# US 9,518,112 B2 · TGF-β1 specific antibodies and methods and uses thereof

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

- Number: US 9,518,112 B2
- Document ID: US9518112B2
- Status: Granted
- Kind: B2
- Application number: 14/383,602
- Filed: 2013-03-06
- Published: 2015-05-14
- Granted: 2016-12-13
- Earliest claimed: 2012-03-08
- Assignees: Ludwig Institute for Cancer Research
- Applicants: Ludwig Institute for Cancer Research, LTD.
- Inventors: Jacques Van Snick; Catherine Uyttenhove; Thierry Boon
- Web page: https://patentgrep.com/patent/US9518112B2

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- G01N 33/57585: {involving compounds identifiable in body fluids}
- G01N 2333/495: Transforming growth factor [TGF]
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Specific binding members, particularly antibodies and fragments thereof, which bind to transforming growth factor beta 1 (TGF-β1) are provided, particularly recognizing human and mouse TGF-β1 and not recognizing or binding TGF-β2 or TGF-β3. Particular antibodies are provided which specifically recognize and neutralize TGF-β1. These antibodies are useful in the diagnosis and treatment of conditions associated with activated or elevated TGF-β1, including cancer, and for modulating immune cells and immune response, including immune response to cancer or cancer antigens. The anti-TGF-β1 antibodies, variable regions or CDR domain sequences thereof, and fragments thereof may also be used in therapy in combination with chemotherapeutics, immune modulators, or anti-cancer agents and/or with other antibodies or fragments thereof. Antibodies of this type are exemplified by the novel antibodies hereof, including antibody 13A1, whose sequences are provided herein.

## Claims

### Claim 1

An isolated antibody molecule or fragment thereof which recognizes human and mouse transforming growth factor beta 1 (TGF-β1) and does not react with TGF-β2, and does not react with TGF-β3, wherein the antibody or fragment neutralizes activity of TGF-β1, and is an antibody or fragment comprising a heavy chain variable region comprising CDR domain sequences CDR1 GYTFTNYW (SEQ ID NO: 11), CDR2 IYPGNSDT (SEQ ID NO: 12) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5) or comprising CDR domain sequences CDR1 GYTFTNYWMH (SEQ ID NO: 3), CDR2 TIYPGNSDTN (SEQ ID NO: 4) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5), and a light chain variable region comprising CDR domain sequences CDR1 ESVDNYGISF (SEQ ID NO: 6), CDR2 YAAS (SEQ ID NO: 7) and CDR3 QQSKEVPRT (SEQ ID NO: 8).

### Claim 2 (depends on 1)

The isolated antibody of claim 1 which is antibody 13A1.

### Claim 3 (depends on 1)

The isolated antibody or fragment of claim 1 which is an antibody or antibody fragment comprising a heavy chain variable region comprising CDR domain sequences CDR1 GYTFTNYW (SEQ ID NO: 11), CDR2 IYPGNSDT (SEQ ID NO: 12) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5) and a light chain variable region comprising CDR domain sequences CDR1 ESVDNYGISF (SEQ ID NO: 6), CDR2 YAAS (SEQ ID NO: 7) and CDR3 QQSKEVPRT (SEQ ID NO: 8).

### Claim 4 (depends on 1)

The isolated antibody or fragment of claim 1 which is an antibody or antibody fragment comprising a heavy chain variable region comprising CDR domain sequences CDR1 GYTFTNYWMH (SEQ ID NO: 3), CDR2 TIYPGNSDTN (SEQ ID NO: 4) and CDR3 EDSRSLYYNGWDYFDY (SEQ ID NO: 5) and a light chain variable region comprising CDR domain sequences CDR1 ESVDNYGISF (SEQ ID NO: 6), CDR2 YAAS (SEQ ID NO: 7) and CDR3 QQSKEVPRT (SEQ ID NO: 8).

### Claim 5 (depends on 1)

The isolated antibody or fragment of claim 1 which is an antibody or antibody fragment comprising a heavy chain variable region amino acid sequence selected from the amino acid sequence SEQ ID NO: 1, or variants thereof having at least 90% amino acid identity to SEQ ID NO:1.

### Claim 6 (depends on 1, 5)

The isolated antibody of claim 1 or 5 comprising a light chain variable region comprising an amino acid sequence selected from the amino acid sequence as set out in SEQ ID NO: 2, or variants thereof having at least 90% amino acid identity to SEQ ID NO:2.

### Claim 7 (depends on 1)

The isolated antibody or fragment of claim 1 which is an antibody or fragment thereof wherein said isolated antibody is the form of an antibody F(ab′)2, scFv fragment, minibody, diabody, triabody or tetrabody.

### Claim 8 (depends on 1)

The isolated antibody or fragment of claim 1 further comprising a detectable or functional label.

### Claim 9 (depends on 8)

The isolated antibody of claim 8, wherein said detectable or functional label is a covalently attached drug.

### Claim 10 (depends on 8)

The isolated antibody of claim 8, wherein said label is a radiolabel.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising an antibody or fragment as defined in claim 1 and a pharmaceutically acceptable vehicle, carrier or diluent.

### Claim 12 (depends on 1)

An immunological composition comprising an antibody or fragment as defined in claim 1 and a pharmaceutically acceptable vehicle, carrier or diluent.

### Claim 13 (depends on 11, 12)

A kit comprising a pharmaceutical dosage form of the pharmaceutical composition of claim 11 or the immunological composition of claim 12, and a separate pharmaceutical dosage form comprising one or more additional anti-cancer agent, wherein the one or more additional anti-cancer agent is selected from the group consisting of cancer or tumor antigen(s), chemotherapeutic agents, and radioimmunotherapeutic agents.

### Claim 14 (depends on 12)

The immunological composition of claim 12 further comprising an adjuvant or one or more antigen, immunoregulatory antibody, or small molecule inhibitor to an immune modulator.

### Claim 15 (depends on 12)

The immunological composition of claim 12 further comprising an adjuvant and one or more antigen, an immunoregulatory antibody, or small molecule inhibitor to an immune modulator.

### Claim 16 (depends on 1)

A kit comprising an antibody or fragment of claim 1, optionally with reagents and/or instructions for use.

### Claim 17 (depends on 1)

A method for enhancing an immune response to a vaccine or antigen or an immunomodulatory agent in a mammal which comprises administering to said mammal an effective amount of an antibody or fragment as defined in claim 1.

### Claim 18 (depends on 1)

A method for decreasing regulatory T-cells (Treg) which comprises contacting T-cells with an effective amount of an antibody or fragment as defined in claim 1.

### Claim 19 (depends on 1)

A method for blocking Treg mediated immune suppression in a mammal which comprises administering to said mammal an effective amount of an antibody or fragment as defined in claim 1.

### Claim 20 (depends on 1)

A method for detecting the presence and/or amount of TGF-β1 comprising:
(A) contacting a biological sample from a mammal with the antibody or fragment of claim 1 under conditions that allow binding of said TGF-β1 to said antibody to occur; and
(B) detecting whether binding has occurred between said TGF-β1 from said sample and the antibody, or determining the amount of binding that has occurred between said TGF-β1 from said sample and the antibody.