Combination therapy using bispecific anti-c-Met/anti-EGFR antibody and c-Src inhibitor

1. A method of treating a cancer comprising co-administering to a subject in need thereof a bispecific anti-c-Met/anti-EGFR antibody and a c-Src inhibitor to a subject, wherein the bispecific anti-c-Met/anti-EGFR antibody comprises an EGFR binding region and an anti-c-Met antibody or antigen-binding fragment thereof, and

wherein the anti c-Met antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO: 1, a CDR-H2 comprising SEQ ID NO: 2, and a CDR-H3 comprising SEQ ID NO: 3, and a light chain variable region comprising a CDR-L1 comprising SEQ ID NO: 10, a CDR-L2 comprising SEQ ID NO: 11, and a CDR-L3 comprising SEQ ID NO: 13,

and wherein the cancer to be treated is colon cancer, lung cancer, colon cancer comprising a K-Ras mutation, or lung cancer comprising an EGFR T790M mutation.

2. The method of claim 1 , wherein the bispecific anti-c-Met/anti-EGFR antibody and the Src inhibitor are co-administered by administering a composition comprising the bispecific anti-c-Met/anti-EGFR antibody and the c-Src inhibitor, or administering a first composition comprising the bispecific anti-c-Met/anti-EGFR antibody and a second composition comprising the c-Src inhibitor, wherein the first composition and second composition are administered simultaneously or sequentially in any order.

3. The method of claim 1 , wherein the anti-c-Met antibody or antigen-binding fragment thereof comprises:

a heavy chain variable region comprising SEQ ID NO: 17; and

a light chain variable region comprising SEQ ID NO: 129 or SEQ ID NO: 18.

4. The method of claim 1 , wherein the anti-c-Met antibody comprises:

a heavy chain comprising SEQ ID NO: 62, the 18th to 462nd positions of SEQ ID NO: 62, SEQ ID NO: 64, the 18th to 461st positions of SEQ ID NO: 64, SEQ ID NO: 66, or the 18th to 460th positions of SEQ ID NO: 66; and

a light chain comprising SEQ ID NO: 68, the 21st to 240th positions of SEQ ID NO: 68, SEQ ID NO: 70, the 21st to 240th positions of SEQ ID NO: 70, or SEQ ID NO: 108.

5. The method of claim 1 , wherein the EGFR binding region comprises an anti-EGFR antibody, antigen-binding fragment thereof, or an anti-EGFR DARPin.

6. The method of claim 5 , wherein the anti-EGFR antibody or antigen-binding fragment thereof is selected from the group consisting of:

(1) cetuximab or antigen binding fragment thereof;

(2) panitumumab or antigen binding fragment thereof;

(3) an anti-EGFR antibody comprising a heavy chain variable region comprising SEQ ID NO: 109, and a light chain variable region comprising SEQ ID NO: 111;

(4) an anti-EGFR antibody comprising a heavy chain variable region comprising SEQ ID NO: 113, and a light chain variable region comprising SEQ ID NO: 114; and

(5) an anti-EGFR antibody comprising a CDR-H1 comprising SEQ ID NO: 115, a CDR-H2 comprising SEQ ID NO: 116, and a CDR-H3 comprising SEQ ID NO: 117, a CDR-L1 comprising SEQ ID NO: 118, a CDR-L2 comprising SEQ ID NO: 119, and a CDR-L3 comprising SEQ ID NO: 120.

7. The method of claim 6 , wherein the anti-EGFR antibody or antigen-binding fragment thereof is an anti-EGFR antibody, an anti-EGFR scFv, or an anti-EGFR scFv-Fc comprising a heavy chain variable region comprising SEQ ID NO: 109, SEQ ID NO: 113, SEQ ID NO: 121, or SEQ ID NO: 122; and a light chain variable region comprising SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 123, or SEQ ID NO: 124.

8. The method of claim 5 , wherein the EGFR binding region comprises an anti-EGFR DARPin, and the anti-EGFR DARPin comprises 1 to 10 units, wherein each unit is independently selected from the group consisting of SEQ ID NOs: 125 to 127.

9. The method of claim 1 , wherein the c-Src inhibitor is at least one selected from the group consisting of dasatinib, saracatinib, bosutinib, 1-Naphthyl PP1 (CAS 221243-82-9), A 419259 trihydrochloride (CAS 364042-47-7), AG 538 (CAS 133550-18-2), AGL 2263 ((E)-2-(3,4-dihydroxybenzoyl)-3-(2-oxo-3H-1,3-benzoxazol-5-yl)prop-2-enenitrile), Bcr-abl Inhibitor II (CAS 607702-99-8), bosutinib (CAS 380843-75-4), altenusin (CAS 31186-12-6), herbimycin A(CAS 70563-58-5), PD 166285 (CAS 212391-63-4), PKC-412 (CAS 120685-11-2), PDGFR Tyrosine Kinase Inhibitor IV (CAS 627518-40-5), Calphostin C (CAS 121263-19-2), PP 1 (CAS 172889-26-8), PP 2 (CAS 172889-27-9), Src Kinase Inhibitor I (CAS 179248-59-0), EGF/FGF/PDGF Receptor Tyrosine Kinase Inhibitor (CAS 1135256-66-4), staurosporine (CAS 62996-74-1), lavendustin A (CAS 125697-92-9), Indirubin-3′-(2,3-dihydroxypropyl)oximether, luteolin (CAS 491-70-3), SU6656 (CAS 330161-87-0), TX-1918 (CAS 503473-32-3), geldanamycin (CAS 0562-34-6), MNS (CAS 1485-00-3), TX-1123 (CAS 157397-06-3), GW5074 (CAS 220904-83-6), Erlotinib HCl (CAS 183319-69-9), NVP-BHG712 (CAS 940310-85-0), GW2580 (CAS 870483-87-7), AEE788 (CAS 497839-62-0), TAK-901 (CAS 934541-31-8), Midostaurin (CAS 120685-11-2), and PD173074 (CAS 219580-11-7), or any combination thereof.

10. A pharmaceutical composition comprising a bispecific anti-c-Met/anti-EGFR antibody of claim 1 and a carrier.