# US 2023/0056881 A1 · Targeted tgfß inhibition

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2023/0056881 A1
- Document ID: US20230056881A1
- Status: Published application
- Kind: A1
- Application number: 17/834,458
- Filed: 2022-06-07
- Published: 2023-02-23
- Earliest claimed: 2014-02-10
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Kin-Ming Lo
- Web page: https://patentgrep.com/patent/US20230056881A1

## CPC

- C07K 14/495: Transforming growth factor [TGF]
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/04: for throat disorders
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 2039/505: {comprising antibodies}
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- C07K 14/71: for growth factors; for growth regulators
- C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 2319/00: Fusion polypeptide
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- 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

This invention relates generally to bifunctional molecules including (a) a TGFβRII or fragment thereof capable of binding TGFβ and (b) an antibody, or antigen binding fragment thereof, that binds to an immune checkpoint protein, such as Programmed Death Ligand 1 (PD-L1), uses of such molecules (e.g., for treating cancer), and methods of making such molecules.

## Claims

### Claim 1

A protein comprising:
a) human Transforming Growth Factor β Receptor II (TGFβRII), or a fragment thereof capable of binding TGFβ; and
b) an antibody, or an antigen-binding fragment thereof, that binds human protein Programmed Death Ligand 1 (PD-L1).

### Claim 2

A polypeptide comprising:
a) at least a variable domain of a heavy chain of an antibody that binds human protein Programmed Death Ligand 1 (PD-L1); and
b) human TGFβRII, or a fragment thereof capable of binding TGFβ.

### Claim 3 (depends on 2)

The polypeptide of claim 2, further comprising an amino acid linker connecting the C-terminus of the variable domain to the N-terminus of the human TGFβRII or fragment thereof.

### Claim 4 (depends on 3)

The polypeptide of claim 3, comprising the amino acid sequence of SEQ ID NO:3.

### Claim 5 (depends on 2)

A nucleic acid comprising a nucleotide sequence encoding a polypeptide according to claim 2.

### Claim 6 (depends on 5)

The nucleic acid of claim 5, further comprising a second nucleotide sequence encoding at least a variable domain of a light chain of an antibody which, when combined with the polypeptide, forms an antigen-binding site that binds PD-L1.

### Claim 7 (depends on 6)

The nucleic acid of claim 6, wherein the second nucleotide sequence encodes the amino acid sequence of SEQ ID NO:1 (secreted anti-PD-L1 lambda light chain).

### Claim 8 (depends on 5)

A cell comprising the nucleic acid of claim 5 and a second nucleic acid encoding at least a variable domain of a light chain of an antibody which, when combined with the polypeptide, forms an antigen-binding site that binds PD-L1.

### Claim at position 9

9-10. (canceled)

### Claim 11 (depends on 8)

A method of producing a protein comprising a) TGFβRII, or a fragment thereof capable of binding TGFβ, and b) an antibody, or an antigen-binding fragment thereof, that binds human protein Programmed Death Ligand 1 (PD-L1), the method comprising maintaining a cell according to claim 8 under conditions permitting expression of the protein.

### Claim 12 (depends on 11)

The method of claim 11, further comprising harvesting the protein.

### Claim 13 (depends on 2)

A protein comprising:
a polypeptide according to claim 2; and
at least a variable domain of a light chain of an antibody which, when combined with the polypeptide, forms an antigen-binding site that binds PD-L1.

### Claim 14 (depends on 13)

The protein of claim 13, comprising two polypeptides each having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO:3, and two additional polypeptides each having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO:1.

### Claim at position 14

15-25. (canceled)

### Claim 26 (depends on 1)

A method of promoting localized depletion of TGFβ, the method comprising administering a protein according to claim 1, wherein the protein binds TGFβ in solution, binds PD-L1 on a cell surface, and carries the bound TGFβ into the cell.

### Claim 27 (depends on 1)

A method of inhibiting SMAD3 phosphorylation in a cell, the method comprising exposing the cell to a protein according to claim 1.

### Claim 28

(canceled)

### Claim 29 (depends on 1)

A method of inhibiting tumor growth, the method comprising exposing the tumor to a protein according to claim 1.

### Claim 30 (depends on 29)

The method of claim 29, further comprising exposing the tumor to radiation or a chemotherapeutic.

### Claim 31

(canceled)

### Claim 32 (depends on 1)

A method of treating cancer, the method comprising administering to a cancer patient a protein according to claim 1.

### Claim 33 (depends on 32)

The method of claim 32, further comprising:
(a) exposing the cancer patient to radiation;
(b) or administering a chemotherapeutic.

### Claim 34

(canceled)

### Claim 35 (depends on 29)

The method according to claim 29, wherein the tumor is selected from the group consisting of colorectal, breast, ovarian, pancreatic, gastric, prostate, renal, cervical, myeloma, lymphoma, leukemia, thyroid, endometrial, uterine, bladder, neuroendocrine, head and neck, liver, nasopharyngeal, testicular, small cell lung cancer, non-small cell lung cancer, melanoma, basal cell skin cancer, squamous cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, glioblastoma, glioma, sarcoma, mesothelioma, and myelodysplastic syndromes.

### Claim 36 (depends on 1)

The protein of claim 1, wherein the antibody, or the antigen-binding fragment thereof, that binds human protein Programmed Death Ligand 1 (PD-L1), comprises a heavy chain variable region polypeptide comprising an HVR-H1, HVR-H2, and HVR-H3 sequence and a light chain variable region polypeptide comprising an HVR-L1, HVR-L2, and HVR-L3 sequence, wherein
the HVR-H1 sequence is X1YX2MX3 (SEQ ID NO:21);
the HVR-H2 sequence is SIYPSGGX4 TFY ADX5 VKG (SEQ ID NO:22);
the HVR-H3 sequence is IKLGTVTTVX6Y (SEQ ID NO:23); and further wherein
X1 is K, R, T, Q, G, A, W, M, I, or S; X2 is V, R, K, L, M, or I; X3 is H, T, N, Q, A, V, Y, W, F, or M; X4 is F or I; X5 is S or T; and X6 is E or D; and wherein the HVR-L1 sequence is TGTX7X8DVGX9YNYVS (SEQ ID NO:28);
the HVR-L2 sequence is X10VX11X12RPS (SEQ ID NO:29);
the HVR-L3 sequence is SSX13TX14X15X16X17RV (SEQ ID NO:30); and further wherein
X7 is N or 5; X8 is T, R, or S; X9 is A or G; X10 is E or D; is I, N or S;
X12 is D, H or N; X13 is F or Y; X14 is N or S; X15 is R, T or S; X16 is G or S; and
X17 is I or T.