# US 10,307,481 B2 · CD37 immunotherapeutics and uses thereof

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- Number: US 10,307,481 B2
- Document ID: US10307481B2
- Status: Granted
- Kind: B2
- Application number: 11/493,132
- Filed: 2006-07-25
- Published: 2007-03-15
- Granted: 2019-06-04
- Earliest claimed: 2005-07-25
- Assignees: Aptevo Research and Development LLC
- Applicants: Laura S. Grosmaire; Martha S. Hayden-Ledbetter; Jeffrey A. Ledbetter; Peter A. Thompson; Sandy A. Simon; William Brady
- Inventors: Laura S. Grosmaire; Martha S. Hayden-Ledbetter; Jeffrey A. Ledbetter; Peter A. Thompson; Sandy A. Simon; William Brady
- Web page: https://patentgrep.com/patent/US10307481B2

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2887: {against CD20}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- C07K 16/3061: {Blood cells}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/53: Hinge
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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

The present invention generally provides methods for B-cell reduction in an individual using CD37-specific binding molecules. In particular, the invention provides methods for B-cell reduction using CD37-specific binding molecules alone, or a combination of CD37-specific binding molecules and CD20-specific binding molecules, in some instances a synergistic combination. The invention further provides materials and methods for treatment of diseases involving aberrant B-cell activity. In addition, the invention provides humanized CD37-specific binding molecules.

## Claims

### Claim 1

A humanized or chimeric CD37-specific immunoglobulin binding protein, comprising:
(a) a light chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 61, a second framework region, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 64, a third framework region, a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a fourth framework region; and
(b) a heavy chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 63, a second framework region, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, a third framework region, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69, and a fourth framework region;
wherein the binding protein binds human CD37.

### Claim 2

A humanized or chimeric CD37-specific immunoglobulin binding protein, comprising:
(a) a light chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 61, a second framework region, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 64, a third framework region, a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a fourth framework region; and
(b) a heavy chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 63, a second framework region, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, a third framework region, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67, and a fourth framework region;
wherein the binding protein binds human CD37.

### Claim 3

A humanized or chimeric CD37-specific immunoglobulin binding protein, comprising:
(a) a light chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 61, a second framework region, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 64, a third framework region, a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and
(b) a heavy chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 63, a second framework region, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, a third framework region, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68;
wherein the binding protein binds human CD37.

### Claim 4 (depends on 1, 2)

The CD37-specific binding protein according to claim 1, 2, or 3 wherein the binding protein comprises a single chain Fv (scFv) polypeptide, an antibody or a binding fragment thereof, or a polypeptide that comprises, from amino to carboxy terminus, an scFv, a human immunoglobulin hinge region, and human immunoglobulin CH2 and CH3 domains.

### Claim 5 (depends on 1, 2)

The CD37-specific binding protein according to claim 1, 2, or 3 wherein the light chain variable region is attached to the heavy chain variable region by a linker peptide comprising (Gly4Ser)n, wherein n is 1, 2, 3, 4, 5, or 6, as set forth in SEQ ID NO:221, 222, 223, 224, 225 or 226.

### Claim 6 (depends on 4)

The CD37-specific binding protein according to claim 4, wherein the light and heavy chain variable regions are connected to the CH2 and CH3 domains via a hinge region comprised of an amino acid sequence selected from the group consisting of SEQ ID NOS:90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 115, 116, 118, 120, 122, 124, 126, and 127.

### Claim 7 (depends on 6)

The CD37-specific binding protein according to claim 6, wherein the hinge region comprises the amino acid sequence of SEQ ID NO:92 or SEQ ID NO:106.

### Claim 8 (depends on 4)

The CD37-specific binding protein according to claim 4, wherein the CH2 and CH3 domains are IgG1CH2 and CH3 domains.

### Claim 9 (depends on 1, 2)

The CD37-specific binding protein according to claim 1, 2, or 3 wherein the binding protein has a binding affinity for human CD37 of about 0.5 nM to about 10 nM.

### Claim 10 (depends on 1, 2)

A composition comprising a CD37-specific immunoglobulin binding protein according to claim 1, 2, or 3 and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 3)

The CD37-specific binding protein of claim 3, wherein the light chain variable region comprises amino acids 21-127 of SEQ ID NO: 52, and the heavy chain variable region comprises amino acids 144-259 of SEQ ID NO: 52.

### Claim 12 (depends on 3)

The CD37-specific binding protein of claim 3, wherein the binding protein comprises a polypeptide according to SEQ ID NO: 52.

### Claim 13 (depends on 1, 2)

The CD37-specific binding protein of claim 1, 2, or 3, wherein
(a) the first light chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 171, the second light chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 182, the third light chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 195, and the fourth light chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 206; and
(b) the first heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 144, the second heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 151, the third heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 158, and the fourth heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO: 161 or 162.

### Claim 14 (depends on 1, 2)

The CD37-specific binding protein of claim 1, 2, or 3, wherein the binding protein is a dimer.