LTBP complex-specific inhibitors of TGFβ and uses thereof
Disclosed herein are inhibitors, such as antibodies, and antigen-binding portions thereof, that selectively bind complexes of LTBP1-TGFβ and/or LTBP3-TGFβ. The application also provides methods of use of these inhibitors for, for example, inhibiting TGFβ activation, and treating subjects suffering from TGFβ-related disorders, such as fibrotic conditions. Methods of selecting a context-dependent or context-independent isoform-specific TGFβ inhibitor for a subject in need thereof are also provided.
1. An antibody, or an antigen-binding fragment thereof, that specifically binds a human latent transforming growth factor beta binding protein 1 (LTBP1)-proTGFβ complex and a human latent transforming growth factor beta binding protein 3 (LTBP3)-proTGFβ complex, comprising a heavy chain variable domain and a light chain variable domain,
wherein the heavy chain variable domain comprises:
a heavy chain complementary determining region 1 (CDRH1) comprising an amino acid sequence set forth as SEQ ID NO: 166,
a heavy chain complementary determining region 2 (CDRH2) comprising an amino acid sequence set forth as SEQ ID NO: 167, and
a heavy chain complementary determining region 3 (CDRH3) comprising an amino acid sequence set forth as SEQ ID NO: 168; and
wherein the light chain variable domain comprises:
a light chain complementary determining region 1 (CDRL1) comprising an amino acid sequence set forth as SEQ ID NO: 169,
a light chain complementary determining region 2 (CDRL2) comprising an amino acid sequence set forth as SEQ ID NO: 170, and,
a light chain complementary determining region 3 (CDRL3) comprising an amino acid sequence set forth as SEQ ID NO: 171.
2. The antibody, or the antigen-binding fragment thereof, of claim 1 , wherein the heavy chain variable domain comprises an amino acid sequence set forth as SEQ ID NO: 318 and the light chain variable domain comprises an amino acid sequence set forth as SEQ ID NO: 319.
3. The antibody, or the antigen-binding fragment thereof, of claim 2 , wherein the heavy chain variable domain consists of SEQ ID NO: 318 and the light chain variable domain consists of SEQ ID NO: 319.
4. A pharmaceutical composition comprising the antibody, or the antigen-binding fragment thereof, of claim 1 .
5. A pharmaceutical composition comprising the antibody, or the antigen-binding fragment thereof, of claim 2 .
6. A pharmaceutical composition comprising the antibody, or the antigen-binding fragment thereof, of claim 3 .
7. The pharmaceutical composition of claim 5 , wherein the composition is formulated for subcutaneous administration.
8. The pharmaceutical composition of claim 6 , wherein the composition is formulated for subcutaneous administration.