Identification and engineering of antibodies with variant Fc regions and methods of using same
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.
1. A polypeptide having a variant Fc region 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, 305 and 243, relative to said wild-type Fc region, wherein said numbering is that of the EU index as in Kabat; and
(C) binds to FcγR with an altered affinity relative to that of said wild-type Fc region.
2. The polypeptide of claim 1 , wherein said modifications comprise the modifications R292P, V305I and F243L.
3. The polypeptide of claim 1 , wherein said variant Fc region of said polypeptide 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.
4. The polypeptide of claim 1 , wherein said variant Fc region of said polypeptide additionally comprises a modification at position 297.
5. The polypeptide of claim 1 , wherein said polypeptide is an antibody that contains said variant Fc region.
6. The antibody of claim 5 , 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).
7. A composition comprising the polypeptide of claim 1 , and a pharmaceutically acceptable carrier.
8. A composition comprising the antibody of claim 5 , and a pharmaceutically acceptable carrier.