Antibody fab and Fc variants
The present invention relates to modified antibodies. In particular, the present invention relates to recombinant monoclonal antibodies having altered ability to induce direct cell death and effector function. In addition, the present invention relates to nucleic acid molecules encoding such antibodies, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the antibodies of the invention, and to methods of using these antibodies in treatment of disease.
1. An antibody comprising a variant heavy chain region comprising at least one amino acid substitution relative to the parent non-substituted heavy chain region of a parent non-substituted antibody,
wherein the amino acid residue Pro151 is substituted with phenylalanine, and
wherein the parent non-substituted antibody is obinutuzumab, and
wherein direct cell death induced by the antibody comprising the variant heavy chain region is altered compared to direct cell death induced by the antibody comprising the parent non-substituted heavy chain region.
2. The antibody according to claim 1 , wherein direct cell death induced by the antibody comprising the variant heavy chain region is increased compared to direct cell death induced by the antibody comprising the parent non-substituted heavy chain region.
3. The antibody according to claim 1 , wherein direct cell death induced by the antibody comprising the variant heavy chain region is decreased compared to direct cell death induced by the antibody comprising the parent non-substituted heavy chain region.
4. The antibody according to claim 1 , wherein the parent non-substituted heavy chain region comprises the amino acid residues Leu234 (EU numbering), Leu235 (EU numbering) and Pro329 (EU numbering), wherein the variant heavy chain region comprises at least one of the amino acid substitutions Leu234Ala, Leu235Ala and Pro329Gly relative to the parent non-substituted heavy chain region, wherein binding to FcγR and Clq is abolished and wherein Fc-mediated effector function is abolished.
5. A pharmaceutical composition comprising an antibody according claim 1 and a pharmaceutically acceptable carrier.