# US 2023/0057012 A1 · Tgfb inhibitors and use thereof

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- Number: US 2023/0057012 A1
- Document ID: US20230057012A1
- Status: Published application
- Kind: A1
- Application number: 17/791,859
- Filed: 2021-01-11
- Published: 2023-02-23
- Earliest claimed: 2020-01-11
- Assignees: Scholar Rock, Inc.
- Applicants: Scholar Rock, Inc.
- Inventors: Stefan Wawersik; Thomas Schurpf; Christopher Chapron; Sandeep Kumar; Adam Fogel
- Web page: https://patentgrep.com/patent/US20230057012A1

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 35/00: Antineoplastic agents
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/32: specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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.

## Claims

### Claim 1

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).

### Claim 2 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSG(X1)WD(X2)D, wherein optionally the X1 is H or Q, and X2 is Y or F (SEQ ID NO: 283);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 3 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDFD (SEQ ID NO: 289);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLES (SEQ ID NO: 292); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 4 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDFD (SEQ ID NO: 289);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 5 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDFD (SEQ ID NO: 289);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASVNES (SEQ ID NO: 293); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 6 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDFD (SEQ ID NO: 289);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNEET (SEQ ID NO: 294); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 7 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDFD (SEQ ID NO: 289);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLES (SEQ ID NO: 292); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 8 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDFD (SEQ ID NO: 289);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 9 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDYD (SEQ ID NO: 287);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLES (SEQ ID NO: 292); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 10 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDYD (SEQ ID NO: 287);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 11 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDYD (SEQ ID NO: 287);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLES (SEQ ID NO: 292); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 12 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGHWDYD (SEQ ID NO: 287);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 13 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGDWDYD (SEQ ID NO: 290);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLES (SEQ ID NO: 292); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 14 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGDWDYD (SEQ ID NO: 290);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 15 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGQWDYD (SEQ ID NO: 291);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLES (SEQ ID NO: 292); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 16 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSGQWDYD (SEQ ID NO: 291);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 17 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGKAT (SEQ ID NO: 288);
iii) the H-CDR3 comprises VSSGDWDYD (SEQ ID NO: 290);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASNLQS (SEQ ID NO: 295); and,
vi) the L-CDR3 comprises QQTYTVPLT (SEQ ID NO: 296).

### Claim 18 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGKAT (SEQ ID NO: 288);
iii) the H-CDR3 comprises VSSGDWDYD (SEQ ID NO: 290);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AASGLES (SEQ ID NO: 284); and,
vi) the L-CDR3 comprises QQTYGVPLT (SEQ ID NO: 285).

### Claim 19 (depends on 1)

The isoform-selective inhibitor of claim 1, wherein:
i) the H-CDR1 comprises GFTFADYA (SEQ ID NO: 276);
ii) the H-CDR2 comprises ISGSGAAT (SEQ ID NO: 282);
iii) the H-CDR3 comprises VSSG(H/D/Q)WD(F/Y)D (SEQ ID NO: 278);
iv) the L-CDR1 comprises QSISSY (SEQ ID NO: 279);
v) the L-CDR2 comprises AAS(G/N)LES (SEQ ID NO: 303); and,
vi) the L-CDR3 comprises QQTY(G/T)VPLT (SEQ ID NO: 281).

### Claim 20

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.

### Claim 21 (depends on 20)

The method of claim 20, wherein the antibody or the antigen-binding fragment thereof binds human LTBP1-proTGFβ1 or human LTBP3-proTGFβ1.

### Claim 22 (depends on 20)

The method of claim 20, wherein the antibody or the antigen binding fragment thereof binds human LTBP1-proTGFβ1, human LTBP3-proTGFβ1, human GARP-proTGFβ1 and LRRC33-proTGFβ1.

### Claim 23 (depends on 20, 21, 22)

A pharmaceutical composition made by the process according to any one of claims 20-22.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The isoform-selective inhibitor of TGFβ1 according to any one of claims 1-19 for use in the treatment of a fibrotic disorder in a subject.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The isoform-selective inhibitor of TGFβ1 according to any one of claims 1-19 for use in a method of decreasing the levels of circulating latent TGFβ in the subject.

### Claim 26 (depends on 25)

The isoform-selective inhibitor of TGFβ1 according to claim 25, wherein the level of circulating latent TGFβ is determined in a sample obtained from the subject.

### Claim 27 (depends on 26)

The isoform-selective inhibitor of TGFβ1 according to claim 26, wherein the sample is a whole blood sample or a blood component.

### Claim 28 (depends on 25)

The isoform-selective inhibitor of TGFβ1 according to claim 25, wherein the circulating latent TGFβ is circulating latent TGFβ1.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

Use of the isoform-selective inhibitor of TGFβ1 according to any one of claims 1-19 in the manufacture of a medicament comprising the antibody or the antigen-binding fragment thereof and a pharmaceutically acceptable excipient.

### Claim 30

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.

### Claim 31

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.

### Claim 32 (depends on 31)

The method of claim 31, wherein the fibrotic condition is liver fibrosis, kidney fibrosis, cardiac fibrosis or lung fibrosis.

### Claim 33 (depends on 32)

The method of claim 32, wherein the fibrotic condition is liver fibrosis associated with NASH.

### Claim 34 (depends on 33)

The method of claim 33, wherein the liver fibrosis is stage 3 or stage 4 fibrosis.

### Claim 35 (depends on 31)

The method of claim 31, further comprising the steps of:
(i) determining the levels of circulating latent TGFβ in the subject prior to administering the TGFβ inhibitor; and
(ii) determining the levels of circulating latent TGFβ in the subject after administering the TGFβ inhibitor,
wherein an increase in circulating latent TGFβ after inhibitor administration, as compared to circulating latent TGFβ before administration, indicates therapeutic efficacy.

### Claim 36

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).

### Claim 37

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).

### Claim 38 (depends on 36, 37)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 36 or claim 37, wherein, the VH comprises EVQLLESGGGLVQPGGSLRLSCAASGFTFADYAMTWVRQAPGKGLEWVSAISGSGAATYFADSVK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVSSGHWDYDYWGQGTLVTVSS (SEQ ID NO: 297), and wherein the VL comprises DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASGLESGVPSRFSGSGSG TDFTLTISSLQPEDFATYYCQQTYGVPLTFGGGTKVEIK (SEQ ID NO: 298).