Identification and Engineering of Antibodies with Variant Fc Regions and Methods of Using Same

• US 20130202606A1
• Filed: 03/18/2013
• Published: 08/08/2013
• Est. Priority Date: 01/09/2003
• Status: Active Grant

• Current Assignee: MacroGenics, Inc.
• Original Assignee: MacroGenics, Inc.
• Inventors: Stavenhagen, Jeffrey, Vijh, Sujata, Rankin, Christopher, Gorlatov, Sergey, Huang, Ling
• Granted Patent: US 8,951,517 B2
• Time in Patent Office: Days
• US Class Current: 424/136.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 16/00 : Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/005 : constructed by phage libraries
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]

Abstract

The present invention relates to molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds FcγRIIIA and/or FcγRIIA with a greater affinity, relative to a comparable molecule comprising the wild-type Fc region. The molecules of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection. The molecules of the invention are particularly useful for the treatment or prevention of a disease or disorder where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by FcγR is desired, e.g., cancer, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.

Claims

1. A method of treating cancer in a patient having a cancer characterized by a cancer antigen, said method comprising administering to said patient a therapeutically effective amount of a polypeptide having a variant Fc region that binds said cancer antigen, wherein said variant Fc region:

(A) contains a CH2 domain and a CH3 domain;

(B) possesses an amino acid sequence that differs from the amino acid sequence of a wild-type Fc region by comprising amino acid modifications at positions 292 and 305, relative to said wild-type Fc region, wherein said numbering is that of the EU index as in Kabat; and

(C) binds to Fcγ

R with an altered affinity relative to that of said wild-type Fc region.

2. The method of claim 1, wherein said amino acid modifications comprise the modifications R292P and V305I.

3. The method of claim 2, wherein said amino acid modifications additionally comprise the modification F243L.

4. The method of claim 1, wherein said amino acid modifications cause said variant Fc region to bind Fcγ

RII with an altered affinity relative to that of said wild-type Fc region.

5. The method of claim 4, wherein said altered Fcγ

RII affinity is an enhanced Fcγ

RIIA binding affinity.

6. The method of claim 4, wherein said altered Fcγ

RII affinity is a decreased Fcγ

RIIB binding affinity.

7. The method of claim 1, wherein said amino acid modifications cause said variant Fc region to bind Fcγ

RIII with an altered affinity relative to that of said wild-type Fc region.

8. The method of claim 7, wherein said altered affinity for an Fcγ

RIII is an increased affinity.

9. The method of claim 7, wherein said Fcγ

RIII is Fcγ

RIIIA.

10. The method of claim 7, wherein said variant Fc region also binds Fcγ

RIIB with decreased affinity relative to that of a wild-type Fc region.

11. The method of claim 7, wherein said variant Fc region also binds Fcγ

RIIA with increased affinity relative to that of a wild-type Fc region.

12. The method of claim 1, wherein said variant Fc region additionally comprises a modification that enhances C1q binding, said modification being:

(1) P247L and N421K;

(2) R255L and P396L;

(3) K370E and P396L;

(4) K392T and P396L;

(5) P396L and V240A;

or

(6) P396L and Q419H.

13. The method of claim 1, wherein said variant Fc region additionally comprises a modification at position 297.

14. The method of claim 1, wherein said polypeptide is an antibody that contains said variant Fc region.

15. The method of claim 14, wherein said antibody is antibody produced by hybridoma clone:

1D5 (ATCC accession number PTA-5958), 1F2 (ATCC accession number PTA-5959), 2D11 (ATCC accession number PTA-5960), 2E1 (ATCC accession number PTA-5961) or 2H9 (ATCC accession number PTA-5962).

16. The method of claim 1, wherein said cancer antigen is selected from the group consisting of MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, N-acetylglucosaminyltransferase, p15, beta-catenin, MUM-1, CDK4, HER-2/neu, human papillomavirus-E6, human papillomavirus-E7, or MUC-1.

17. The method of claim 1, wherein said cancer antigen is characteristic of a breast, ovarian, prostate, cervical, or pancreatic carcinoma.