Antibody Fc variants

• US 8,969,526 B2
• Filed: 03/27/2012
• Issued: 03/03/2015
• Est. Priority Date: 03/29/2011
• Status: Active Grant

• Current Assignee: Roche Glycart AG (Roche Holding AG)
• Original Assignee: Roche Glycart AG (Roche Holding AG)
• Inventors: Baehner, Monika, Jenewein, Stefan, Kubbies, Manfred, Moessner, Ekkehard, Schlothauer, Tilman
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US13/431,489
• Publication Number:
  US 20120251531A1
• Time in Patent Office: 1,071 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: Y10S 435/81 Packaged device or kit

Abstract

The invention relates to engineered polypeptides comprising Fc variants and their uses. More specifically, Fc variants are described exhibiting reduced effector function. These variants cause a benefit for a patient suffering from a disease which could be treated with an antibody for which it is desirable to reduce the effector function elicited by antibodies.

Claims

1. An isolated polypeptide comprising an Fc variant of a wild-type human IgG1 Fc region or a wild-type human IgG4 Fc region, said Fc variant comprising an amino acid substitution at position Pro329 with glycine or arginine and at least one further amino acid substitution, wherein said at least one further amino acid substitution is L234A and L235A of the human IgG1 Fc region or S228P and L235E of the human IgG4 Fc region wherein the residues are numbered according to the EU index of Kabat, and wherein said polypeptide exhibits a reduced affinity to human Fcγ

RIIIA, and Fcγ

RIIA, and Fcγ

RI compared to the polypeptide comprising the wildtype IgG Fc region, wherein the affinity to each of human Fcγ

RIIIA, and Fcγ

RIIA, and Fcγ

RI is reduced by 1.15 fold to 100 fold compared to the polypeptide comprising the wildtype IgG Fc region, and wherein the antibody-dependent cell-mediated cytotoxicity (ADCC) induced by said polypeptide is 0-20% of the ADCC induced by the polypeptide comprising the wild-type human IgG Fc region.

2. The polypeptide according to claim 1, wherein the affinity to at least one further human receptor is reduced by 1.15 fold to 100 fold compared to the polypeptide comprising the wild-type human IgG Fc region, wherein the further human receptor is Clq.

3. The polypeptide according to claim 1, wherein the polypeptide is an antibody or an Fc fusion protein.

4. The polypeptide according to claim 1, wherein thrombocyte aggregation induced by the polypeptide is reduced by at least 10% compared to the thrombocyte aggregation induced by the polypeptide comprising the wild-type human IgG Fc region.

5. The polypeptide according to claim 1, wherein CDC induced by the polypeptide is reduced by at least 50% compared to the CDC induced by the polypeptide comprising the wild-type human IgG Fc region.

6. The polypeptide according to any one of claims 1, 2, or 3-5, wherein the polypeptide is an anti-CD9 antibody comprising the heavy chain variable region of SEQ ID NO:

9 and the variable light chain region of SEQ ID NO;

8.

7. A pharmaceutical formulation comprising the polypeptide according to claim 6.

8. An article of manufacture comprising the polypeptide according to claim 6.