# US 11,439,637 B2 · Antiproliferative compounds and bispecific antibody against BCMA and CD3 for combined use

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- Number: US 11,439,637 B2
- Document ID: US11439637B2
- Status: Granted
- Kind: B2
- Application number: 16/419,971
- Filed: 2019-05-22
- Published: 2019-12-19
- Granted: 2022-09-13
- Earliest claimed: 2018-05-23
- Assignees: Celgene Corporation
- Applicants: Celgene Corporation
- Inventors: Daniel W. Pierce; Lilly L. Wong
- Web page: https://patentgrep.com/patent/US11439637B2

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61P 35/00: Antineoplastic agents
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/421: {Immunoglobulin superfamily}
- A61K 40/4215: {Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30}
- A61P 35/02: specific for leukemia
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- C07K 2317/31: multispecific
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Provided herein is are methods of using 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof and a bispecific antibody specifically binding to human B cell maturation antigen (BCMA) and to human CD3ε (CD3) provided herein, in treating, preventing or managing multiple myeloma.

## Claims

### Claim 1

A method of treating multiple myeloma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula 1
or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof;
in combination with a bispecific antibody comprising a first binding part specifically binding to human B cell maturation antigen (BCMA) and a second binding part specifically binding to human CD3ε (CD3), characterized in that said first binding part comprises a VH region comprising a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17 and a VL region comprising a CDR3L region of SEQ ID NO:20 and a CDR1L and CDR2L region combination selected from the group of
i) CDR1L region of SEQ ID NO:23 and CDR2L region of SEQ ID NO:24,
ii) CDR1L region of SEQ ID NO:25 and CDR2L region of SEQ ID NO:26, or
iii) CDR1L region of SEQ ID NO:27 and CDR2L region of SEQ ID NO:28.

### Claim 2

A method of treating multiple myeloma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula 2
or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof;
in combination with a bispecific antibody comprising a first binding part specifically binding to human B cell maturation antigen (BCMA) and a second binding part specifically binding to human CD3ε (CD3), characterized in that said first binding part comprises a VH region comprising a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17 and a VL region comprising a CDR3L region of SEQ ID NO:20 and a CDR1L and CDR2L region combination selected from the group of
i) CDR1L region of SEQ ID NO:23 and CDR2L region of SEQ ID NO:24,
ii) CDR1L region of SEQ ID NO:25 and CDR2L region of SEQ ID NO:26, or
iii) CDR1L region of SEQ ID NO:27 and CDR2L region of SEQ ID NO:28.

### Claim 3 (depends on 1)

The method of claim 1, wherein the multiple myeloma is relapsed, refractory or resistant.

### Claim 4 (depends on 3)

The method of claim 3, wherein the multiple myeloma is refractory or resistant to lenalidomide.

### Claim 5 (depends on 3)

The method of claim 3, wherein the multiple myeloma is refractory or resistant to pomalidomide.

### Claim 6 (depends on 1)

The method of claim 1, wherein the multiple myeloma is newly diagnosed multiple myeloma.

### Claim 7 (depends on 1)

The method of claim 1, wherein the multiple myeloma is plasma cell leukemia.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is administered prior to the bispecific antibody.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is administered concurrently with the bispecific antibody.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is administered subsequent to the bispecific antibody.

### Claim 11 (depends on 1)

The method of claim 1, additionally comprising administering an additional active agent.

### Claim 12 (depends on 2)

The method of claim 2, wherein the multiple myeloma is relapsed, refractory or resistant.

### Claim 13 (depends on 12)

The method of claim 12, wherein the multiple myeloma is refractory or resistant to lenalidomide.

### Claim 14 (depends on 12)

The method of claim 12, wherein the multiple myeloma is refractory or resistant to pomalidomide.

### Claim 15 (depends on 2)

The method of claim 2, wherein the multiple myeloma is newly diagnosed multiple myeloma.

### Claim 16 (depends on 2)

The method of claim 2, wherein the multiple myeloma is plasma cell leukemia.

### Claim 17 (depends on 2)

The method of claim 2, wherein the compound is administered prior to the bispecific antibody.

### Claim 18 (depends on 2)

The method of claim 2, wherein the compound is administered concurrently with the bispecific antibody.

### Claim 19 (depends on 2)

The method of claim 2, wherein the compound is administered subsequent to the bispecific antibody.

### Claim 20 (depends on 2)

The method of claim 2, additionally comprising administering an additional active agent.