# US 10,370,450 B2 · Anti-DR6 antibodies and methods of immune regulation

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- Number: US 10,370,450 B2
- Document ID: US10370450B2
- Status: Granted
- Kind: B2
- Application number: 15/037,766
- Filed: 2014-11-19
- Published: 2016-10-06
- Granted: 2019-08-06
- Earliest claimed: 2013-11-20
- Assignees: National University Corporation Hokkaido University
- Applicants: National University Corporation Hokkaido University
- Inventors: Daisuke Fujikura; Toshimitsu Uede
- Web page: https://patentgrep.com/patent/US10370450B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- G01N 33/5041: {involving analysis of members of signalling pathways}
- G01N 33/6863: {Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/70: characterized by effect upon binding to a cell or to an antigen
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/21: containing a His-tag
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- G01N 2333/70578: NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95
- G01N 2333/70596: Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
- G01N 2800/24: Immunology or allergic disorders
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- 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 problems: It is an object of the present invention to provide an immune regulating agent capable of modulating a receptor function concerning immune regulation of DR6, and a method for screening thereof. The object aims to provide: The present invention relates to an immune regulating agent containing a physiologically active substance having an ability to bind specifically to DR6 and an ability to regulate signal transduction induced by specific binding between DR6 and Sdc1, as an active component. The immune regulating agent of the present invention can be used for treating or preventing diseases caused by excessive or abnormal immune response in mammals or diseases for which enhancement of immune function is desired in mammals, as an immune regulating agent based on a hitherto unknown mechanism, capable of regulating signal transduction induced by specific binding between DR6 and Sdc1.

## Claims

### Claim 1

A method for regulating IL-2 production by T cells expressing Death Receptor 6 in a mammal, comprising administering to the mammal an effective amount of a physiologically active substance,
wherein the physiologically active substance is one or more anti-Death Receptor 6 antibodies selected from the group consisting of the following (a) to (g) and functional fragments thereof:
(a) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 14, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 16, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 18, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 20, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 22,
(b) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 24, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 26, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 28, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 30, a light chain CDR2 consisting of the amino acid sequence of Tyr-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 32,
(c) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 34, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 36, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 38, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 40, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 42,
(d) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 44, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 46, a heavy chain CDR3 consisting of the amino add sequence represented by SEQ ID NO: 48, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 50, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino add sequence represented by SEQ ID NO: 52,
(e) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 54, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 56, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 58, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 60, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 62,
(f) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 64, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 66, a heavy chain CDR3 consisting of the amino add sequence represented by SEQ ID NO: 68, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 70, a light chain CDR2 consisting of the amino acid sequence of Arg-Val-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 72, and
(g) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino add sequence represented by SEQ ID NO: 74, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 76, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 78, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 80, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 82.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (a) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 14, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 16, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 18, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 20, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino add sequence represented by SEQ ID NO: 22.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (b) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 24, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 26, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 28, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 30, a light chain CDR2 consisting of the amino acid sequence of Tyr-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 32.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (c) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 34, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 36, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 38, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 40, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 42.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (d) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 44, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 46, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 48, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 50, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 52.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (e) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 54, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 56, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 58, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 60, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 62.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (f) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 64, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 66, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 68, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 70, a light chain CDR2 consisting of the amino acid sequence of Arg-Val-Ser, and a light chain CDR3 consisting of the amino add sequence represented by SEQ ID NO: 72.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the physiologically active substance is (g) an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 74, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 76, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 78, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 80, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 82.

### Claim 9

A method for suppressing proliferation of CD4+ T cells expressing Death Receptor 6 in a mammal, comprising administering to the mammal an effective amount of a physiologically active substance,
wherein the physiologically active substance is an anti-Death Receptor 6 antibody comprising a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 14, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 16, a heavy chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 18, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 20, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 22.

### Claim 10

A method for treating systemic lupus erythematosus (SLE) in a mammal, comprising administering to the mammal an effective amount of an anti-Death Receptor 6 antibody, wherein the antibody comprises a heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 14, a heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 16, a heavy chain CDR3 consisting of the amino add sequence represented by SEQ ID NO: 18, a light chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 20, a light chain CDR2 consisting of the amino acid sequence of Trp-Ala-Ser, and a light chain CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 22.