Multimer of extracellular domain of cell surface functional molecule

• US 8,574,872 B2
• Filed: 06/01/2012
• Issued: 11/05/2013
• Est. Priority Date: 03/03/2006
• Status: Active Grant

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Minato, Nagahiro, Tanaka, Yoshimasa, Shibayama, Shiro
• Primary Examiner(s): NOAKES, SUZANNE MARIE
• Application Number:
  US13/486,189
• Publication Number:
  US 20120269859A1
• Time in Patent Office: 522 Days
• Field of Search: None
• US Class Current: 435/69.7
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 33/08 : for Pneumocystis carinii
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 14/70503 : Immunoglobulin superfamily
• CPC Class Codes: C07K 14/70532 : B7 molecules, e.g. CD80, CD86
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

As a substance which pharmacologically regulates the function of a cell surface functional molecule, a substance which has specificity and an activity or efficacy equal or superior to an antibody and does not require an advanced production technique and facility for application thereof to a pharmaceutical product has been demanded. The invention relates to a multimer of an extracellular domain of a cell surface functional molecule, particularly a tetramer of an extracellular domain of PD-1 or PD-L1. Further, the invention relates to an application of such a tetramer as a preventive and/or therapeutic agent for cancer, cancer metastasis, immunodeficiency, an infectious disease or the like and an application of PD-1 or PD-L1 as a testing or diagnostic agent or a research agent for such a disease.

Claims

1. A multimer comprising 2 to 10 extracellular domains of Programmed Cell Death-Ligand 1 (PD-L1), wherein the extracellular domains of PD-L1 are serially-concatenated directly or with peptide linkers, and wherein said PD-L1 is human PD-L1 or mouse PD-L1,

wherein the human PD-L1 has the amino acid sequence SEQ ID NO:

17, and wherein the mouse PD-L1 has the amino acid sequence of SEQ ID NO;

18.

2. The multimer according to claim 1, wherein each of the extracellular domains of PD-L1 comprises a region selected from (a) and (b):

(a) residues 1-238 or residues 18-230 of human PD-L1; and

(b) residues 1-237 or residues 18-229 of mouse PD-L1.

3. The multimer according to claim 2, wherein 1 to 3 amino acid(s) in each of the extracellular domains of PD-L1 is/are substituted by other amino acid(s).

4. The multimer according to claim 1, wherein the multimer is a tetramer.

5. The multimer according to claim 1, wherein each of the extracellular domains of PD-L1 is serially-concatenated with peptide linkers.

6. The multimer according to claim 1, wherein each peptide linker comprises 2 to 15 amino acids.

9. The multimer according to claim 6, comprising the amino acid sequence of SEQ ID NO:

5 or 7.

10. A pharmaceutical composition comprising the multimer according to claim 1 as an active ingredient.

11. A pharmaceutical composition comprising the multimer according to claim 1 and at least one ingredient selected from the group consisting of chemotherapy drugs, cancer treatment adjuvants, immunomodulators, cancer antigens, antiviral agents, antibiotic preparations, antimicrobials, fungal treatments and vaccines.

12. A Programmed Cell Death-1 detection reagent comprising the multimer according to claim 1.

13. A method of treatment of cancers, cancer metastasis, immune deficiency syndrome or infectious diseases, comprising administering an effective amount of the multimer according to claim 1 to a patient in need thereof.

7. The multimer according to 2to 10 extracellular domains of Programmed Cell Death-Ligand (PD-L1) wherein the extracellular of PD-L1 are bound to a carrier via a non-peptide linker, and wherein said PD-L1 or mouse PD-L1,

wherein the human PD-L1 has the amino acid sequence of SEQ ID NO:

17, and wherein the mouse PD-L1 has the amino acid sequence of SEQ ID NO;

18.

8. The multimer according to claim 7, wherein the carrier is an avidin streptavidin or a derivative thereof and the non-peptide linker is a biotin.