Tgfb inhibitors and use thereof
AssigneeScholar Rock, Inc.
InventorsStefan Wawersik, Thomas Schurpf, Christopher Chapron, Sandeep Kumar, Adam Fogel
Life of this patent
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Abstract
Disclosed herein are novel inhibitors of TGFβ1 activation with durable inhibitory effects. Methods directed to the selection of a suitable TGFβ inhibitor for various disease conditions and patient populations are also provided.
Claims38
An isoform-selective inhibitor of TGFβ1 activation,
- wherein the inhibitor is a monoclonal antibody or an antigen-binding fragment thereof, which selectively inhibits TGFβ1 activation;
- wherein the monoclonal antibody or the antigen-binding fragment thereof binds each of human LTBP1-proTGFβ1 and/or human LTBP3-proTGFβ1 with a monovalent dissociation rate of 10.0e-4 (1/s) as measured by a surface plasmon resonance (SPR)-based assay, and optionally with a KD of <1.0 nM;
- and,
- wherein the monoclonal antibody or the antigen-binding fragment thereof comprises the following six CDRs:
- i) an H-CDR1 comprising GFTFADYA (SEQ ID NO:
- 276);
- ii) an H-CDR2 comprising ISGSG(X1)AT, wherein optionally the X1 is A or K (SEQ ID NO:
- 277);
- iii) an H-CDR3 comprising VSSG(X1)WD(X2)D, wherein optionally X1 is H, D or Q;
- and
- wherein further optionally X2 is F or Y (SEQ ID NO:
- 278);
- iv) an L-CDR1 comprising QSISSY (SEQ ID NO:
- 279);
- v) an L-CDR2 comprising AAS(X1)(X2)(X3)(X4), wherein optionally X1 is N, G or V;
- wherein further optionally X2 is L, N or E;
- wherein further optionally X3 is Q or E;
- and
- wherein further optionally X4 is S or T (SEQ ID NO:
- 280);
- and,
- vi) an L-CDR3 comprising QQTY(X1)VPLT, wherein optionally X1 is T or G (SEQ ID NO:
- 281).
A method of making a pharmaceutical composition comprising an isoform-selective inhibitor of TGFβ1 activation, the method comprising the steps of:
- i) selecting an antibody or an antigen-binding fragment thereof that selectively binds a human latent TGFβ1 complex with a sub-nanomolar affinity (KD<1.0 nM) and with a dissociation rate of <10×10−4 (kOFF<10.0E-4) as measured by an in vitro binding assay (e.g., BLI- or SPR-based technique) with Fab fragments and inhibits activation of TGFβ1 in a cell-based potency assay;
- ii) producing the antibody or an engineered construct comprising an antigen-binding fragment of the antibody, in a cell culture, wherein optionally the cell culture is a mammalian cell culture, and wherein further optionally the cell culture has a volume of ≥250 L;
- iii) formulating the antibody or the antigen-binding fragment thereof into a pharmaceutical composition comprising the inhibitor and a pharmaceutically acceptable excipient.
A method of treating a disease involving extracellular matric (ECM) dysregulation in a subject, the method comprising steps of:
- selecting a TGFβ inhibitor that inhibits TGFβ1 but does not inhibit one or both of TGFβ2 and/or TGFβ3;
- administering to a subject having a disease involving ECM dysregulation the TGFβ inhibitor in an amount effective to treat the disease, wherein optionally the disease is a fibrosis or cancer, wherein further optionally the cancer comprises a solid tumor or the cancer is a myeloproliferative disorder.
A method of treating fibrosis in a subject, the method comprising steps of
- selecting a TGFβ inhibitor that inhibits TGFβ1 but does not inhibit one or both of TGFβ2 and TGFβ3;
- administering to a subject having a fibrotic condition the TGFβ inhibitor in an amount effective to treat the fibrotic condition.
An isolated monoclonal antibody or an antigen-binding fragment thereof, which selectively inhibits TGFβ1 activation, comprising:
- a heavy chain complementary determining region 1 (CDRH1) comprising GFTFADYA (SEQ ID NO:
- 276);
- a heavy chain complementary determining region 2 (CDRH2) comprising ISGSGAAT (SEQ ID NO:
- 282);
- a heavy chain complementary determining region 3 (CDRH3) comprising VSSGHWDYD (SEQ ID NO:
- 287);
- a light chain complementary determining region 1 (CDRL1) comprising QSISSY (SEQ ID NO:
- 279);
- a light chain complementary determining region 2 (CDRL2) comprising AASGLES (SEQ ID NO:
- 284);
- and,
- a light chain complementary determining region 3 (CDRL3) comprising QQTYGVPLT (SEQ ID NO:
- 285).
An isolated monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein, the VH comprises a sequence having at least 95% identity to EVQLLESGGGLVQPGGSLRLSCAASGFTFADYAMTWVRQAPGKGLEVWSAISGSGAATYFADSVK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVSSGHWDYDYWGQGTLVTVSS (SEQ ID NO:
- 297), and wherein the VL comprises a sequence having at least 95% identity to DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASGLESGVPSRFSGSGSG TDFTLTISSLQPEDFATYYCQQTYGVPLTFGGGTKVEIK (SEQ ID NO:
- 298).
Dependencies are inferred from the claim text.