# US 10,766,965 B2 · Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies

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- Number: US 10,766,965 B2
- Document ID: US10766965B2
- Status: Granted
- Kind: B2
- Application number: 15/160,476
- Filed: 2016-05-20
- Published: 2017-01-12
- Granted: 2020-09-08
- Earliest claimed: 2015-05-20
- Assignees: Janssen Biotech, Inc.; Tufts Medical Center, Inc.
- Applicants: Janssen Biotech, Inc.; Tufts Medical Center, Inc.
- Inventors: Chakra Chaulagain; Raymond Comenzo; Parul Doshi; Xun Ma; Amy Sasser
- Web page: https://patentgrep.com/patent/US10766965B2

## CPC

- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/664: Amides of phosphorus acids
- A61K 31/69: Boron compounds
- A61K 38/05: Dipeptides
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- 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
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C12Y 302/01035: Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
- A61K 2039/505: {comprising antibodies}
- 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 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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
- C12Y: ENZYMES

## Abstract

The present invention relates to methods of treatment of light chain amyloidosis and other CD38-positive hematological malignancies with anti-CD38 antibodies.

## Claims

### Claim 1

A method of treating a patient having relapsed or refractory light chain amyloidosis (AL), comprising administering to the patient in need thereof an anti-CD38 antibody which is an IgG1 isotype comprising a heavy chain variable region (VH) sequence of SEQ ID NO: 4 and a light chain variable region (VL) sequence of SEQ ID NO: 5 for a time sufficient to treat relapsed or refractory AL.

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient has been treated with a proteasome inhibitor, cyclophosphamide and/or a corticosteroid.

### Claim 3 (depends on 2)

The method of claim 2, wherein the proteasome inhibitor is bortezomib.

### Claim 4 (depends on 2)

The method of claim 2, wherein the corticosteroid is dexamethasone.

### Claim 5 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody is administered in combination with a second therapeutic agent.

### Claim 6 (depends on 2)

The method of claim 2, wherein the anti-CD38 antibody is administered in combination with a second therapeutic agent.

### Claim 7 (depends on 5)

The method of claim 5, wherein the second therapeutic agent is a proteasome inhibitor, cyclophosphamide or a corticosteroid.

### Claim 8 (depends on 7)

The method of claim 7, wherein the proteasome inhibitor is bortezomib or ixazomib.

### Claim 9 (depends on 7)

The method of claim 7, wherein the corticosteroid is dexamethasone.

### Claim 10 (depends on 5)

The method of claim 5, wherein the second therapeutic agent is bortezomib, ixazomib, carfilzomib, panobinostat, cyclophosphamide, melphalan, thalidomide, lenalidomide, pomalidomide, dexamethasone or interferon alpha.

### Claim 11 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody is administered in combination with a proteasome inhibitor, cyclophosphamide and a corticosteroid.

### Claim 12 (depends on 11)

The method of claim 11, wherein the proteasome inhibitor is bortezomib.

### Claim 13 (depends on 11)

The method of claim 11, wherein the proteasome inhibitor is ixazomib.

### Claim 14 (depends on 11)

The method of claim 11, wherein the corticosteroid is dexamethasone.

### Claim 15 (depends on 11)

The method of claim 11, wherein the proteasome inhibitor is bortezomib and the corticosteroid is dexamethasone.

### Claim 16 (depends on 11)

The method of claim 11, wherein the proteasome inhibitor is ixazomib and the corticosteroid is dexamethasone.

### Claim 17 (depends on 5)

The method of claim 5, wherein the anti-CD38 antibody and the second therapeutic agent are administered simultaneously, sequentially or separately.

### Claim 18 (depends on 11)

The method of claim 11, wherein the proteasome inhibitor, cyclophosphamide and the corticosteroid are administered simultaneously, sequentially or separately.

### Claim 19 (depends on 1)

The method of claim 1, wherein the patient is further treated with radiotherapy.

### Claim 20 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody does not mediate killing of CD34-positive hematopoietic progenitor cells by complement dependent cytotoxicity (CDC).

### Claim 21 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody induces killing of CD38 positive plasma cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or modulation of CD38 enzymatic activity.

### Claim 22 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody comprises a heavy chain comprising an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO: 12 and a light chain comprising an amino an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO: 13.

### Claim 23 (depends on 22)

The method of claim 22, wherein the anti-CD38 antibody comprises the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO: 13.

### Claim 24 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody is human.

### Claim 25 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody is administered intravenously.

### Claim 26 (depends on 1)

The method of claim 1, further comprising performing hematopoietic stem cell transplantation (HSCT) after administering the effective amount of anti-CD38 antibody to the patient having relapsed or refractory AL.

### Claim 27 (depends on 26)

The method of claim 26, wherein the HSCT is allogeneic, autologous or syngeneic.

### Claim 28 (depends on 26)

The method of claim 26, wherein the HSCT comprises transplantation of blood stem cells derived from bone marrow, blood or amniotic fluid.

### Claim 29 (depends on 26)

The method of claim 26, wherein the patient has completed chemotherapy and/or radiation therapy prior to HSCT.

### Claim 30 (depends on 1)

The method of claim 1, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising the anti-CD38 antibody and a hyaluronidase.

### Claim 31

A method of induction of selective killing of CD38+ hematological cancer cells and preservation of CD38+CD34+ hematopoietic stem cells in a patient with relapsed or refractory light chain amyloidosis (AL), comprising:
contacting CD38+ cells of the patient with an anti-CD38 antibody which is an IgG1 isotype comprising a heavy chain variable region (VH) sequence of SEQ ID NO: 4 and a light chain variable region (VL) sequence of SEQ ID NO: 5;
wherein CD38+ hematological cancer cells within the patient are killed and CD38+CD34+ hematopoietic stem cells within the patient are preserved.

### Claim 32

A method of performing a hematopoietic stem cell transplant (HSCT) in a patient with relapsed or refractory light chain amyloidosis (AL), comprising:
introducing hematopoietic stem cells into the patient; and
administering to the patient an anti-CD38 antibody after introduction of the hematopoietic stem cells, the anti-CD38 antibody comprising a heavy chain variable region (VH) sequence of SEQ ID NO: 4 and a light chain variable region (VL) sequence of SEQ ID NO: 5, wherein the anti-CD38 antibody is an IgG1 isotype and induces killing of CD38+ hematological cancer cells, and wherein CD38+CD34+ hematopoietic stem cells within the transplant survive.

### Claim 33

A method of performing a hematopoietic stem cell transplant (HSCT) in a patient with relapsed or refractory light chain amyloidosis (AL), comprising:
administering to the patient an anti-CD38 antibody which is an IgG1 isotype comprising a heavy chain variable region (VH) sequence of SEQ ID NO: 4 and a light chain variable region (VL) sequence of SEQ ID NO: 5; and
introducing hematopoietic stem cells into the patient after administration of the anti-CD38 antibody, wherein the anti-CD38 antibody induces killing of CD38+ hematological cancer cells, and wherein CD38+CD34+ hematopoietic stem cells within the transplant survive.