# US 11,078,291 B2 · BCMA antibodies and use of same to treat cancer and immunological disorders

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- Number: US 11,078,291 B2
- Document ID: US11078291B2
- Status: Granted
- Kind: B2
- Application number: 16/411,867
- Filed: 2019-05-14
- Published: 2020-01-02
- Granted: 2021-08-03
- Earliest claimed: 2016-02-17
- Assignees: Seagen Inc.
- Applicants: Seagen Inc.
- Inventors: Django Sussman; Maureen Ryan; Lori Westendorf; Michael Feldhaus
- Web page: https://patentgrep.com/patent/US11078291B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 38/05: Dipeptides
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61P 35/00: Antineoplastic agents
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/41: Glycosylation, sialylation, or fucosylation
- C07K 2317/522: CH1 domain
- C07K 2317/524: CH2 domain
- C07K 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides humanized antibodies that specifically bind to BCMA. The antibodies are useful for treatment and diagnoses of various cancers and immune disorders as well as detecting BCMA.

## Claims

### Claim 1

An isolated antibody or a binding fragment thereof that binds to human B-cell maturation antigen (BCMA), wherein the antibody or binding fragment comprises a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92.

### Claim 2 (depends on 1)

The isolated antibody or binding fragment of claim 1, wherein the antibody is a monoclonal antibody.

### Claim 3 (depends on 1)

The isolated antibody or binding fragment of claim 1, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.

### Claim 4 (depends on 3)

The isolated antibody or binding fragment of claim 3, wherein the heavy chain constant region is a mutant form of a natural human constant region and has reduced binding to an Fcγ receptor relative to the natural human constant region.

### Claim 5 (depends on 3)

The isolated antibody or binding fragment of claim 3, wherein the heavy chain constant region is of immunoglobulin G1 (IgG1) isotype.

### Claim 6 (depends on 3)

The isolated antibody or binding fragment of claim 3, wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:5 and the light chain constant region comprises the amino acid sequence of SEQ ID NO:3.

### Claim 7 (depends on 3)

The isolated antibody or binding fragment of claim 3, wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:7 (S293C) and the light chain constant region comprises the amino acid sequence of SEQ ID NO:3.

### Claim 8 (depends on 3)

The isolated antibody or binding fragment of claim 3, which is non-fucosylated.

### Claim 9 (depends on 1)

The isolated antibody or binding fragment of claim 1, which is an antibody binding fragment.

### Claim 10 (depends on 9)

The isolated antibody or binding fragment of claim 9, wherein the antibody binding fragment is selected from the group consisting of a Fab, a Fab′, and a F(ab′)2.

### Claim 11 (depends on 1)

The isolated antibody or binding fragment of claim 1, which is a humanized antibody.

### Claim 12 (depends on 1)

The isolated antibody or binding fragment of claim 1, which is a naked antibody or binding fragment.

### Claim 13 (depends on 1)

The isolated antibody or binding fragment of claim 1, which is conjugated to a cytotoxic or cytostatic agent.

### Claim 14 (depends on 13)

The isolated antibody or binding fragment of claim 13, which is conjugated to a cytotoxic agent.

### Claim 15 (depends on 14)

The isolated antibody or binding fragment of claim 14, wherein the cytotoxic agent is conjugated to the antibody or the binding fragment via an enzyme-cleavable linker.

### Claim 16 (depends on 14)

The isolated antibody or binding fragment of claim 14, wherein the cytotoxic agent is a DNA minor groove binder.

### Claim 17 (depends on 16)

The isolated antibody or binding fragment of claim 16, wherein the cytotoxic agent has the formula:

### Claim 18 (depends on 14)

The isolated antibody or binding fragment of claim 14, wherein the cytotoxic agent is monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

### Claim 19

A bispecific antibody or binding fragment thereof that binds to human B-cell maturation antigen (BCMA), wherein the bispecific antibody or binding fragment comprises a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92.

### Claim 20

An isolated antibody or a binding fragment thereof that binds to human B-cell maturation antigen (BCMA), wherein the antibody or binding fragment comprises a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19.

### Claim 21 (depends on 20)

The isolated antibody or binding fragment of claim 20, wherein the antibody is a monoclonal antibody.

### Claim 22 (depends on 20)

The isolated antibody or binding fragment of claim 20, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.

### Claim 23 (depends on 22)

The isolated antibody or binding fragment of claim 22, wherein the heavy chain constant region is a mutant form of a natural human constant region and has reduced binding to an Fcγ receptor relative to the natural human constant region.

### Claim 24 (depends on 22)

The isolated antibody or binding fragment of claim 22, wherein the heavy chain constant region is of immunoglobulin G1 (IgG1) isotype.

### Claim 25 (depends on 22)

The isolated antibody or binding fragment of claim 22, wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:5 and the light chain constant region comprises the amino acid sequence of SEQ ID NO:3.

### Claim 26 (depends on 22)

The isolated antibody or binding fragment of claim 22, wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:7 (S293C) and the light chain constant region comprises the amino acid sequence of SEQ ID NO:3.

### Claim 27 (depends on 22)

The isolated antibody or binding fragment of claim 22, which is non-fucosylated.

### Claim 28 (depends on 20)

The isolated antibody or binding fragment of claim 20, which is an antibody binding fragment.

### Claim 29 (depends on 20)

The isolated antibody or binding fragment of claim 20, which is a naked antibody or binding fragment.

### Claim 30 (depends on 20)

The isolated antibody or binding fragment of claim 20, wherein the antibody or binding fragment is conjugated to a cytotoxic or cytostatic agent.

### Claim 31 (depends on 20)

The isolated antibody or binding fragment of claim 20, which is conjugated to a cytotoxic agent.

### Claim 32 (depends on 31)

The isolated antibody or binding fragment of claim 31, wherein the cytotoxic agent is conjugated to the antibody or the binding fragment via an enzyme-cleavable linker.

### Claim 33 (depends on 31)

The isolated antibody or binding fragment of claim 31, wherein the cytotoxic agent is a DNA minor groove binder.

### Claim 34 (depends on 33)

The isolated antibody or binding fragment of claim 33, wherein the cytotoxic agent has the formula:

### Claim 35 (depends on 31)

The antibody or binding fragment of claim 31, wherein the cytotoxic agent is monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

### Claim 36

A bispecific antibody or binding fragment thereof, wherein the bispecific antibody or binding fragment comprises a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19 that bind to human B-cell maturation antigen (BCMA).

### Claim 37

An isolated, monoclonal, immunoglobulin G1 (IgG1) antibody that binds to human B-cell maturation antigen (BCMA), wherein the antibody comprises a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92.

### Claim 38 (depends on 37)

A pharmaceutical composition comprising the antibody of claim 37 and a pharmaceutically acceptable carrier.

### Claim 39

An isolated, monoclonal, immunoglobulin G1 (IgG1) antibody that binds to human B-cell maturation antigen (BCMA), wherein the antibody comprises a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19.

### Claim 40 (depends on 39)

A pharmaceutical composition comprising the antibody of claim 39 and a pharmaceutically acceptable carrier.

### Claim 41

An isolated, monoclonal, non-fucosylated antibody that binds to human B-cell maturation antigen (BCMA), wherein the antibody comprises a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92.

### Claim 42 (depends on 41)

The antibody of claim 41, which is an immunoglobulin G1 (IgG1) antibody.

### Claim 43 (depends on 41)

The antibody of claim 41, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region, and wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:5 and the light chain constant region comprises the amino acid sequence of SEQ ID NO:3.

### Claim 44 (depends on 41)

A pharmaceutical composition comprising the antibody of claim 41 and a pharmaceutically acceptable carrier.

### Claim 45

An isolated, monoclonal, non-fucosylated antibody that binds to human B-cell maturation antigen (BCMA), wherein the antibody comprises a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19.

### Claim 46 (depends on 45)

The antibody of claim 45, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region, and wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:5 and the light chain constant region comprises the amino acid sequence of SEQ ID NO:3.

### Claim 47 (depends on 46)

A pharmaceutical composition comprising the antibody of claim 46 and a pharmaceutically acceptable carrier.

### Claim 48 (depends on 45)

A pharmaceutical composition comprising the antibody of claim 45 and a pharmaceutically acceptable carrier.

### Claim 49

A composition comprising a plurality of antibodies or binding fragments thereof that bind to human B-cell maturation antigen (BCMA), wherein
(a) the antibodies or binding fragments comprise a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92; and
(b) less than 10% of the antibodies in the composition are fucosylated.

### Claim 50 (depends on 49)

The composition of claim 49, wherein less than 5% of the antibodies or binding fragments in the composition are fucosylated.

### Claim 51 (depends on 49)

The composition of claim 49, wherein less than 3% of the antibodies or binding fragments in the composition are fucosylated.

### Claim 52 (depends on 49)

The composition of claim 49, wherein less than 2% of the antibodies or binding fragments in the composition are fucosylated.

### Claim 53

A composition comprising a plurality of antibodies or binding fragments thereof that bind to human B-cell maturation antigen (BCMA), wherein
(a) the antibodies or binding fragments comprise a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19; and
(b) less than 10% of the antibodies in the composition are fucosylated.

### Claim 54 (depends on 53)

The composition of claim 53, wherein less than 5% of the antibodies or binding fragments in the composition are fucosylated.

### Claim 55 (depends on 53)

The composition of claim 53, wherein less than 3% of the antibodies or binding fragments in the composition are fucosylated.

### Claim 56 (depends on 53)

The composition of claim 53, wherein less than 2% of the antibodies or binding fragments in the composition are fucosylated.

### Claim 57

A composition comprising a plurality of immunoglobulin G1 (IgG1) antibodies that bind to human B-cell maturation antigen (BCMA), wherein
(a) the antibodies comprise a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92; and
(b) less than 5% of the antibodies in the composition are fucosylated.

### Claim 58

A composition comprising a plurality of immunoglobulin G1 (IgG1) antibodies that bind to human B-cell maturation antigen (BCMA), wherein
(a) the antibodies comprise
(i) a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19; and
(ii) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO:5, and a light chain constant region comprising the amino acid sequence of SEQ ID NO:3; and
(b) less than 5% of the antibodies in the composition are fucosylated.

### Claim 59

A composition comprising a plurality of monoclonal antibodies with reduced fucosylation that bind to human B-cell maturation antigen (BCMA), wherein
(a) the antibodies in the composition are produced by a process comprising culturing a host cell that express the antibodies in a culture medium suitable to produce antibodies with reduced fucosylation, and isolating the antibodies with reduced fucosylation from the culture medium; and
(b) the antibodies in the composition comprise a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92.

### Claim 60 (depends on 59)

The composition of claim 59, wherein the culture medium contains 2-fluorofucose in an amount sufficient to reduce fucosylation of the antibodies.

### Claim 61 (depends on 59)

The composition of claim 59, wherein the culture medium is fucose free.

### Claim 62

A composition comprising a plurality of monoclonal antibodies with reduced fucosylation that bind to human B-cell maturation antigen (BCMA), wherein
(a) the antibodies in the composition are produced by a process comprising culturing a host cell that expresses the antibodies in a culture medium suitable to produce antibodies with reduced fucosylation, and isolating the antibodies with reduced fucosylation from the culture medium; and
(b) the antibodies in the composition comprise a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19.

### Claim 63 (depends on 62)

The composition of claim 62, wherein the culture medium contains 2-fluorofucose in an amount sufficient to reduce fucosylation of the antibodies.

### Claim 64 (depends on 62)

The composition of claim 62, wherein the culture medium is fucose free.

### Claim 65

A composition comprising a plurality of monoclonal, immunoglobulin G1 (IgG1) antibodies that bind to human B-cell maturation antigen (BCMA), wherein:
(a) the antibodies in composition are produced by process comprising culturing a host cell that expresses the antibodies in a culture medium containing 2-fluorofucose, and isolating the antibodies from the culture medium;
(b) antibodies in the composition comprise a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs:90, 91 and 92; and
(c) less than 5% of the antibodies in the composition are fucosylated.

### Claim 66

A composition comprising a plurality of monoclonal, immunoglobulin G1 (IgG1) antibodies that bind to human B-cell maturation antigen (BCMA), wherein:
(a) the antibodies in composition are produced by process comprising culturing a host cell that expresses the antibodies in a culture medium containing 2-fluorofucose, and isolating the antibodies from the culture medium;
(b) the antibodies in the composition comprise a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:19; and
(c) less than 5% of the antibodies in the composition are fucosylated.