# US 2020/0399371 A1 · Use of bispecific antigen-binding molecules that bind muc16 and cd3 in combination with 4-1bb co-stimulation

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- Number: US 2020/0399371 A1
- Document ID: US20200399371A1
- Status: Published application
- Kind: A1
- Application number: 16/906,634
- Filed: 2020-06-19
- Published: 2020-12-24
- Earliest claimed: 2019-06-21
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Jessica R. Kirshner; Alison Crawford; Danica Chiu
- Web page: https://patentgrep.com/patent/US20200399371A1

## CPC

- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- A61B 6/037: {Emission tomography}
- A61B 6/481: {involving the use of contrast agents}
- A61K 51/1042: {against T-cell receptor (TcR)-CD3 complex}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- C07K 16/3092: {against tumour-associated mucins}
- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/31: multispecific
- C07K 2317/75: Agonist effect on antigen
- 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)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- 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

Provided herein are method of treating cancer using bispecific antigen-binding molecules that bind to Mucin 16 (MUC16) and CD3. According to certain embodiments, the antibodies useful herein bind human MUC16 with high affinity and bind CD3 to induce human T cell proliferation. According to certain embodiments, bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human MUC16 are particularly useful herein. In certain embodiments, the bispecific antigen-binding molecules in combination with an anti-4-1BB agonist are capable of inhibiting the growth of tumors expressing MUC16, for example, ovarian tumors. The bispecific antigen-binding molecules in combination with an anti-4-1BB agonist are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and/or therapeutically beneficial, for example, in the treatment of various cancers.

## Claims

### Claim 1

A method of treating a cancer or inhibiting the growth of a tumor comprising administering to a subject in need thereof a therapeutically effective amount each of (a) an anti-CD3/anti-MUC16 bispecific antigen-binding molecule; and (b) an anti-4-1 BB agonist.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, corneal cancer, pancreatic cancer, endometrial cancer, fallopian tube cancer, mesothelioma, non-small cell lung cancer, intrahepatic cholangiocarcinoma-mass forming type, uterine cancer, cervical cancer, gastric cancer, or colorectal carcinoma.

### Claim 3 (depends on 2)

The method of claim 2, wherein the cancer is ovarian cancer.

### Claim 4 (depends on 2)

The method of claim 2, wherein the cancer is breast cancer.

### Claim 5 (depends on 1)

The method of claim 1, wherein the anti-CD3/anti-MUC16 bispecific antibody and the anti-4-1BB agonist are administered separately.

### Claim 6 (depends on 1)

The method of claim 1, wherein the anti-CD3/anti-MUC16 bispecific antibody and the anti-4-1BB agonist are co-administered.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anti-CD3/anti-MUC16 bispecific antibody is administered prior to, concurrent with or after the anti-4-1 BB agonist.

### Claim 8 (depends on 7)

The method of claim 7, wherein the anti-CD3/anti-MUC16 bispecific antibody is administered prior to the anti-4-1 BB agonist.

### Claim 9 (depends on 7)

The method of claim 7, wherein the anti-CD3/anti-MUC16 bispecific antibody is administered the same day as the anti-4-1BB agonist.

### Claim 10 (depends on 1)

The method of claim 1, wherein the anti-CD3/anti-MUC16 bispecific antibody is administered in combination with the anti-4-1BB agonist.

### Claim 11 (depends on 1)

The method of claim 1, wherein the anti-4-1BB agonist is selected from a small molecule or an antibody.

### Claim 12 (depends on 11)

The method of claim 11, wherein the anti-4-1 BB agonist is an antibody selected from the group consisting of urelumab and utomilumab.

### Claim 13 (depends on 1)

The method of claim 1, wherein the bispecific antigen-binding molecule comprises a first antigen-binding domain, and the first antigen-binding domain specifically binds human CD3 and comprises a heavy chain variable region (HCVR-1) amino acid sequence of SEQ ID NO: 2.

### Claim 14 (depends on 1)

The method of claim 1, wherein the bispecific antigen-binding molecule comprises a second antigen-binding domain, and the second antigen-binding domain specifically binds human MUC16 and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1.

### Claim 15 (depends on 1)

The method of claim 1, wherein the bispecific antigen-binding molecule comprises a first antigen-binding domain that specifically binds CD3 and comprises a HCVR-1 amino acid sequence of SEQ ID NO: 2 and a second antigen-binding domain that specifically binds MUC16 and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1.

### Claim 16 (depends on 13)

The method of claim 13, wherein the bispecific antigen-binding molecule comprises a common light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 3.

### Claim 17 (depends on 1)

The method of claim 1, wherein the tumor volume is decreased relative to tumor volume in a subject administered the anti-CD3/anti-MUC16 bispecific antigen-binding molecule in the absence of an anti-4-1BB agonist.

### Claim 18 (depends on 1)

The method of claim 1, wherein tumor free survival time is increased in the subject relative to tumor free survival time in a subject administered the anti-CD3/anti-MUC16 bispecific antigen-binding molecule in the absence of an anti-4-1 BB agonist.

### Claim 19 (depends on 18)

The method of claim 18, wherein the increase in tumor free survival time occurs without weight loss in the subject.

### Claim 20 (depends on 1)

The method of claim 1, wherein subsequent exposure to tumor cells elicits a memory response in the subject treated with the anti-CD3/anti-MUC16 bispecific antigen-binding molecule in the presence of an anti-4-1 BB agonist.

### Claim 21

A pharmaceutical composition comprising:
(a) a bispecific antigen-binding molecule comprising: (i) first antigen-binding domain that specifically binds human CD3 and comprises a HCVR-1 amino acid sequence of SEQ ID NO: 2 and (ii) a second antigen-binding domain that specifically binds human MUC16 and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1;
(b) an anti-4-1BB agonist; and
(c) a pharmaceutically acceptable carrier or diluent.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21, wherein the bispecific antigen-binding molecule of part (a) comprises a common LCVR amino acid of SEQ ID NO: 3.

### Claim 23

A radiolabeled antibody conjugate comprising a bispecific antigen-binding molecule that binds MUC16 and CD3, a chelating moiety, and a positron emitter.

### Claim 24 (depends on 23)

The conjugate of claim 23, wherein the bispecific antigen-binding molecule thereof is covalently bonded to the chelating moiety, L, of formula (A):
-L-MZ (A)
wherein M is the positron emitter; and z, independently at each occurrence, is 0 or 1; and wherein at least one of z is 1.

### Claim 25 (depends on 23)

The conjugate of claim 23, wherein the chelating moiety comprises desferrioxamine.

### Claim 26 (depends on 23)

The conjugate of claim 23, wherein the positron emitter is 89Zr.

### Claim 27 (depends on 24)

The conjugate of claim 24, wherein -L-M is
and wherein the positron emitter Zr is 89Zr.

### Claim 28 (depends on 24)

The conjugate of claim 24, wherein the bispecific antigen-binding molecule is covalently bonded to one, two, or three moieties of Formula (A).

### Claim 29 (depends on 27)

The conjugate of claim 27, wherein the bispecific antigen-binding molecule comprises a first antigen-binding domain that specifically binds CD3 and comprises a HCVR-1 amino acid sequence of SEQ ID NO: 2 and a second antigen-binding domain that specifically binds MUC16 and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1.

### Claim 30 (depends on 23)

A method of imaging a tissue that expresses MUC16 comprising administering a radiolabeled bispecific antibody conjugate of claim 23 to the tissue; and visualizing MUC16 expression by positron emission tomography (PET) imaging.