ERBB-2 AND ERBB3 BINDING BISPECIFIC ANTIBODIES FOR USE IN THE TREATMENT OF CELLS THAT HAVE AN NRG1 FUSION GENE

1 . A method of treating an individual that has an ErbB-2 and ErbB-3 positive cell, which cell comprises an NRG1 fusion gene comprising at least a portion of the NRG1-gene fused to a sequence from a different chromosomal location, the method comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2 and a second antigen-binding site that can bind an extracellular part of ErbB-3.

2 . The method of claim 1 , wherein the NRG1 fusion gene comprises at least the 3′ end of the NRG1-gene fused to a 5′ sequence from a different chromosomal location.

3 . The method of claim 1 , wherein the cell is a cancer cell.

4 . The method of claim 3 wherein the cancer cell is associated with an NRG1-fusion.

5 . The method of claim 3 , wherein the cancer cell is driven by NRG1-fusion.

6 . The method of claim 1 , wherein the cell is a breast cancer cell, an ovarian cancer cell, a lung cancer cell, such as non-small cell lung cancer, or a metastasis thereof.

7 . A method of treating an individual that has an ErbB-2 and ErbB-3 positive tumor, wherein cells of the tumor express an NRG1 fusion gene comprising at least the 3′ end of the NRG1-gene fused to a 5′ sequence from a different chromosomal location, the method comprising administering to the individual a bispecific antibody that comprises a first antigen-binding site that can bind an extracellular part of ErbB-2 and a second antigen-binding site that can bind an extracellular part of ErbB-3.

8 . The antibody for use method of claim 7 , wherein the tumor is breast cancer, an ovarian cancer, a lung cancer, such as non-small cell lung cancer, or a metastasis thereof.

9 . The antibody for use method of any of the preceding claim 1 ,

wherein the NRG1-fusion gene expresses a protein that comprises an NRG1 EGF-like domain.

10 . The antibody for use method of any of the preceding claim 1 ,

wherein the NRG-fusion is a fusion of NRG1 and a gene on human chromosome 8.

11 . The antibody for use method of claim 10 , wherein the gene on human chromosome 8 encodes an excreted protein or a cellular membrane associated protein.

12 . The antibody for use method of any of the preceding claim 1 ,

wherein the NRG1 fusion gene is a fusion of the 3′ end of the NRG1-gene with the 5′ sequence of one of the genes selected from the group consisting of CD74; DOC4; TNFRSF10B; CLU;

VAMP2; SLC3A2; RBPMS; WRN; SDC4; KIF13B; SLECA2; PDE7A; ATP1B1; CDK1;

BMPRIB; MCPH1 and RAB2IL1.

13 . The method of claim 1 , wherein the cell is of an epithelial origin.

14 . The method of claim 1 , wherein the individual has undergone a therapy that targeted towards EGFR inhibition, preferably with an EGFR binding antibody.

15 . The method of claim 1 , wherein the ErbB-1 cell-surface receptor density, ErbB-2 cell-surface receptor density, ErbB-3 cell-surface receptor density, ErbB-4 cell-surface receptor density, or a combination thereof on the cell is determined.

16 . The method of claim 1 , wherein the cell or tumor has less than 400,000 ErbB-1 cell-surface receptors per cell.

17 . The method of claim 1 , further comprising administering to the individual an ErbB-1 inhibitor.

18 . The method of claim 1 , wherein said first antigen-binding site can bind domain I of ErbB-2 and said second antigen-binding site can bind domain III of ErbB-3.

19 . The method of claim 18 , wherein

i) at least the CDR1, CDR2 and CDR3 sequences of an ErbB-2 specific heavy chain variable region selected from the group consisting of MF2926, MF2930, MF1849; MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, MF2889, MF2913, MF1847, MF3001, MF3003 and MF1898 or wherein CDR sequences that differ in at most 3 amino acids

ii) at least the CDR1, CDR2 and CDR3 sequences of an ErbB-3 specific heavy chain variable region selected from the group consisting of MF3178; MF3176; MF3163; MF3099; MF3307; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, or wherein said antibody comprises CDR sequences that differ in at most 3 amino acids,

i) an ErbB-2 specific heavy chain variable region sequence selected from the group consisting of the heavy chain variable region sequences of MF2926, MF2930, MF1849; MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, MF2889, MF2913, MF1847, MF3001, MF3003 and MF1898, or wherein a heavy chain variable region sequence that differs in at most 15 amino acids from the heavy chain variable region sequences of MF2926, MF2930, MF1849; MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, MF2889, MF2913, MF1847, MF3001, MF3003 or MF1898; and/or

ii) an ErbB-3 specific heavy chain variable region sequence selected from the group consisting of the heavy chain variable region sequences of MF3178; MF3176; MF3163; MF3099; MF3307; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, or wherein a heavy chain variable region sequence that differs in at most 15 amino acids from the heavy chain variable region sequences of MF3178; MF3176; MF3163; MF3099; MF3307; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 or MF6074.

20 . The method of claim 18 , wherein the antibody comprises at least the CDR1, CDR2 and CDR3 sequences of the ErbB 2 specific heavy chain variable region MF3958 and the antibody comprises at least the CDR1, CDR2 and CDR3 sequences of the ErbB 3 specific heavy chain variable region MF3178.

21 . The method of claim 1 , wherein the variable domain that comprises said first antigen binding site and the variable domain that comprises said second antigen binding site comprise a light chain variable region comprising the IgVK1-39 gene segment.