174.

[0204] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:175. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 175. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 175. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 175. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 175.

[0205] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:176. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 176. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 176. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 176. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 176.

[0206] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:177. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 177. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 177. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 177. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 177.

[0207] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:178. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 178. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 178. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 178. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 178.

[0208] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:179. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 179. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 179. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 179. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 179.

[0209] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:180. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 180. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 180. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 180. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 180.

[0210] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:181. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 181. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 181. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 181. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 181.

[0211] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:182. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 182. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 182. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 182. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 182.

[0212] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:183. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 183. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 183. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 183. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 183.

[0213] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:184. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 184. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 184. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 184. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 184.

[0214] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:185. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 185. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 185. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 185. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 185.

[0215] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:186. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 186. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 186. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 186. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 186.

[0216] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:187. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 187. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 187. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 187. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 187.

[0217] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:188. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 188. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 188. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 188. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 188.

[0218] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO: 189. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 189. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 189. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 189. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 189.

[0219] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:191. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 191. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 191. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 191. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 191.

[0220] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:192. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 192. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 192. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 192. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 192.

[0221] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:193. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 193. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 193. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 193. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 193.

[0222] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:194. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 194. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 194. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 194. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 194.

[0223] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:195. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 195. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 195. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 195. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 195.

[0224] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:196. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 196. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 196. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 196. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 196.

[0225] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:197. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 197. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 197. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 197. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 197.

[0226] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:198. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 198. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 198. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 198. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 198.

[0227] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:199. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 199. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 199. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 199. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 199.

[0228] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:200. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 200. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 200. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 200. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 200.

[0229] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:201. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 201. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 201. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 201. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 201.

[0230] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:202. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 202. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 202. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 202. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 202.

[0231] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:203. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 203. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 203. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 203. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 203.

[0232] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:204. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 204. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 204. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 204. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 204.

[0233] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:205. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 205. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 205. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 205. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 205.

[0234] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:206. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 206. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 206. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 206. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 206.

[0235] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO:207. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 207. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 207. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 207. In some embodiments, the integrin a5pi antibody or antigenbinding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 207.

[0236] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence identical to SEQ ID NO: 208. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 208. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 208. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 208. In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a light chain comprising an amino acid sequence at least 99% identical to SEQ ID NO: 208.

[0237] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 123 and a light chain comprising an amino acid sequence of SEQ ID NO: 166.

[0238] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 124 and a light chain comprising an amino acid sequence of SEQ ID NO: 167.

[0239] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 125 and a light chain comprising an amino acid sequence of SEQ ID NO: 168.

[0240] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 126 and a light chain comprising an amino acid sequence of SEQ ID NO: 169.

[0241] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 127 and a light chain comprising an amino acid sequence of SEQ ID NO: 170.

[0242] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 128 and a light chain comprising an amino acid sequence of SEQ ID NO: 171.

[0243] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 129 and a light chain comprising an amino acid sequence of SEQ ID NO: 172.

[0244] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 130 and a light chain comprising an amino acid sequence of SEQ ID NO: 173.

[0245] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 131 and a light chain comprising an amino acid sequence of SEQ ID NO: 174.

[0246] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 132 and a light chain comprising an amino acid sequence of SEQ ID NO: 175.

[0247] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 133 and a light chain comprising an amino acid sequence of SEQ ID NO: 176.

[0248] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 134 and a light chain comprising an amino acid sequence of SEQ ID NO: 177.

[0249] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 135 and a light chain comprising an amino acid sequence of SEQ ID NO: 178.

[0250] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 136 and a light chain comprising an amino acid sequence of SEQ ID NO: 179.

[0251] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 137 and a light chain comprising an amino acid sequence of SEQ ID NO: 180.

[0252] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 138 and a light chain comprising an amino acid sequence of SEQ ID NO: 181.

[0253] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 139 and a light chain comprising an amino acid sequence of SEQ ID NO: 182.

[0254] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 140 and a light chain comprising an amino acid sequence of SEQ ID NO: 183.

[0255] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 141 and a light chain comprising an amino acid sequence of SEQ ID NO: 184.

[0256] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 142 and a light chain comprising an amino acid sequence of SEQ ID NO: 185.

[0257] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 143 and a light chain comprising an amino acid sequence of SEQ ID NO: 186.

[0258] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 144 and a light chain comprising an amino acid sequence of SEQ ID NO: 187.

[0259] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 145 and a light chain comprising an amino acid sequence of SEQ ID NO: 188.

[0260] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 146 and a light chain comprising an amino acid sequence of SEQ ID NO: 189.

[0261] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 148 and a light chain comprising an amino acid sequence of SEQ ID NO: 191.

[0262] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 149 and a light chain comprising an amino acid sequence of SEQ ID NO: 192.

[0263] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 150 and a light chain comprising an amino acid sequence of SEQ ID NO: 193.

[0264] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 151 and a light chain comprising an amino acid sequence of SEQ ID NO: 194.

[0265] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 152 and a light chain comprising an amino acid sequence of SEQ ID NO: 195.

[0266] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 153 and a light chain comprising an amino acid sequence of SEQ ID NO: 196.

[0267] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 154 and a light chain comprising an amino acid sequence of SEQ ID NO: 197.

[0268] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 155 and a light chain comprising an amino acid sequence of SEQ ID NO: 198.

[0269] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 156 and a light chain comprising an amino acid sequence of SEQ ID NO: 199.

[0270] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 157 and a light chain comprising an amino acid sequence of SEQ ID NO: 200.

[0271] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 158 and a light chain comprising an amino acid sequence of SEQ ID NO: 201.

[0272] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 159 and a light chain comprising an amino acid sequence of SEQ ID NO: 202.

[0273] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 160 and a light chain comprising an amino acid sequence of SEQ ID NO: 203.

[0274] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 161 and a light chain comprising an amino acid sequence of SEQ ID NO: 204.

[0275] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 162 and a light chain comprising an amino acid sequence of SEQ ID NO: 205.

[0276] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 163 and a light chain comprising an amino acid sequence of SEQ ID NO: 206.

[0277] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 164 and a light chain comprising an amino acid sequence of SEQ ID NO: 207.

[0278] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 164 and a light chain comprising an amino acid sequence of SEQ ID NO: 208.

[0279] In some embodiments, the antibody or antigen binding fragment thereof has an affinity (Kd) to integrin a5pi of between 0.1 nM and 100 nM, as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an affinity (Kd) to integrin a5pi of between 0.1 nM and 50 nM, as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an affinity (Kd) to integrin a5pi of between 0.1 nM and 30 nM, as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an affinity (Kd) to integrin a5pi of between 0.1 nM and 15 nM, as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an affinity (Kd) to integrin a5pi of between 1 nM and 5 nM, as measured by a cell adhesion assay.

[0280] In some embodiments, the antibody or antigen binding fragment thereof has an IC50 value of between 0.1 nM and 100 nM as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an IC50 value of between 0.1 nM and 50 nM as measured by a cell adhesion assay. In some embodiments, the antibodyor antigen binding fragment thereof has an IC50 value of between 0.1 nM and 30 nM as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an IC50 value of between 0.1 nM and 15 nM as measured by a cell adhesion assay. In some embodiments, the antibody or antigen binding fragment thereof has an IC50 value of between 0.1 nM and 5 nM as measured by a cell adhesion assay.Therapeutic Use

[0281] The present invention provides, among other things, a method of treating a heart or lung disease in a subject, comprising administering an integrin a5pi antibody or antigen binding fragment thereof. In some embodiments, the present invention provides a method of treating a disease associated with increased expression or activity of integrin a5pi, comprising administering an integrin a5pi antibody or antigen binding fragment thereof. In some embodiments, the present invention provides integrin a5pi antibodies or antigen binding fragments thereof for use in treating a disease associated with increased expression or activity of integrin a5pi in a subject in need of treatment thereof, comprising administering the integrin a5pi antibody or antigen binding fragment thereof. In some embodiments, the present invention provides integrin a5pi antibodies or antigen binding fragments thereof, for use in the manufacture of a medicament.

[0282] In some embodiments, the disease is characterized by the World HealthOrganization (WHO) group.

[0283] In some embodiments, the disease is pulmonary hypertension, WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, and WHO Group 5 pulmonary hypertension.

[0284] In some embodiments, the disease is characterized by the World Health Organization (WHO) class system. In some embodiments, the disease is characterized by WHO functional class based on cardiac function. In some embodiments, the disease is pulmonary hypertension, WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, WHO Class IV pulmonary hypertension.

[0285] In some embodiments, the disease is Persistent / recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4). In some embodiments, the disease is Pulmonary Arterial Hypertension (PAH) (WHO Group 1).

[0286] In some embodiments, the patient has Persistent / recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH. In some embodiments, patient has Pulmonary Arterial Hypertension (PAH) (WHO Group 1).

[0287] In some embodiments, the treatment is administered to improve exercise capacity and WHO functional class. In some embodiments, the treatment is administered to improve exercise capacity, improve WHO functional class and to delay clinical worsening.

[0288] In some embodiments, the disease is heart failure or right ventricle failure. In some embodiments, the disease is heart failure. In some embodiments, the disease is right ventricle failure.

[0289] In some embodiments, the present invention provides a method of treating pulmonary arterial hypertension (PAH) in a subject, comprising administering an integrin a5pi antibody or antigen binding fragment thereof.

[0290] In some embodiments, the integrin a5pi antibody or antigen binding fragment thereof is administered orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, or intrapulmonarily.

[0291] Also provided is a method for the treatment of a subject suffering from fibrosis or a fibrosis related disorder, comprising administering to said subject a therapeutically effective amount of an integrin a5pi antibody or antigen binding fragment thereof according to the invention. The term “fibrosis” as used herein refers to a condition characterized by a deposition of extracellular matrix components in the skin or organs, including lungs, kidneys, heart, liver, skin and joints, resulting in scar tissue. The term also refers to the process of formation of scar tissue.

[0292] In some embodiments, the fibrosis-related disorder is a disorder or condition which may occur as a result of fibrosis, or which is associated with fibrosis. In some embodiments, fibrosis and / or a fibrosis-related disorders is a disease or condition selected from the group consisting of kidney fibrosis, liver fibrosis, liver cirrhosis, pulmonary fibrosis, skin fibrosis, biliary fibrosis, peritoneal fibrosis, myocardial fibrosis, pancreatic fibrosis, bone marrow and / or myelofibrosis, reperfusion injury after hepatic or kidney transplantation, Interstitial Lung Disease (ILD), cystic fibrosis (CF), atherosclerosis, systemic sclerosis, osteosclerosis, spinal disc herniation and other spinal cord injuries, fibromatosis, fibromyalgia, arthritis, restenosis. In some embodiments, the fibrosis-related disorder ispulmonary fibrosis. Pulmonary fibrosis includes idiopathic pulmonary fibrosis and scleroderma lung fibrosis.Pulmonary Hypertension

[0293] Pulmonary hypertension (PH) is a syndrome characterized by increased pulmonary artery pressure. PH is defined hemodynamically as a systolic pulmonary artery pressure greater than 30 mm Hg or evaluation of mean pulmonary artery pressure greater than 25 mm Hg. See Zaiman et al., Am. J. Respir. Cell Mol. Biol. 33:425-31 (2005). Further, PH, as a result of the increased pressure, damages both the large and small pulmonary arteries. The walls of the smallest blood vessels thicken and are no longer able to transfer oxygen and carbon dioxide normally between the blood and the lungs. In time, pulmonary hypertension leads to thickening of the pulmonary arteries and narrowing of the passageways through which blood flows. Once pulmonary hypertension develops, the right side of the heart works harder to compensate; however, the increased effort causes it to become enlarged and thickened. Proliferation of smooth muscle and endothelial cells which normally exist in a quiescent state leads to remodeling of the vessels with obliteration of the lumen of the pulmonary vasculature. This causes a progressive rise in pulmonary pressures as blood is pumped through decreased lumen area. The enlarged right ventricle places a person at risk for pulmonary embolism because blood tends to pool in the ventricle and in the legs. If clots form in the pooled blood, they may eventually travel and lodge in the lungs. The progressive rise in pressure also places an additional workload on the right ventricle which eventually fails and leads to premature death in these patients.

[0294] Various pathologic changes occur in pulmonary arteries as a result of PH. Persistent vasoconstriction and structural remodeling of the pulmonary vessels are cardinal features of PH. Pulmonary vascular smooth muscle cells undergo a phenotypic switch from contractile normal phenotype to a synthetic phenotype leading to cell growth and matrix deposition. Histological examination of tissue samples from patients with pulmonary hypertension shows intimal thickening, as well as smooth muscle cell hypertrophy, especially for those vessels <100 pM diameter. Further, abnormal smooth muscle cells often overexpress endothelin and serotonin transporters, which likely play a role in the development of PH.

[0295] The most common symptom of pulmonary hypertension initially is shortness of breath upon exertion. Some people feel light-headed or fatigued upon exertion, and anangina-like chest pain is common. Because body tissues are not receiving enough oxygen, general weakness is another problem. Other symptoms, such as coughing and wheezing, may be caused by an underlying lung disease. Edema, particularly of the legs, may occur because fluid may leak out of the veins and into the tissues, signaling that cor pulmonale has developed. Some people with pulmonary hypertension have connective tissue disorders, especially scleroderma. When people have both conditions, pulmonary hypertension and connective tissue disorders, Raynaud's phenomenon often develops before symptoms of pulmonary hypertension appear, sometimes as long as years earlier.

[0296] Treatment of some types of pulmonary hypertension is often directed at the underlying lung disease. Currently, the treatment options available for those suffering from PH target cellular dysfunction that leads to constriction of the vasculature. Therapies such as prostanoids, phosphodiesterase-5 inhibitors and endothelin receptor antagonists primarily work by causing dilation of the pulmonary vessels. Vasodilators, such as calcium channel blockers, nitric oxide, and prostacyclin, are often helpful for pulmonary hypertension associated with scleroderma, chronic liver disease, and HIV infection. In contrast, these drugs have not been proven effective for people with pulmonary hypertension due to an underlying lung disease. For most people with pulmonary hypertension due to an unknown cause, vasodilators, such as prostacyclin, drastically reduce blood pressure in the pulmonary arteries. Prostacyclin given intravenously through a catheter surgically implanted in the skin improves the quality of life, increases survival, and reduces the urgency of lung transplantation. Unfortunately, many patients respond poorly to these therapies or stop responding to them over time. The only remaining option at that point in time is a single or double lung transplantation to treat PH. Although there is some evidence that available therapies have secondary effects on vascular remodeling, there are currently no therapies that target abnormal cell proliferation in PAH.

[0297] In some embodiments, the pulmonary hypertension is pulmonary venous hypertension (PVH). In some embodiments, the PVH is due to left heart failure. In some embodiments, the pulmonary hypertension is pulmonary hypertension associated with disorders of the respiratory system and / or hypoxia. In some embodiments, the pulmonary hypertension is pulmonary hypertension due to chronic thrombotic and / or embolic disease. In some embodiments, the pulmonary hypertension is miscellaneous pulmonary hypertension. In some embodiments, the miscellaneous pulmonary hypertension is associated with sarcoidosis, eosinophilic granuloma, histicytosis X, lymphangiolomyiomatosis, orcompression of pulmonary vessels (e.g., adenopath, tumor, or fibrosing medianstinitis). In some embodiments, the pulmonary hypertension is associated with chronic obstructive pulmonary disease (COPD). In some embodiments, the pulmonary hypertension is associated with pulmonary fibrosis. In some embodiments, the pulmonary hypertension is associated with cardiac fibrosis. In some embodiments, the pulmonary hypertension is early-stage pulmonary hypertension or advanced pulmonary hypertension.

[0298] In some embodiments, the subject suffers from pulmonary venous hypertension (PVH). In some embodiments, the PVH is due to left heart failure. In some embodiments, the subject suffers from a disorder of the respiratory system and / or hypoxia. In some embodiments, the subject suffers from a chronic thrombotic and / or embolic disease. In some embodiments, the subject suffers from sarcoidosis, eosinophilic granuloma, histicytosis X, lymphangiolomyiomatosis, or compression of pulmonary vessels (e.g., due to an adenopathy, a tumor, or fibrosing medianstinitis). In some embodiments, the subject suffers from chronic obstructive pulmonary disease (COPD). In some embodiments, the subject suffers from pulmonary fibrosis. In some embodiments, the subject suffers from cardiac fibrosis. In some embodiments, the subject suffers from early-stage pulmonary hypertension or advanced pulmonary hypertension.

[0299] In some embodiments, one or more symptoms of the pulmonary hypertension are ameliorated. In some embodiments, the pulmonary hypertension is delayed. In some embodiments, the pulmonary hypertension is prevented. In some embodiments, the methods of treatment provided herein reduce pulmonary pressure. In some embodiments, the methods of treatment provided herein inhibit and / or reduce abnormal cell proliferation in the pulmonary artery.

[0300] In some embodiments, the pulmonary hypertension is characterized by the World Health Organization (WHO) group.

[0301] In some embodiments, the pulmonary hypertension is WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, and WHO Group 5 pulmonary hypertension.

[0302] In some embodiments, the pulmonary hypertension is characterized by the World Health Organization (WHO) class system. In some embodiments, the pulmonary hypertension is characterized by WHO functional class based on cardiac function. In someembodiments, the pulmonary hypertension is characterized as WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, WHO Class IV pulmonary hypertension.

[0303] In some embodiments, the subject suffers from pulmonary hypertension characterized by the World Health Organization (WHO) group.

[0304] In some embodiments, the subject suffers from WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, or WHO Group 5 pulmonary hypertension.

[0305] In some embodiments, the subject suffers from a disease characterized by the World Health Organization (WHO) class system. In some embodiments, the subject suffers from a disease characterized by WHO functional class based on cardiac function. In some embodiments, the subject suffers from pulmonary hypertension classified by WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, WHO Class IV pulmonary hypertension.

[0306] In some embodiments, the pulmonary hypertension is associated with pulmonary capillary hemangiomatosis.Pulmonary Arterial Hypertension (PAH)

[0307] In some embodiments, the present invention provides a method of treating Pulmonary Arterial Hypertension (PAH), comprising administering an integrin a5pi antibody or antigen binding fragment thereof. PAH is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular overload and eventually cardiac failure. PAH results in progressive obstruction and decreased compliance of pulmonary arteries (PA), leading to right ventricular (RV) failure and premature death. Like cancer cells, PA smooth muscle cells (PASMCs) and endothelial cells (PAECs) exhibit exaggerated proliferation and resistance to apoptosis in response to increased PA stiffness caused by extracellular matrix (ECM) remodeling. Integrins signaling could promote PAH-PASMCs and PAH-PAECs proliferation and resistance to apoptosis contributing to PAs vascular remodeling, while in the RV, maladaptive hypertrophy, and fibrosis, leading to RV failure inPAH. Integrin a5pi antibodies can reverse PAs vascular remodeling and prevent RV dysfunction in PAH.

[0308] PAH is a chronic disorder that involves all layers of the pulmonary vessels. Vasoconstriction, structural changes in the pulmonary vessel wall (vascular remodeling) and thrombosis contribute to the increased pulmonary vascular resistance in PAH. Structural and functional changes of the endothelium lead to endothelial dysfunction. Increased vasoconstrictive factors (e.g., endothelin) and decreased vasodilation capacity (e.g., less prostacyclin) result in vasoconstriction and increased pulmonary vascular resistance. Current treatments that seek to address vasoconstriction may slow the progression of PAH or ameliorate the clinical symptoms for a limited time, but they have not proven to substantially reduce overall PAH morbidity and mortality rates. Underlying structural changes to the pulmonary vessels - vascular remodeling - are not affected by these treatments.

[0309] Vascular remodeling that occurs in PAH is characterized by proliferative and obstructive changes involving many cell types, including endothelial cells, smooth muscle cells and fibroblasts. Vascular remodeling can manifest itself, for example, as medial thickening of pulmonary vessels due to smooth muscle cell hyperplasia and hypertrophy, formation of a neointima made of smooth muscle cells and / or myofibroblasts, and / or formation of plexiform lesions, which consist of localized proliferations of endothelial cells, smooth muscle cells, lymphocytes, and mast cells. Vascular remodeling results in obstruction of the vessel lumen leading to pulmonary hypertension. There is a need for therapies that address the proliferative aspect of PAH.

[0310] In some embodiments, the pulmonary hypertension is pulmonary arterial hypertension (PAH). In some variations, the PAH is idiopathic PAH. In some variations, the PAH is familial PAH. In some variations, the PAH is associated with persistent pulmonary hypertension of a newborn. In some variations, the PAH is associated with pulmonary venoocclusive disease.

[0311] In some embodiments, the pulmonary hypertension is associated with lung diseases. In some embodiments, the lung disease is Idiopathic pulmonary fibrosis (IPF) or interstitial pneumonia (IIP). IPF is a type of idiopathic interstitial pneumonia (IIP), which in turn is a type of interstitial lung disease (also known as diffuse parenchymal lung disease (DPLD)). Interstitial lung disease concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues. Other forms ofidiopathic interstitial pneumonias include non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP) and acute interstitial pneumonia (AIP). Examples of known causes of interstitial lung disease include sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, asbestosis and collagen vascular diseases such as scleroderma and rheumatoid arthritis.

[0312] Accordingly, in some embodiments, the subject suffers from a lung disease such as Idiopathic pulmonary fibrosis (IPF) or interstitial pneumonia (IIP). In some embodiments, the subject suffers from idiopathic interstitial pneumonia (IIP), diffuse parenchymal lung disease (DPLD), non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), or acute interstitial pneumonia (AIP). In some embodiments, the subject suffers from sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, asbestosis or a collagen vascular disease such as scleroderma or rheumatoid arthritis.

[0313] Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs.Heart Failure

[0314] In some embodiments, the present invention provides a method of treating heart failure (HF), comprising administering an integrin a5pi antibody or antigen binding fragment thereof. Heart failure refers to any condition characterized by the heart’s inability to pump an adequate supply of blood to the body. The physiological state in which cardiac output is insufficient to meet the needs of the body or to do so only at a higher filing pressure. There are many underlying causes of HF, including myocardial infarction, coronary artery disease, valvular disease, hypertension, and myocarditis. Chronic heart failure is associated with neurohormonal activation and alterations in autonomic control. Although these compensatory neurohormonal mechanisms provide valuable support for the heart under normal physiological circumstances, they also play a fundamental role in the development and subsequent progression of HF.

[0315] For example, one of the body's main compensatory mechanisms for reduced blood flow in HF is to increase the amount of salt and water retained by the kidneys. Retaining salt and water, instead of excreting it via urine, increases the volume of blood in the bloodstream and helps to maintain blood pressure. However, the larger volumes of blood also cause the heart muscle, particularly the ventricles, to become enlarged. As the heartchambers become enlarged, the wall thickness decreases and the heart's contractions weaken, causing a downward spiral in cardiac function. Another compensatory mechanism is vasoconstriction of the arterial system, which raises the blood pressure to help maintain adequate perfusion, thus increasing the load that the heart must pump against.

[0316] In low ejection fraction (EF) heart failure, high pressures in the heart result from the body's attempt to maintain the high pressures needed for adequate peripheral perfusion. However, as the heart weakens because of such high pressures, the disorder becomes exacerbated. Pressure in the left atrium may exceed 25 mmHg, at which stage, fluids from the blood flowing through the pulmonary circulatory system transudate or flow out of the pulmonary capillaries into the pulmonary interstitial spaces and into the alveoli, causing lung congestion and if untreated the syndrome of acute pulmonary edema and death.Right Ventricle Failure

[0317] In some embodiments, the present invention provides a method of treating right ventricle (RV) failure, comprising administering an integrin a5pi antibody or antigen binding fragment thereof. In some embodiments, the RV failure results from RV volume overload. In some embodiments, the RV volume overload is due to septal defects or valvular regurgitation. In some embodiments, the RV pressure overload is due to other WHO groups of pulmonary hypertension or outflow obstructions. In some embodiments, the RV failure is due to pulmonary artery stenosis.

[0318] In some embodiments, the present invention provides a method of treating an RV cardiomyopathy comprising administering an integrin a5pi inhibitor (e.g., small molecule compounds and antibodies disclosed herein). In some embodiments, the RV cardiomyopathy is due to infarction, arrythmia, or fibrosis.

[0319] In some embodiments, integrin a5pi antibodies or antigen binding fragments thereof maintain cardiac output. In some embodiments, integrin a5pi antibodies or antigen binding fragments thereof prevent maladaptation of the RV. In some embodiments, administering the integrin a5pi antibodies or antigen binding fragments thereof results in improved hypertrophy and / or fibrosis. In some embodiments, administering the integrin a5pi antibodies or antigen binding fragments thereof prevents hypertrophy and / or fibrosis.Methods of treatment

[0320] The present invention provides method of treating a heart or lung disease in a subject, comprising administering an integrin a5pi antibody or antigen binding fragmentthereof. In one aspect, the present invention provides a method of treating a disease associated with increased expression or activity of integrin a5pi, comprising administering an integrin a5pi antibody or antigen binding fragment thereof. In some embodiments, the disease is characterized by the World Health Organization (WHO) group.

[0321] In some embodiments, the disease is pulmonary hypertension, WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, and WHO Group 5 pulmonary hypertension.

[0322] In some embodiments, the disease is characterized by the World Health Organization (WHO) class system. In some embodiments, the disease is characterized by WHO functional class based on cardiac function. In some embodiments, the disease is pulmonary hypertension, WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, WHO Class IV pulmonary hypertension.

[0323] In some embodiments, the disease is Persistent / recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4). In some embodiments, the disease is Pulmonary Arterial Hypertension (PAH) (WHO Group 1).

[0324] In some embodiments, the patient has Persistent / recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH. In some embodiments, patient has Pulmonary Arterial Hypertension (PAH) (WHO Group 1).

[0325] In some embodiments, the treatment is administered to improve exercise capacity and WHO functional class. In some embodiments, the treatment is administered to improve exercise capacity, improve WHO functional class and to delay clinical worsening.

[0326] In some embodiments, the disease is heart failure or right ventricle failure. In some embodiments, the disease is heart failure. In some embodiments, the disease is right ventricle failure.

[0327] In one aspect, the present invention provides a method of treating pulmonary arterial hypertension (PAH) in a subject, comprising administering an integrin a5pi antibody or antigen binding fragment thereof.

[0328] In some embodiments, the integrin a5pi antibody is administered orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, or intrapulmonarily.

[0329] Also provided is a method for the treatment of a subject suffering from fibrosis or a fibrosis related disorder, comprising administering to said subject a therapeutically effective amount of integrin a5pi antibody according to the invention. The term “fibrosis” as used herein refers to a condition characterized by a deposition of extracellular matrix components in the skin or organs, including lungs, kidneys, heart, liver, skin and joints, resulting in scar tissue. The term also refers to the process of formation of scar tissue.

[0330] In some embodiments, the fibrosis-related disorder is a disorder or condition which may occur as a result of fibrosis, or which is associated with fibrosis. In some embodiments, fibrosis and / or a fibrosis-related disorders is a disease or condition selected from the group consisting of kidney fibrosis, liver fibrosis, liver cirrhosis, pulmonary fibrosis, skin fibrosis, biliary fibrosis, peritoneal fibrosis, myocardial fibrosis, pancreatic fibrosis, bone marrow and / or myelofibrosis, reperfusion injury after hepatic or kidney transplantation, Interstitial Lung Disease (ILD), cystic fibrosis (CF), atherosclerosis, systemic sclerosis, osteosclerosis, spinal disc herniation and other spinal cord injuries, fibromatosis, fibromyalgia, arthritis, restenosis. Pulmonary fibrosis includes idiopathic pulmonary fibrosis and scleroderma lung fibrosis.Therapeutic Dose

[0331] In some embodiments, the method of treating a disease associated with increased expression or activity of integrin a5pi, comprises administering an integrin a5pi antibody or antigen binding fragment thereof at a dose of 1 mg / kg to 1000 mg / kg. In some embodiments, the method of treating a heart or lung disease in a subject, comprises administering an integrin a5pi antibody or antigen binding fragment thereof at a dose of 1 mg / kg to 1000 mg / kg. In some embodiments, embodiments, the disease is characterized by the World Health Organization (WHO) group as discussed above.

[0332] In some embodiments, the dose is at least 2 mg / kg, at least 4 mg / kg, at least 6 mg / kg, or at least 8 mg / kg. In some embodiments, the dose is at least 10 mg / kg, at least 20 mg / kg, at least 30 mg / kg, at least 40 mg / kg, at least 50 mg / kg, at least 60 mg / kg, at least 70 mg / kg, at least 80 mg / kg, at least 90 mg / kg or at least 100 mg / kg. In some embodiments, thedose is at least 200 mg / kg, at least 300 mg / kg, at least 400 mg / kg, at least 500 mg / kg, at least600 mg / kg, at least 700 mg / kg, at least 800 mg / kg, at least 900 mg / kg, or at least 1000 mg / kg.Cardiac function parameters

[0333] Various endpoint parameters can be assessed to determine efficacy of a treatment of the present invention, e.g., A5B1 level, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (PAP), cardiac index (CI), mean pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), six-minute walk distance (6 MWD), brain natriuretic peptide (BNP) level, diffusion of lung capacity (DLCO), and death or survival. See, Chung et al. Chest (2010), 138(6): 1383-1394.

[0334] PVR is commonly used as an endpoint parameter for determination of efficacy of treatment for PAH. A PVR of a subject of >240 dyn sec / cm5is an indication of mild PAH. A PVR of a subject of 600-800 dyn sec / cm5indicates moderate to severe PAH. After treatment using the methods and compositions of the invention, a decrease in PVR in a subject of 130 dyn sec / cm5or more indicates efficacious treatment. For example, administration of an integrin a5pi antibody to a subject with PAH that leads to a decrease in PVR of 180-350 dyn sec / cm5indicates efficacious treatment.

[0335] Mean pulmonary arterial pressure (PAP) is also used as an endpoint parameter to determine efficacy of treatment for PAH. A subject without PAH has a mean PAP ranging from about 15-24 mmHg. A subject having mild PAH has a mean PAP of about 25-30 mmHg (e.g., >25 mmHg at rest or 30 mmHg with exercise). A subject having severe PAH has a PAP of greater than 30 mmHg, for e.g., 40-70 mmHg or 60-70 mmHg. After treatment, a decrease in PAP of greater than 1.5 mmHg indicates efficacious treatment. In some embodiments, treatment leads to a decrease in PAP of greater than 5, 10, 20, 40, or 50 mmHg, which is indicative of efficacious treatment.

[0336] Cardiac index (CI) is also used as an endpoint parameter for determining efficacy of treatment for PAH. A low or decreased CI is indicative of heart failure. For e.g., a CI of 2.5 L / min / m2or less is indicative of PAH or heart failure. After treatment, a CI increase of more than 0.3 L / min / m2is indicative of efficacious treatment.

[0337] Mean pulmonary capillary wedge pressure (PCWP) can be used as an endpoint parameter for determining efficacy of treatment for PAH. A mean PCWP of less than or equal to 18 mmHg (e.g., less than or equal to 10 mmHg) indicates a subject havingPAH. After treatment, an increase in mean PCWP of greater than 0.5 mmHg is indicative of efficacious treatment.

[0338] Right atrial pressure (RAP) is also used as an endpoint parameter to determine efficacy of treatment for PAH. A subject not suffering from PAH has a normal RAP of 0-8 mmHg. A RAP of 8 mmHg or greater is indicative of PAH. A subject suffering from severe PAH has a RAP of about 20 mmHg. After treatment, a decrease of greater than 0.5 mmHg is indicative of efficacious treatment.

[0339] Six-minute walk distance (6 MWD) is used as an endpoint parameter to determine efficacy of treatment of PAH. The mean 6 MWD of patients with CTD-PAH is about 300 m. After treatment, an increase in 6 MWD of 25 m or more, or greater than 10% increase indicates efficacious treatment. For example, after treatment, a 6 MWD of 1000 m or more indicates efficacious treatment.

[0340] Brain Natriuretic Peptide (BNP) is used as an endpoint parameter to determine efficacy of treatment of PAH. BNP is a sensitive marker for the worsening of heart failure and is a predictor of mortality in PAH patients. Normal levels of BNP are <100 pg / mL, e.g., 30-90 pg / mL. Higher levels of BNP indicate worsening of heart failure. A BNP level of about 100-200 pg / mL, e.g., 160 pg / mL or higher, indicates early heart failure. A BNP level of about 200-1000 pg / mL indicates real heart failure. The mean BNP level of CTD-PAH patients is about 430 pg / mL. After treatment, any reduction in BNP level indicates efficacious treatment.

[0341] N-Terminal pro Brain Natriuretic Peptide (NT -proBNP): Reproducible, noninvasive parameters are useful in following patients with PAH. BNP is produced in the cardiac ventricles and is elevated in PPH / IPAH. BNP levels have recently been shown to be closely related to functional impairment in PPH / IPAH patients and parallel the extent of pulmonary hemodynamic changes and right heart failure. BNP levels longitudinally correlate with the functional assessments being made over the course of the study. Plasma NT-pro-BNP are measured by a sandwich immunoassay using polyclonal antibodies that recognize epitopes located in the N-terminal segment (1 to 76) of pro-BNP (1 to 108) (Elecsys analyzer, Roche Diagnostics, Manheim, Germany).

[0342] Diffusion of lung capacity (DLCO), or diffusion capacity of CO, is also used as an endpoint parameter to determine efficacy of treatment of PAH. DLCO measures the ability of carbon monoxide (CO) to diffuse across membranes. A subject not suffering fromPAH has a normal DLCO of greater than 80%. A subject suffering from PAH has an abnormal DLC of less than 80%, less than 65%, or less than 45%. After treatment, any increase in % DLCO indicates efficacious treatment.

[0343] In some embodiments, administration of the integrin a5pi antibody modulates the level of a biomarker in the subject, wherein the biomarker is selected from the group consisting of survivin, PCNA, Ki67, and annexin V.Standard-of-Care (SoC) and Combination therapy

[0344] As described herein, a method of treating a disease associated with increased expression or activity of integrin a5pi, comprising administering an integrin a5pi antibody or antigen binding fragment thereof can include a combination therapy in which a patient in need of treatment is administered an integrin a5pi antibody or antigen binding fragment thereof in combination with one or more drugs approved for the treatment of PH, PAH, heart failure, or right ventricle failure.

[0345] Approved drugs currently used in the treatment of PH, PAH, heart failure and right ventricle failure in the US or the European Union (EU) include the orally administered PDE-5 inhibitors: sildenafil (Revatio) and tadalafil (Adeirca); the dual endothelin-1 A receptor antagonist (ERA): bosentan (Tracleer), ambrisentan (Letairis in US; Volibris internationally). Patients with more advanced disease are often treated with prostacyclins or prostacyclin analogs such as iloprost (Ventavis) or treprostinil (Tyvaso) given as multiple daily inhalations, epoprostenol (Flolan / Veletri) or treprostinil (Remodulin) given as continuous intravenous infusions, or treprostinil also used as a continuous subcutaneous infusion. Intravenous injection of sildenafil is approved for patients who are currently prescribed but are temporarily unable to take oral sildenafil. Inhaled nitric oxide (INOmax) is approved for the neonatal form of PAH — persistent pulmonary hypertension of the newborn (PPHN). Thus, in accordance with the invention, combination therapies of any of these drugs and an integrin a5pi antibody are useful in the treatment of PAH or a disorder disclosed herein.

[0346] In some embodiments, the second therapy is selected from the group consisting of anticoagulants, diuretics, a digitalis glycosideglycosides, calcium channel blockers, endothelin receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, prostanoids, prostanoids receptor agonists, soluble guanylate cyclase stimulators, and / or surgery.

[0347] In some embodiments, the second therapy is oxygen, Warfarin, furosemide, bumetanide, bendroflumethiazide, metolazone, spironolactone, amiloride, Digoxin, nifedipine, diltiazem, nicardipine, amlodipine, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, epoprostenol, iloprost, treprostinil, riociguat, selexipag, surgery, pulmonary endarterectomy, and / or atrial septostomy.

[0348] In some embodiments, the second therapy is macitentan and / or tadalafil.

[0349] Flolan (prostacyclin analog) is an approved therapy for PAH but is extremely cumbersome and inconvenient to use (intravenous), and has unique safety concerns. As a result, Flolan is usually reserved for patients with severe functional status or rapidly progressive PAH. Patients must constitute the drug in sterile conditions several times daily. The drug is available as a freeze-dried preparation that needs to be dissolved in alkaline buffer. Because of its short half-life (3-5 min) and stability (8 h at room temperature), Flolan must be maintained in a refrigerated state while given by continuous infusion through a central venous catheter via a portable pump that is worn in a bag around the waist (CADD pump, Smith's Medical MD, St. Paul, Minn.). In 2008, the FDA also approved a new continuous intravenous formulation of epoprostenol that is stable at room temperature for up to 24 h after dilution and may be stored up to 5 days at refrigerator temperature before use (GeneraMedix Inc., Liberty Corner, N.J.). In 2009, GeneraMedix Inc. sold this formulation to Actelion, which began to market the drug (under the brand name Veletri) in April 2010. In late 2010, the Veletri label was expanded to allow preparation of medication up to 7 days at refrigerator temperature or up to 48 h at room temperature in advance of use. Thus, in one embodiment of the invention, an integrin a5pi antibody or antigen binding fragment thereof is administered in combination with epoprostenol, in any of its approved forms, to treat PAH.

[0350] Remodulin (continuous subcutaneous infusion form of prostacyclin analog) was not generally used as initial therapy because of its expense, route of delivery, and limited efficacy. In 2004, the FDA and Health Canada approved an intravenous formulation of Remodulin for patients with PAH class II-IV disease who cannot tolerate the subcutaneous form. In early 2006, the FDA expanded the Remodulin label to include patients requiring transition from Flolan. In 2009, United Therapeutics received FDA approval for an inhaled formulation of treprostinil (Tyvaso). Thus, in one embodiment of the invention, an integrin a5pi antibody or antigen binding fragment thereof is administered in combination with treprostinil to treat PAH.

[0351] Ventavis (iloprost), a prostacyclin analogue administered via inhalation is also marketed in several member countries of the EU as Ilomedine as an intravenous formulation. The label for inhaled iloprost in the EU is restricted to patients with idiopathic PAH and functional class III symptoms. In contrast, the label in the US is broader: patients with PAH (regardless of etiology) and class III or IV symptoms. It is required 6 to 9 times a day administration. Thus, in one embodiment of the invention, an integrin a5pi antibody or antigen binding fragment thereof is administered in combination with iloprost, in any of its approved forms, to treat PAH.

[0352] In 2001, the nonselective ERA Tracleer (bosentan) became the first oral PAH therapy and was available only through a special centralized access program in the US because of its significant risk of (reversible) liver injury, teratogenicity, testicular atrophy, and male sterility. Treatment with Tracleer consists of an initial dosage of 62.5 mg twice daily for 4 weeks, followed by a maintenance dose of 125 mg twice daily. Tracleer was initially indicated for patients with PAH and moderate or severe functional status (WHO class III, IV). In 2008 (EU) and 2009 (US), the label was expanded to patients with mild symptoms (functional class II). Thus, in one embodiment of the invention, an integrin a5pi antibody or antigen binding fragment thereof is administered in combination with bosentan, in any of its approved forms, to treat PAH.

[0353] Ambrisentan is the oral selective ERA-receptor antagonist marketed by Gilead Sciences in the US (Letairis) and by GlaxoSmithKline in other regions (Volibris) for the once-daily treatment of patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. As with bosentan, ambrisentan has class effects of teratogenicity, testicular injury, reduced male fertility, and anemia. Thus, in one embodiment of the invention, an integrin a5pi antibody or antigen binding fragment thereof is administered in combination with ambrisentan, in any of its approved forms, to treat PAH.

[0354] The oral PDE-5 inhibitor Revatio (sildenafil) was approved in the US for the treatment of PAH (WHO Group I) to improve exercise ability and delay of clinical worsening at a dose of 20 mg three times daily, regardless of functional class or etiology. The EU label is restricted to improvement of exercise capacity in patients with PAH, which is either idiopathic or associated with collagen vascular disease and with functional class III status. In 2009, the FDA approved an intravenous form of Revatio given as an injection (10 mg 3 -times a day) for a patient unable to take the oral formulation. In May 2010, the EU approved Revatio as an oral suspension (compounded from 20 mg tablets) for the treatment of pediatricpatient aged 1 to 17 years with PAH. Thus, in one embodiment of the invention, an integrin a5pi antibody or antigen binding fragment thereof is administered in combination with sildenafil, in any of its approved forms, to treat PAH.

[0355] The oral PDE-5 Inhibitor Adeirca (tadalafil) 40 mg once daily is indicated in the US to improve exercise ability in patients with PAH (WHO Group I) regardless of etiology or functional class (Packet Insert). The EU label is restricted to patients with functional class II and III status. Tadalafil has a long half-life (35 h) in patients with PAH (US Packet Insert) has also shown benefit in patients with PAH on concomitant bosentan.

[0356] Thus, the method of treating the patient may involve administering at least one additional active agent, i.e., in addition to an integrin a5 pi inhibitor. The additional active agent may be, for example, a vasodilator such as prostacyclin, epoprostenol, and sildenafil; an endothelin receptor antagonist such as bosentan; a calcium channel blocker such as amlodipine, diltiazem, and nifedipine; an anticoagulant such as warfarin; a diuretic, a prostanoid (e.g., prostacyclin or PGI2), drugs for treating diseases associated with overactive B cells or dysfunctional B cells such as Rituximab, and / or a Type V phosphodiesterase (PDE5) inhibitor.

[0357] When the method of the invention involves combination therapy, i.e., wherein a secondary agent such as a vasodilator is co-administered with an integrin a5pi antibody or antigen binding fragment thereof, the agents may be administered separately, at the same, or at different times of the day, or they may be administered in a single composition. Thus, the present invention provides novel pharmaceutical formulations in which an integrin a5pi antibody or antigen binding fragment thereof is combined with one of the active agents discussed above and unit dose forms of those formulations.

[0358] In the combination therapies of the invention, each agent can be administered in an “immediate release” manner or in a “controlled release manner.” When the additional active agent is a vasodilator, for instance, any dosage form containing both active agents i.e., both the integrin a5pi antibody and the vasodilator, can provide for immediate release or controlled release of the vasodilator, and either immediate release or controlled release of an integrin a5pi antibody.

[0359] As a general example, a combination dosage form of the invention for once- daily administration might contain in the range of about 1 mg to about 1000 mg of an integrin a5pi inhibitor of an integrin a5pi inhibitor, in a controlled release (e.g., sustained release) orimmediate release form, and either sildenafil in immediate release form, or in controlled release form, with the additional active agent present in an amount that provides a weight ratio of an integrin a5piinhibitor to sildenafil, or a weight ratio of an integrin a5piinhibitor to sildenafil, specified as above. In other formulations of the invention, two or more additional active agents, which may or may not be in the same class of drug (e.g., vasodilators), can be present in combination, along with an integrin a5pi inhibitor. In such a case, the effective amount of either or each individual additional active agent present will generally be reduced relative to the amount that would be required if only a single added agent were used.

[0360] The additional active agent may also be, as discussed above, a Type V phosphodiesterase inhibitor, administered with an integrin a5pi antibody or antigen binding fragment thereof, or with both the integrin a5pi antibody and a vasodilator. Examples of Type V phosphodiesterase inhibitors include, without limitation, avanafil, sildenafil, tadalafil, zaprinast, dipyridamole, vardenafil and acid addition or other pharmaceutically acceptable salts thereof. Sildenafil is an excellent example. In an exemplary embodiment, an integrin a5pi antibody is co-administered with a Type V phosphodiesterase inhibitor selected from the group consisting of avanafil, tadalafil, and sildenafil, and the daily dose of a compound of the integrin a5pi antibody is a given above for the monotherapeutic regimen.

[0361] In one embodiment, the vasodilator is selected from sildenafil, avanafil, tadalafil, zaprinast, dipyridamole, vardenafil, bosentan, and pharmaceutically acceptable salts thereof.

[0362] The additional active agent may also be, as discussed above, an endothelin receptor antagonist, e.g., bosentan, sitaxsentan, or ambrisentan, with bosentan being an exemplary active agent.Pharmaceutical Compositions

[0363] Compositions of the invention can be formulated in any suitable form, such as liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, and the like. The optimal form for any composition depends on the intended mode of administration, the nature of the composition or combination, and therapeutic application or other intended use. A typical mode for delivery for a composition of the invention is by parenteral administration (e.g., intravenousadministration). In one aspect, a composition of the invention is administered to a human patient by intravenous infusion or injection.

[0364] In some embodiments, this disclosure provides compositions, e.g., pharmaceutical compositions, which include an integrin a5pi antibody or antigen binding fragment thereof described herein, formulated together with a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).

[0365] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion. Therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high antibody concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. The antibody molecules described herein can be administered by a variety of methods. Several are known in the art, and for many therapeutic,prophylactic, or diagnostic applications, an appropriate route / mode of administration is intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results.Methods of Manufacturing

[0366] In one aspect, the present invention provides, among other things, a method of manufacturing an integrin a5pi antibody or antigen binding fragment. In some embodiments, the method of manufacturing comprises a method of making an integrin a5pi antibody or antigen binding fragment thereof. In some embodiments, the method comprises culturing a host cell comprising a nucleic acid encoding an integrin a5pi antibody or antigen binding fragment thereof under conditions that allow production of the antibody or antigen binding fragment thereof.Nucleic Acids

[0367] In some embodiments, the present invention provides nucleic acids encoding the integrin a5pi antibodies or antigen binding fragments thereof. For example, in some embodiments, a nucleic acid encodes the CDRs of an integrin a5pi antibody described herein. In some embodiments, a nucleic acid encodes the heavy chain or light chain variable region of an integrin a5pi antibody.

[0368] In some embodiments, the present disclosure provides a first and second nucleic acid encoding heavy and light chain variable regions, respectively, of an integrin a5pi antibody or antigen binding fragment disclosed herein, e.g., an antibody of Table A, or an antigen binding fragment, e.g., the variable regions of any of the antibodies disclosed herein. The nucleic acid can comprise a nucleotide sequence encoding any one of the amino acid sequences in the tables herein, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto).

[0369] In some embodiments, the nucleic acid encodes at least one, two, or three CDRs from a heavy chain variable region having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In some embodiments, the nucleic acid encodes at least one, two, or three CDRs from a light chain variable region having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or moresubstitutions, e.g., conserved substitutions). In some embodiments, the nucleic acid encodes at least one, two, three, four, five, or six CDRs from heavy and light chain variable regions having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions).

[0370] The nucleic acids disclosed herein include deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[0371] In some embodiments, the application includes host cells and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or separate host cell, as described in more detail below.Vectors

[0372] Further provided herein are vectors that comprise nucleic acids encoding the integrin a5pi antibodies or antigen binding fragments thereof (e.g., heavy and light chain variable regions and CDRs of the antibody molecules), as described herein.

[0373] In some embodiments, the vector comprises a nucleic acid described herein. For example, the vector can comprise a first and second nucleic acid encoding heavy and light chain variable regions, respectively, of integrin a5pi antibody or antigen binding fragment thereof as described herein.

[0374] In some embodiments, the vector comprises a nucleic acid encoding at least one, two, or three CDRs from a heavy chain variable region having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In some embodiments, the vectorcomprises a nucleic acid encoding at least one, two, or three CDRs from a light chain variable region having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions). In some embodiments, the vector comprises a nucleic encoding at least one, two, three, four, five, or six CDRs from heavy and light chain variable regions having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, e.g., conserved substitutions).

[0375] The vectors include, but are not limited to, a virus, plasmid, cosmid, lambda phage or a yeast artificial chromosome (YAC). Numerous vector systems can be employed. For example, one class of vectors utilizes DNA elements which are derived from animal viruses such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV or MOMLV) or SV40 virus. Another class of vectors utilizes RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern Equine Encephalitis virus and Flaviviruses.

[0376] Additionally, cells which have stably integrated the DNA into their chromosomes may be selected by introducing one or more markers which allow for the selection of transfected host cells. The marker may provide, for example, prototropy to an auxotrophic host, biocide resistance (e.g., antibiotics), or resistance to heavy metals such as copper, or the like. The selectable marker gene can be either directly linked to the DNA sequences to be expressed or introduced into the same cell by cotransformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include splice signals, as well as transcriptional promoters, enhancers, and termination signals.

[0377] Once the expression vector or DNA sequence containing the constructs has been prepared for expression, the expression vectors may be transfected or introduced into an appropriate host cell. Various techniques may be employed to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid-based transfection or other conventional techniques. In the case of protoplast fusion, the cells are grown in media and screened for the appropriate activity.

[0378] Methods and conditions for culturing the resulting transfected cells and for recovering the antibody or antigen binding fragment thereof produced by the methods described herein are known to those skilled in the art and may be varied or optimized depending upon the specific expression vector and mammalian host cell employed, based upon the present description.Cells

[0379] The present disclosure also provides cells (e.g., host cells) comprising a nucleic acid encoding an integrin a5pi antibody or antigen binding fragment as described herein. For example, the host cells may comprise a nucleic acid molecule having a nucleotide sequence encoding an amino acid sequence described in any of Table B, a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or capable of hybridizing under the stringency conditions described herein), or a portion of one of said nucleic acids.

[0380] In some embodiments, the host cells are genetically engineered to comprise nucleic acids encoding the integrin a5pi antibodies or antigen binding fragments described herein.

[0381] In some embodiments, the host cells are genetically engineered by using an expression cassette. The phrase “expression cassette,” refers to nucleotide sequences, which are capable of affecting expression of a gene in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or helpful in effecting expression may also be used, such as, for example, an inducible promoter.

[0382] The disclosure also provides host cells comprising the vectors described herein.

[0383] The cell can be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, S / 9 cells. In an embodiment, the cell (e.g., host cell) is an isolated cell.EXAMPLES

[0384] The following examples describe some of the preferred modes of making and practicing the present invention. However, it should be understood that these examples are for illustrative purposes only and are not meant to limit the scope of the invention.Example 1. Anti-a5pi integrin antibodies effectively block cell adhesion

[0385] In this example, the potency of exemplary integrin a5pi antibodies was assessed by a ligand binding assay and a cell adhesion assay in both serum free and HS conditions.

[0386] Exemplary integrin a5pi antibodies were generated and produced in Tables A and B.. The potency of the integrin a5pi antibodies was first assessed in a ligand binding assay for integrin a5pi. Antibodies were tested in both serum free and HS conditions.Potency was measured by percent inhibition and the calculated IC50. Exemplary results can be seen in FIG. 1. Results are summarized in Table 1. The IC50 values in this example are provided by category as follows: A: IC50 is < 5 nM; B: IC50 is between 5 and 300 nM; and C: IC50 is > 300 nM. As shown, the tested antibodies effectively inhibited ligand from binding to a5piin both serum free and HS conditions.Table 1. Exemplary Integrin a5pi Antibody Potency from Ligand Binding Assays.

[0387] Five of the exemplary integrin a5pi antibodies were tested in in an a5pi cell adhesion assay in triplicates. Antibodies were tested with 1 mM MgCL2 and 1 mM CaCh in both serum free and HS conditions. The average results of the trials are summarized in Table 2. As shown, all antibodies tested had low IC50 values, a high potency.Table 2. Average Potency of Exemplary Integrin a5pi Antibodies from Cell Adhesion Assays. Averages were calculated over 3 trials.

[0388] This example demonstrated the potency of exemplary integrin a5pi antibodies is comparable to or higher than reference antibodies.Example 2. Binding affinity of anti-a5pi integrin antibodies

[0389] In this example, the binding affinity of exemplary integrin a5pi antibodies is determined through surface plasmon resonance (SPR).

[0390] The binding affinity, or KD, of exemplary integrin a5pi antibodies was determined through SPR and summarized in Table 3. The KD values in this example are provided by category as follows: A: KD is < 15 nM; B: KD is between 15 and 300 nM; and C: KD is > 300 nM. As shown, the tested antibodies all have binding affinities in the nanomolar range, indicating a high affinity for the ecto domain of integrin a5pi .Table 3. Integrin a5pi Antibody Binding Affinity with Human a5pi Ecto Domain.

[0391] This example showed that exemplary integrin a5pi antibodies have binding affinities in the low nanomolar range.Example 3. Anti-proliferative activity of anti-a5pi integrin antibodies in vitro

[0392] This example demonstrates in vitro inhibition of proliferation by integrin a5pi antibodies in human pulmonary artery smooth muscle cells (hPASMCs).

[0393] Integrin a5pi antibodies were evaluated to determine whether the antibodies could impair proliferation. Plates were coated with fibronectin (FN-FL) at 10 ug / mL. Cells were then seeded in media containing 2.5% fetal bovine serum (FBS). The next day integrin a5pi antibodies were added and proliferation was monitored for up to 5 days. Proliferation was measured by CellTiter-Glo® Luminescent Cell Viability Assay (CTG) which determined the number of viable cells in culture. The proliferation curves of the tested antibodies can be found in FIG. 2. The calculated IC50 values can be seen in Table 4. The IC50 values in thisexample are provided by category as follows: A: IC50 is < 5 nM; B: IC50 is between 5 and 300 nM; and C: IC50 is > 300 nM.Table 4. Integrin a5pi Antibody Anti-Proliferation Activity.

[0394] The control antibodies, the human isotype and IgG, had no effect on cell proliferation, whereas the anti-a5pi antibodies effectively inhibited proliferation.

[0395] This example showed the impact of integrin a5pi antibodies in reducing proliferation in hPASMCs, indicating potential for integrin a5pi antibodies to treat diseases associated with the proliferation of pulmonary arterial smooth muscle cells.Example 4. Anti-a5pi integrin antibodies of the present invention compete with each other for binding integrin a5pi.

[0396] This example demonstrates that the anti-a5pi integrin antibodies of the present invention compete with each other for binding to a5pi integrin as determined by ELISA.

[0397] The results in FIG. 3 shows that all of the tested anti- a5pi integrin antibodies of the present invention compete with each other.EQUIVALENTS AND SCOPE

[0398] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims.

Claims

CLAIMS1. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment comprises a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 shown in Table A.

2. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), and a HCDR3 comprising an amino acid sequence of ARGRGYSSGWFDY (SEQ ID NO: 54); and a LCDR1 comprising an amino acid sequence of QSVLHNSHNENY (SEQ ID NO:83), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYYSTPWT (SEQ ID NO: 105).

3. The antibody or antigen binding fragment thereof of claim 2, wherein the antibody or antigen binding fragment comprises:(1) a variable heavy chain (VH) comprising an amino acid sequence at least 90% identical to SEQ ID NO: 130, and(2) a variable light chain (VL) comprising an amino acid sequence at least 90% identical to SEQ ID NO: 173.

4. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), and a HCDR3 comprising an amino acid sequence of ARGRGYTSGWFDY (SEQ ID NO: 54); and a LCDR1 comprising an amino acid sequence of QSVLHTSHNENY (SEQ ID NO:84), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYFSTPWT (SEQ ID NO: 106).

5. The antibody or antigen binding fragment thereof of claim 4, wherein the antibody or antigen binding fragment comprises:(1) a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 131, and(2) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 174.

6. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GFSFSYDS (SEQ ID NO: 8), a HCDR2 comprising an amino acid sequence of ISGSSSTI (SEQ ID NO: 39), and a HCDR3 comprising an amino acid sequence of ARGAGTGVFDY (SEQ ID NO: 59); and a LCDR1 comprising an amino acid sequence of QDISSF (SEQ ID NO: 88), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPWT (SEQ ID NO: 111).

7. The antibody or antigen binding fragment thereof of claim 6, wherein the antibody or antigen binding fragment comprises:(1) a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 140, and(2) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 183.8 An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO: 40), and a HCDR3 comprising an amino acid sequence of ARGFAL (SEQ ID NO: 61); and a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of QQYISYPIT (SEQ ID NO: 114).

9. The antibody or antigen binding fragment thereof of claim 8, wherein the antibody or antigen binding fragment comprises:(1) a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 144, and(2) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 187.

10. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GFTFSNYG (SEQ ID NO: 25), a HCDR2 comprising an amino acid sequence of IWYDGSNK (SEQ ID NO: 48), and a HCDR3 comprising an amino acid sequence of ARGEGPGILDY (SEQ ID NO: 76); and a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPFT (SEQ ID NO: 119).

11. The antibody or antigen binding fragment thereof of claim 10, wherein the antibody or antigen binding fragment comprises: a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 163, and a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 206.

12. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GFTFSSSG (SEQ ID NO: 15), a HCDR2 comprising an amino acid sequence of ISYDGSNK (SEQ ID NO: 43), and a HCDR3 comprising an amino acid sequence of ARGIAAAVLDY (SEQ ID NO: 65); and a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHKSYQLS (SEQ ID NO: 117).

13. The antibody or antigen binding fragment thereof of claim 10, wherein the antibody or antigen binding fragment comprises: a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 152, and a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 195.

14. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPHRGDT (SEQ ID NO: 28), and a HCDR3 comprising an amino acid sequence of ARGGWELGISLAFDI (SEQ ID NO: 51); and a LCDR1 comprising an amino acid sequence of QGISSY (SEQ ID NO: 79), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of QQLNSYLYT (SEQ ID NO: 103).

15. The antibody or antigen binding fragment thereof of claim 10, wherein the antibody or antigen binding fragment comprises: a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 123, and a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 166.

16. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO: 40), and a HCDR3 comprising an amino acid sequence of ARGFQH (SEQ ID NO: 60); and a LCDR1 comprising an amino acid sequence of SPNIGSNT (SEQ ID NO: 90), a LCDR2 comprising an amino acid sequence of NNN (SEQ ID NO: 99), and a LCDR3 comprising an amino acid sequence of AAWDDSLNGPGV (SEQ ID NO: 112).

17. The antibody or antigen binding fragment thereof of claim 10, wherein the antibody or antigen binding fragment comprises: a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 142, and a light chain comprising an amino acid sequence at least 90% identical to SEQID NO: 185.

18. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GFTFSSYA (SEQ ID NO: 20), a HCDR2 comprising an amino acid sequence of ISYDGSNK (SEQ ID NO: 43), and a HCDR3 comprising an amino acid sequence of AREGGYYDRSGYYHYYYGMDV (SEQ ID NO: 71); and a LCDR1 comprising an amino acid sequence of QSVSSY (SEQ ID NO: 94), a LCDR2 comprising an amino acid sequence of DAS (SEQ ID NO: 101), and a LCDR3 comprising an amino acid sequence of QQRSNWMFT (SEQ ID NO: 120).

19. The antibody or antigen binding fragment thereof of claim 10, wherein the antibody or antigen binding fragment comprises: a heavy chain comprising an amino acid sequence at least 90% identical toSEQ ID NO: 158, and a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 201.

20. An antibody or antigen binding fragment thereof that binds a5pi, wherein the antibody or antigen binding fragment thereof comprises: a HCDR1 comprising an amino acid sequence of GFTFSSST (SEQ ID NO: 3), a HCDR2 comprising an amino acid sequence of VSSSGAYK (SEQ ID NO: 33), and a HCDR3 comprising an amino acid sequence of ARGTGSGAFDY (SEQ ID NO: 56); and a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPLT (SEQ ID NO: 108).

21. The antibody or antigen binding fragment thereof of claim 10, wherein the antibody or antigen binding fragment comprises: a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 133, and a light chain comprising an amino acid sequence at least 90% identical to SEQID NO: 176.

22. An antibody or an antigen binding fragment thereof that binds integrin a5pi, wherein the antibody competes for binding to integrin a5pi with a reference antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 shown in Table A.

23. An antibody or an antigen binding fragment thereof that binds integrin a5pi, wherein antibody or an antigen binding fragment thereof binds the same epitope or the overlapping epitope on integrin a5pi recognized by a reference antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 shown in Table A.

24. The antibody or an antigen binding fragment thereof of claim 22 or 23, wherein the reference antibody comprises:(a) a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence of ARGRGYSSGWFDY (SEQ ID NO: 54), a LCDR1 comprising an amino acid sequence of QSVLHNSHNENY (SEQ ID NO: 83), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYYSTPWT (SEQ ID NO: 105); or(b) a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1), a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31), a HCDR3 comprising an amino acid sequence of ARGRGYTSGWFDY (SEQ ID NO: 55), a LCDR1 comprising an amino acid sequence of QSVLHTSHNENY (SEQ ID NO: 84), a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97), and a LCDR3 comprising an amino acid sequence of QQYFSTPWT (SEQ ID NO: 106); or(c) a HCDR1 comprising an amino acid sequence of GFSFSYDS (SEQ ID NO: 8), a HCDR2 comprising an amino acid sequence of ISGSSSTI (SEQ ID NO:39), a HCDR3 comprising an amino acid sequence of ARGAGTGVFDY (SEQ ID NO: 59), a LCDR1 comprising an amino acid sequence of QDISSF (SEQ ID NO: 87), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPWT (SEQ ID NO: 111); or(d) a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9), a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO:40), a HCDR3 comprising an amino acid sequence of ARGFAL (SEQ ID NO: 61), aLCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of QQYISYPIT (SEQ ID NO: 114); or(e) a HCDR1 comprising an amino acid sequence of GFTFSNYG (SEQ ID NO: 25), a HCDR2 comprising an amino acid sequence of IWYDGSNK (SEQ ID NO: 48), a HCDR3 comprising an amino acid sequence of ARGEGPGILDY (SEQ ID NO: 76), a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85), a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96), and a LCDR3 comprising an amino acid sequence of LQHNSYPFT (SEQ ID NO: 119).

25. An antibody or an antigen-binding fragment that binds a5pi integrin comprising(a) a means for inhibiting binding of fibronectin to a5pi integrin; and optionally,(b) an Fc domain.

26. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from GFTGSNYG (SEQ ID NO: 25);(ii) a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from IWYDGSNK (SEQ ID NO: 48); and(iii) a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 5 amino acids ARGEGPGILDY (SEQ ID NO: 76); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85);(ii) a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96); and(iii) a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 4 amino acids from LQHNSYPFT (SEQ ID NO: 119).

27. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 4 amino acids from GFSFSYDS (SEQ ID NO: 8);(ii) a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 6 amino acids from ISGSSSTI (SEQ ID NO: 39); and(iii) a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 5 amino acids ARGAGTGVFDY (SEQ ID NO: 59); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 3 amino acids from QDISSF (SEQ ID NO: 87);(ii) a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96); and(iii) a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from LQHNSYPWT (SEQ ID NO: 111).

28. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence of GGSFSGYY (SEQ ID NO: 9);(ii) a HCDR2 comprising an amino acid sequence of INHSGST (SEQ ID NO: 40); and(iii) a HCDR3 comprising an amino acid sequence of ARGFQH (SEQ ID NO: 60); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from SSNIGSNT (SEQ ID NO: 88);(ii) a LCDR2 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from SNN (SEQ ID NO: 98); and(iii) a LCDR3 comprising an amino acid sequence of AAWDDSLNGPGV (SEQ ID NO: 112).

29. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from GGSFSGYY (SEQ ID NO: 9);(ii) a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from INHSGST (SEQ ID NO: 40); and(iii) a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from ARGFAL (SEQ ID NO: 61); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from QGISNY (SEQ ID NO: 85);(ii) a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96); and(iii) a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from QQYISYPIT (SEQ ID NO: 114).

30. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from GGTFSSNA (SEQ ID NO: 27);(ii) a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from IIPIFGTV (SEQ ID NO: 50); and(iii) a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 6 amino acids from ARGSGSGAFDI (SEQ ID NO: 78); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence of QGISNY (SEQ ID NO: 85);(ii) a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96); and(iii) a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from LQHNSYPWT (SEQ ID NO: 111).

31. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from GYTFTGYY (SEQ ID NO: 1);(ii) a HCDR2 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from INPHSGGT (SEQ ID NO: 29); and(iii) a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 3 amino acids from ARGGWKLGISLAFDI (SEQ ID NO: 52); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence of QGISSY (SEQ ID NO: 79);(ii) a LCDR2 comprising an amino acid sequence of AAS (SEQ ID NO: 96); and(iii) a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acids from QQLKSYLYT (SEQ ID NO: 104).

32. An antibody or antigen binding fragment thereof that binds a5pi, comprising a VH and a VL, wherein the VH comprises:(i) a HCDR1 comprising an amino acid sequence of GYTFTGYY (SEQ ID NO: 1);(ii) a HCDR2 comprising an amino acid sequence of INPNSGGT (SEQ ID NO: 31); and(iii) a HCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from ARGRGYTSGWFDY (SEQ ID NO: 55); and wherein the VL comprises:(i) a LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 4 amino acids from QSVLHTSHNENY (SEQ ID NO: 84);(ii) a LCDR2 comprising an amino acid sequence of WAS (SEQ ID NO: 97); and(iii) a LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 1 amino acid from QQYFSTPWT (SEQ ID NO: 106).

33. The antibody or antigen binding fragment thereof of claim 22, wherein the HCDR3 comprises an amino acid sequence that is identical or differs by 1 amino acid from ARGRGYTSGWFDY (SEQ ID NO: 55); the LCDR1 comprises an amino acid sequence that is identical or differs by 1 amino acid from QSVLHTSHNENY (SEQ ID NO: 84); and the LCDR3 comprises an amino acid sequence that is identical or differs by 1 amino acid from QQYFSTPWT (SEQ ID NO: 106).

34. An antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment comprises a variable heavy chain (VH) and a variable light chain (VL) comprising amino acid sequences at least 90% identical to sequences shown in Table B.

35. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment comprises a VH and a VL comprising amino acid sequences identical to sequences shown in Table B.

36. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is a Fab, a single chain Fv (scFv), a single domain antibody (sdAb), a VHH, one or more CDRs, a variable heavy chain (VH), a variable light chain (VL), a Fab-like bispecific antibody (bsFab), a single-domain antibody- linked Fab (s-Fab), an antibody, or a combination thereof.

37. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof further comprises an Fc domain.

38. The antibody or antigen binding fragment thereof of any one of the preceding claims, wherein the Fc domain is derived from IgGl, IgG2a, IgG2b, IgG3, or IgG4.

39. The antibody or antigen binding fragment thereof of claim 38, wherein the Fc domain is derived from IgGl.

40. The antibody or antigen binding fragment thereof of claim 38, wherein the Fc domain is derived from IgG2a or IgG2b.

41. A nucleic acid encoding an antibody or antigen binding fragment thereof of any one of the preceding claims.

42. A vector comprising the nucleic acid of claim 41.

43. A host cell comprising the nucleic acid of claim 31 or the vector of claim 42.

44. A method of making an antibody or antigen binding fragment thereof of any of claims 1-40, wherein the method comprises: culturing a host cell comprising a nucleic acid encoding the antibody or antigen binding fragment thereof under conditions that allow production of the antibody or antigen binding fragment thereof.

45. A composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-40, the nucleic acid of claim 41, the vector of claim 42, or the host cell of claim 43.

46. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-40, nucleic acid of claim 41, the vector of claim 42, or the host cell of claim 43, and a carrier.

47. A method of treating pulmonary arterial hypertension (PAH) in a subject, comprising administering the antibody or an antigen binding fragment thereof of any one of the preceding claims.

48. A method of treating pulmonary arterial hypertension (PAH) in a subject, comprising administering a pharmaceutical composition comprising: a) an antibody means for inhibiting binding of fibronectin to a5pi integrin; and b) one or more physiologically acceptable carriers, excipients or diluents.

49. A method of treating a heart or lung disease in a subject, comprising administering the antibody or an antigen binding fragment thereof of any one of claims 1-40.

50. The method of claim 49, wherein the disease is pulmonary hypertension WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, WHO Group 5 pulmonary hypertension, WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, WHO Class IV pulmonary hypertension.

51. The method of claim 49, wherein the disease is cardiac fibrosis, heart failure or right ventricle failure.I l l

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