Methods of treating a subject having an EGFR-positive and/or ErbB-3-positive tumor
The invention relates in one aspect to bispecific antibodies comprising a first antigen-binding site that binds EGFR and a second antigen-binding site that binds Erb B-3, wherein the antibody has a half maximal growth inhibitory concentration (IC50) of less than 200 pM for inhibiting EGFR and/or Erb B-3 ligand induced growth of Bx PC3 cells or Bx PC3-luc2 cells. Further described are method for producing the bispecific antibodies and means and methods for the treatment of subjects with the antibodies.
1. A method for the treatment of a subject having a EGFR, ErbB-3 or EGFR/ErbB-3 positive tumor or at risk of having said tumor comprising administering to the subject a bispecific antibody comprising a first variable domain comprising a first antigen-binding site that binds domain III of EGFR, wherein said first variable domain comprises a heavy chain variable region comprising a CDR1 comprising SEO ID NO: 9, a CDR2 comprising SEO ID NO: 11, and a CDR3 comprising SEO ID NO: 13; and a second variable domain comprising a second antigen-binding site that binds domain III of Erb-B3, wherein said second variable domain comprises a heavy chain variable region comprising a CDR1 comprising SEO ID NO: 90, a CDR2 comprising SEO ID NO: 156, and a CDR3 comprising SEO ID NO: 92, wherein said first and said second variable domains each comprise a common light chain comprising a CDR1 sequence of SEO ID NO:157, a CDR2 sequence of AAS, and a CDR3 sequence of SEQ ID NO:158, and wherein the heavy chain variable regions of the bispecific antibody are different from each other.
2. The method according to claim 1 , wherein the tumor cell is a breast cancer cell, an ovarian cancer cell, a gastric cancer cell, a colorectal cancer cell, a pancreatic cancer cell or a lung cancer cell.
3. The method of claim 1 , wherein said first variable domain comprises a heavy chain variable region at least 90% identical to SEQ ID NO: 7.
4. The method of claim 1 , wherein said second variable domain comprises a heavy chain variable region at least 90% identical to SEQ ID NO: 120.
5. The method of claim 1 , wherein the antibody is afucosylated in order to enhance ADCC.
6. The method of claim 1 , wherein the antibody comprises two different immunoglobulin heavy chains with compatible heterodimerization domains.
7. The method of claim 6 , wherein said compatible hetero-dimerization domains are compatible immunoglobulin heavy chain CH3 hetero-dimerization domains.
8. The method of claim 4 , wherein a pharmaceutical composition comprises the bispecific antibody.
9. The method of claim 1 , wherein the common light chain comprises a light chain variable region IGKV1-39.
10. The method of claim 9 , wherein the common light chain comprises a germ-line light chain variable region IGKV1-39.
11. The method of claim 1 , wherein said first variable domain comprises a heavy chain variable region comprising SEQ ID NO: 7.
12. The method of claim 11 , wherein said second variable domain comprises a heavy chain variable region comprising SEQ ID NO: 120.