Isoform-selective TGFβ1 inhibitors and use thereof
Disclosed herein are monoclonal antibodies and antigen-binding fragments thereof capable of selectively inhibiting TGFβ1 with high potency. Related compositions, methods and therapeutic use are also disclosed.
1. An isolated antibody or an antigen-binding fragment thereof that binds pro-transforming growth factor beta 1 (proTGβ1) comprising:
a heavy chain complementary determining region 1 (H-CDR1) having an amino acid sequence set forth in SEQ ID NO: 107;
a heavy chain complementary determining region 2 (H-CDR2) having an amino acid sequence set forth in SEQ ID NO: 103;
a heavy chain complementary determining region 3 (H-CDR3) having an amino acid sequence set forth in SEQ ID NO: 6;
a light chain complementary determining region 1 (L-CDR1) having an amino acid sequence set forth in SEQ ID NO: 105;
a light chain complementary determining region 2 (L-CDR2) having an amino acid sequence set forth in SEQ ID NO: 106; and,
a light chain complementary determining region 3 (L-CDR3) having an amino acid sequence set forth in SEQ ID NO: 12.
2. The isolated antibody or an antigen-binding fragment thereof of claim 1 , comprising a heavy chain variable domain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:13 and a light chain variable domain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:15.
3. The isolated antibody or antigen-binding fragment thereof of claim 2 , comprising a heavy chain variable domain sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:13 and a light chain variable domain sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:15.
4. The isolated antibody or antigen-binding fragment thereof of claim 3 , comprising a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO:13 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO:15.
5. The isolated antibody or antigen-binding fragment thereof of claim 3 , comprising a heavy chain variable domain sequence consisting of the amino acid sequence of SEQ ID NO:13 and a light chain variable domain sequence consisting of the amino acid sequence of SEQ ID NO:15.
6. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof that binds pro-transforming growth factor beta 1 (proTGFβ1) comprising:
a heavy chain complementary determining region 1 (H-CDR1) having an amino acid sequence set forth in SEQ ID NO: 107;
a heavy chain complementary determining region 2 (H-CDR2) having an amino acid sequence set forth in SEQ ID NO: 103;
a heavy chain complementary determining region 3 (H-CDR3) having an amino acid sequence set forth in SEQ ID NO: 6;
a light chain complementary determining region 1 (L-CDR1) having an amino acid sequence set forth in SEQ ID NO: 105;
a light chain complementary determining region 2 (L-CDR2) having an amino acid sequence set forth in SEQ ID NO: 106; and,
a light chain complementary determining region 3 (L-CDR3) having an amino acid sequence set forth in SEQ ID NO: 12.
7. The pharmaceutical composition of claim 6 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable domain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:13 and a light chain variable domain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:15.
8. The pharmaceutical composition of claim 7 , wherein the heavy chain variable domain sequence is at least 95% identical to the amino acid sequence of SEQ ID NO:13, and wherein the light chain variable domain sequence is at least 95% identical to the amino acid sequence of SEQ ID NO:15.
9. The pharmaceutical composition of claim 8 , wherein the heavy chain variable domain sequence comprises the amino acid sequence of SEQ ID NO:13, and wherein the light chain variable domain sequence comprises the amino acid sequence of SEQ ID NO:15.
10. The pharmaceutical composition of claim 8 , wherein the heavy chain variable domain sequence consists of the amino acid sequence of SEQ ID NO:13, and wherein the light chain variable domain sequence consists of the amino acid sequence of SEQ ID NO:15.