# US 2019/0169306 A1 · Cancer and b-cell related disease therapy

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- Number: US 2019/0169306 A1
- Document ID: US20190169306A1
- Status: Published application
- Kind: A1
- Application number: 16/321,367
- Filed: 2017-07-28
- Published: 2019-06-06
- Earliest claimed: 2016-07-29
- Assignees: University of Southampton
- Applicants: University of Southampton
- Inventors: Martin John Glennie; Aymen Al-Shamkhani; Mark Steven Cragg; Sean Hua Lim
- Web page: https://patentgrep.com/patent/US20190169306A1

## CPC

- C07K 16/2887: {against CD20}
- A61P 35/00: Antineoplastic agents
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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)
- 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

The disclosure relates to a method of treatment or prevention of B-cell related disease in a subject comprising the administration of a binding molecule capable of binding to a B-cell and promoting killing of the B-cell; and an immunostimulatory agent arranged to stimulate effector lymphocytes, such as NK and/or T cells. Additionally, an anti-CD27 binding agent for use in a combination therapy with an anti-CD20 binding agent for the treatment or prevention of B-cell related disease in a subject. The disclosure also relates to a method of treatment or prevention of cancer in a subject comprising the administration of a cancer-cell-depleting binding agent capable of binding to the cancer cell and promoting killing of the cancer cell; and an immunostimulatory agent arranged to stimulate NK and/or T-cell activation. Additionally, an anti-CD27 binding agent for use in a combination therapy with a cancer-cell-depleting binding agent for the treatment or prevention of cancer in a subject.

## Claims

### Claim 1

A method of treatment or prevention of B-cell related disease in a subject comprising the administration of a binding molecule capable of binding to a B-cell and promoting killing of the B-cell; and an immunostimulatory agent arranged to stimulate effector lymphocytes, such as NK and/or T cells.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the B-cell related disease is cancer.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the B-cell related disease is B-cell lymphoma.

### Claim 4

The method according to any preceding claim, wherein the binding molecule capable of binding to a B-cell is an anti-CD20 binding molecule.

### Claim 5

The method according to any preceding claim, wherein the B-cell binding molecule comprises an antibody, antibody fragment or antibody mimetic.

### Claim 6

The method according to any preceding claim, wherein the B-cell binding molecule comprises:
rituximab, or a variant thereof;
at least a variable domain of rituximab;
at least the CDRs of rituximab;
a B-cell binding molecule that competes for binding with rituximab; or
a B-cell binding molecule that binds the same epitope as rituximab.

### Claim 7 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
obinutuzumab, or a variant therof;
at least a variable domain of obinutuzumab;
at least the CDRs of obinutuzumab;
a B-cell binding molecule that competes for binding with obinutuzumab; or
a B-cell binding molecule that binds the same epitope as obinutuzumab.

### Claim 8 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
ocrelizumab, or a variant therof;
at least a variable domain of ocrelizumab;
at least the CDRs of ocrelizumab;
a B-cell binding molecule that competes for binding with ocrelizumab; or
a B-cell binding molecule that binds the same epitope as ocrelizumab.

### Claim 9 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
ofatumumab, or a variant therof;
at least a variable domain of ofatumumab;
at least the CDRs of ofatumumab;
a B-cell binding molecule that competes for binding with ofatumumab; or
a B-cell binding molecule that binds the same epitope as ofatumumab.

### Claim 10 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
veltuzumab, or a variant therof;
at least a variable domain of veltuzumab;
at least the CDRs of veltuzumab;
a B-cell binding molecule that competes for binding with veltuzumab; or
a B-cell binding molecule that binds the same epitope as veltuzumab.

### Claim 11 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
TRU-015, or a variant therof;
at least a variable domain of TRU-015;
at least the CDRs of TRU-015;
a B-cell binding molecule that competes for binding with TRU-015; or
a B-cell binding molecule that binds the same epitope as TRU-015.

### Claim 12 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
EMAB-6, or a variant therof;
at least a variable domain of EMAB-6;
at least the CDRs of EMAB-6;
a B-cell binding molecule that competes for binding with EMAB-6; or
a B-cell binding molecule that binds the same epitope as EMAB-6.

### Claim 13 (depends on 1, 2, 3, 4, 5)

The method according to any of claims 1 to 5, wherein the B-cell binding molecule comprises:
RhumAb v114, or a variant therof;
at least a variable domain of RhumAb v114;
at least the CDRs of RhumAb v114;
a B-cell binding molecule that competes for binding with RhumAb v114; or
a B-cell binding molecule that binds the same epitope as RhumAb v114.

### Claim 14

The method according to any preceding claim, wherein the B-cell binding molecule is capable of ADCC or ADCP (Antibody-Dependent Cell-mediated Cytotoxicity/Phagocytosis) killing of the B-cell.

### Claim 15

The method according to any preceding claim, wherein the B-cell binding molecule comprises a fully human monoclonal antibody of the IgG1 isotype.

### Claim 16

The method according to any preceding claim, wherein the immunostimulatory agent arranged to stimulate NK cells, and optionally T cells, comprises or consists of a binding molecule arranged to bind to the NK and optionally T cells.

### Claim 17

The method according to any preceding claim, wherein the NK- and optionally T-cell binding molecule comprises an anti-CD27 binding molecule.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The method according to any of claims 1 to 16, wherein the NK cell binding molecule comprises any one of anti-CD27 binding molecule; anti-CD137 binding molecule, anti-NKp46 binding molecule, anti-NKp30 binding molecule, anti-NKG2D binding molecule, anti-CD16 binding molecule, or anti-OX40 binding molecule.

### Claim 19

The method according to any preceding claim, wherein the NK cell binding molecule is an agonist of the NK cell or NK cell activity; optionally wherein the NK cell binding molecule is also an agonist of the T-cell or T-cell activity.

### Claim 20

The method according to any preceding claim, wherein the NK cell binding molecule comprises an antibody, antibody fragment or antibody mimetic.

### Claim 21

The method according to any preceding claim, wherein the NK cell binding molecule comprises:
varlilumab, or a variant therof;
at least a variable domain of varlilumab;
at least the CDRs of varlilumab;
a B-cell binding molecule that competes for binding with varlilumab; or
a B-cell binding molecule that binds the same epitope as varlilumab.

### Claim 22

The method according to any preceding claim, wherein the NK- and optionally T-cell binding molecule is fully human monoclonal antibody of the IgG2 or IgG4 isotype.

### Claim 23

The method according to any preceding claim, wherein the NK cell binding molecule does not bind or stimulate T-cells.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The method according to any of claims 1 to 22, wherein the NK cell binding molecule also binds T-cells.

### Claim 25

The method according to any preceding claim, wherein the administration of the B-cell binding molecule and the immunostimulatory agent is sequential.

### Claim 26

The method according to any preceding claim, wherein the B-cell binding molecule and the immunostimulatory agent are administered between about 4 hours and about 48 hours apart.

### Claim 27

The method according to any preceding claim, wherein the B-cell binding molecule and the immunostimulatory agent are administered between about 12 hours and about 24 hours apart.

### Claim 28

The method according to any preceding claim, wherein the B-cell binding molecule and/or the immunostimulatory agent are administered in combination with another therapeutically active agent.

### Claim 29

A method of treatment or prevention of B-cell related disease in a subject comprising the administration of an anti-CD20 binding molecule and an anti-CD27 binding molecule to the subject.

### Claim 30 (depends on 29)

The method according to claim 29, wherein the anti-CD20 binding molecule comprises rituximab, or similar, and the anti-CD27 binding molecule comprises varlilumab, or similar.

### Claim 31

A method of treatment or prevention of B-cell related disease in a subject comprising the administration of rituximab and varlilumab to the subject.

### Claim 32

An anti-CD27 binding agent for use in a combination therapy with an anti-CD20 binding agent for the treatment or prevention of B-cell related disease in a subject.

### Claim 33

A composition comprising a B-cell binding molecule, such as an anti-CD20 binding agent and an immunostimulatory agent, such as an anti-CD27 binding agent.

### Claim 34 (depends on 33)

The composition according to claim 33, wherein the B-cell binding molecule is an anti-CD20 binding agent.

### Claim 35 (depends on 33, 34)

The composition according to claim 33 or claim 34, wherein the immunostimulatory agent is an anti-CD27 binding agent.

### Claim 36

A kit for treatment or prevention of B-cell related disease in a subject, the kit comprising a B-cell binding molecule, such as an anti-CD20 binding agent and an immunostimulatory agent, such as an anti-CD27 binding agent.

### Claim 37 (depends on 36)

The kit according to claim 36, wherein the B-cell binding molecule is an anti-CD20 binding agent.

### Claim 38 (depends on 36, 37)

The composition according to claim 36 or claim 37, wherein the immunostimulatory agent is an anti-CD27 binding agent.

### Claim 39 (depends on 33, 34, 35)

A composition according to any of claims 33 to 35, for use as a medicament.

### Claim 40 (depends on 33, 34, 35, 36, 37)

A composition according to any of claims 33 to 35, or kit according to any of claims 36 to 37, for use in the treatment or prevention of B-cell related disease in a subject.

### Claim 41

A method of treatment or prevention of cancer in a subject comprising the administration of a cancer-cell-depleting binding agent capable of binding to the cancer cell and promoting killing of the cancer cell; and an immunostimulatory agent arranged to stimulate NK and/or T-cell activation.

### Claim 42

An anti-CD27 binding agent for use in a combination therapy with a cancer-cell-depleting binding agent for the treatment or prevention of cancer in a subject.

### Claim 43

A composition for treatment or prevention of cancer in a subject, the composition comprising a cancer-cell-depleting binding agent and an immunostimulatory agent, such as an anti-CD27 binding agent.

### Claim 44 (depends on 43)

The composition according to claim 43, wherein the immunostimulatory agent is an anti-CD27 binding agent.

### Claim 45

A kit for treatment or prevention of cancer in a subject, the kit comprising a cancer-cell-depleting binding agent and an immunostimulatory agent, such as an anti-CD27 binding agent.

### Claim 46 (depends on 45)

The kit according to claim 45, wherein the immunostimulatory agent is an anti-CD27 binding agent.

### Claim 47 (depends on 41, 42, 43, 44, 45, 46)

The method according to claim 41, the anti-CD27 binding agent for use in a combination therapy according to claim 42, the composition according to claim claim 43 or 44, or the kit according to claim 45 or 46, wherein the cancer-cell-depleting binding agent comprises an anti-gp75 binding agent or anti-CD38 binding agent.

### Claim 48 (depends on 43, 44, 45, 46, 47)

A composition according to any of claims 43 to 44 and 47, or kit according to any of claims 45 to 47, for use in the treatment or prevention of cancer.

### Claim 49 (depends on 41, 42, 43, 44, 45, 46, 47, 48)

The method of treatment according to claim 41 or 47, the anti-CD27 binding agent for use according to claim 42 or 47, the kit according to claim 43, 44 or 47, or the composition according to claim 45, 46 or 47, or the composition for use according to claim 48, wherein the cancer is a solid tumour cancer.