# US 12,215,161 B2 · Combination therapies and patient stratification with bispecific anti-EGFR/c-Met antibodies

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- Number: US 12,215,161 B2
- Document ID: US12215161B2
- Status: Granted
- Kind: B2
- Application number: 17/817,295
- Filed: 2022-08-03
- Published: 2023-04-27
- Granted: 2025-02-04
- Earliest claimed: 2019-02-26
- Assignees: Janssen Biotech, Inc.
- Applicants: Janssen Biotech, Inc.
- Inventors: Sheri Moores; Smruthi Vijayaraghavan
- Web page: https://patentgrep.com/patent/US12215161B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 2039/505: {comprising antibodies}
- C07K 2317/31: multispecific
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to combination therapies and patient stratification with bispecific anti-EGFR/c-Met antibodies.

## Claims

### Claim 1

A method of inducing trogocytosis from a donor cancer cell that expresses EGFR, c-Met, or EGFR and c-Met to an acceptor macrophage cell or an acceptor monocyte cell, the method comprising contacting the donor cancer cell with a bispecific anti-EGFR/c-Met antibody for a time sufficient to induce trogocytosis from the donor cancer cell to the acceptor macrophage cell or the acceptor monocyte cell,
wherein the bispecific anti-EGFR/c-Met antibody comprises:
a first domain that binds EGFR, wherein the first domain comprises a heavy chain complementarity determining region (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; and
a second domain that binds c-Met, wherein the second domain comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

### Claim 2 (depends on 1)

The method of claim 1, wherein
the first domain that binds EGFR comprises a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 14; and
the second domain that binds c-Met comprises a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 16.

### Claim 3 (depends on 2)

The method of claim 2, wherein the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype.

### Claim 4 (depends on 3)

The method of claim 3, wherein the bispecific anti-EGFR/c-Met antibody comprises a HC1 comprising the amino acid sequence of SEQ ID NO: 17, a LC1 comprising the amino acid sequence of SEQ ID NO: 18, a HC2 comprising the amino acid sequence of SEQ ID NO: 19, and a LC2 comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 5 (depends on 4)

The method of claim 4, wherein the donor cancer cell has a wild-type EGFR, an EGFR activating mutation, an EGFR gene amplification, increased levels of circulating HGF, a wild-type c-Met, a c-Met activating mutation, a c-Met gene amplification, or a mutant KRAS.

### Claim 6 (depends on 5)

The method of claim 5, wherein the EGFR activating mutation comprises a L718Q, G719A, G719X (X being any amino acid), L861X (X being any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M substitution, deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, Val, and Ala (SVA) between S768 and V769, insertion of Asn and Ser (NS) between P772 and H773, insertion of one or more amino acids between D761 and E762, A763 and Y764, Y764 and Y765, M766 and A767, A767 and V768, S768 and V769, V769 and D770, D770 and N771, N771 and P772, P772 and H773, H773 and V774, V774 and C775, one or more deletions in EGFR exon 20, one or more insertions in EGFR exon 20, or any combination thereof.

### Claim 7 (depends on 5)

The method of claim 5, wherein the mutant KRAS comprises a G12V, G12C, or G12A substitution.

### Claim 8 (depends on 1)

The method of claim 1, wherein the contacting step is done in vitro.

### Claim 9 (depends on 1)

The method of claim 1, wherein the contacting step comprises administering the bispecific anti-EGFR/c-Met antibody to a subject.

### Claim 10 (depends on 9)

The method of claim 9, wherein the subject has an EGFR, c-Met, or EGFR and c-Met expressing cancer.

### Claim 11 (depends on 10)

The method of claim 10, wherein the subject has a newly diagnosed EGFR, c-Met, or EGFR and c-Met expressing cancer.

### Claim 12 (depends on 10)

The method of claim 10, wherein the subject is resistant or has acquired resistance to treatment with a prior anti-cancer therapy.

### Claim 13 (depends on 12)

The method of claim 12, wherein the prior anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

### Claim 14 (depends on 13)

The method of claim 13, wherein the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

### Claim 15 (depends on 13)

The method of claim 13, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 16 (depends on 10)

The method of claim 10, wherein the cancer cell expressing EGFR, c-Met, or EGFR and c-Met is derived from epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, cancer of the nose, pancreatic cancer, skin cancer, oral cancer, cancer of the tongue, esophageal cancer, vaginal cancer, cervical cancer, cancer of the spleen, testicular cancer, gastric cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, HCC, or sporadic or hereditary papillary renal cell carcinoma PRCC.

### Claim 17 (depends on 16)

The method of claim 16, comprising further administering one or more anti-cancer therapies to the subject.

### Claim 18 (depends on 17)

The method of claim 17, wherein the one or more anti-cancer therapies comprise a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

### Claim 19 (depends on 18)

The method of claim 18, wherein the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

### Claim 20 (depends on 19)

The method of claim 19, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 21 (depends on 20)

The method of claim 20, wherein the kinase inhibitor is lazertinib.

### Claim 22 (depends on 1)

The method of claim 1, wherein the acceptor cell is the macrophage cell.

### Claim 23 (depends on 1)

The method of claim 1, wherein the acceptor cell is the monocyte cell.

### Claim 24 (depends on 6)

The method of claim 6, wherein the EGFR activating mutation comprises one or more insertions in EGFR exon 20.

### Claim 25 (depends on 6)

The method of claim 6, wherein the EGFR activating mutation comprises L858R, deletion of E746-A750, or deletion of R748-P753.

### Claim 26 (depends on 25)

The method of claim 25, wherein the EGFR activating mutation comprises L858R.

### Claim 27 (depends on 25)

The method of claim 25, wherein the EGFR activating mutation comprises deletion of E746-A750, or deletion of R748-P753.

### Claim 28 (depends on 16)

The method of claim 16, wherein the cancer cell expressing EGFR, c-Met, or EGFR and c-Met is derived from non-small cell lung cancer (NSCLC).

### Claim 29

A method of inducing trogocytosis from a donor cancer cell that expresses EGFR, c-Met, or EGFR and c-Met to an acceptor macrophage cell or an acceptor monocyte cell, the method comprising contacting the donor cancer cell with a bispecific anti-EGFR/c-Met antibody for a time sufficient to induce trogocytosis from the donor cancer cell to the acceptor macrophage cell or the acceptor monocyte cell,
wherein the bispecific anti-EGFR/c-Met antibody comprises:
a first domain that binds EGFR, wherein the first domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 14; and a second domain that binds c-Met, wherein the second domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 16.

### Claim 30 (depends on 29)

The method of claim 29, wherein the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype.

### Claim 31 (depends on 29)

The method of claim 29, wherein the acceptor cell is the macrophage cell.

### Claim 32 (depends on 29)

The method of claim 29, wherein the acceptor cell is the monocyte cell.

### Claim 33 (depends on 29)

The method of claim 29, wherein the donor cancer cell has a wild-type EGFR, an EGFR activating mutation, an EGFR gene amplification, increased levels of circulating HGF, a wild-type c-Met, a c-Met activating mutation, a c-Met gene amplification, or a mutant KRAS.

### Claim 34 (depends on 29)

The method of claim 29, wherein the EGFR activating mutation comprises a L718Q, G719A, G719X (X being any amino acid), L861X (X being any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M substitution, deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, Val, and Ala (SVA) between S768 and V769, insertion of Asn and Ser (NS) between P772 and H773, insertion of one or more amino acids between D761 and E762, A763 and Y764, Y764 and Y765, M766 and A767, A767 and V768, S768 and V769, V769 and D770, D770 and N771, N771 and P772, P772 and H773, H773 and V774, V774 and C775, one or more deletions in EGFR exon 20, one or more insertions in EGFR exon 20, or any combination thereof.

### Claim 35 (depends on 34)

The method of claim 34, wherein the EGFR activating mutation comprises one or more insertions in EGFR exon 20.

### Claim 36 (depends on 34)

The method of claim 34, wherein the EGFR activating mutation comprises L858R, deletion of E746-A750, or deletion of R748-P753.

### Claim 37 (depends on 36)

The method of claim 36, wherein the EGFR activating mutation comprises L858R.

### Claim 38 (depends on 36)

The method of claim 36, wherein the EGFR activating mutation comprises deletion of E746-A750, or deletion of R748-P753.

### Claim 39 (depends on 33)

The method of claim 33, wherein the mutant KRAS comprises a G12V, G12C, or G12A substitution.

### Claim 40 (depends on 29)

The method of claim 29, wherein the contacting step is done in vitro.

### Claim 41 (depends on 29)

The method of claim 29, wherein the contacting step comprises administering the bispecific anti-EGFR/c-Met antibody to a subject.

### Claim 42 (depends on 41)

The method of claim 41, wherein the subject has an EGFR, c-Met, or EGFR and c-Met expressing cancer.

### Claim 43 (depends on 41)

The method of claim 41, wherein the subject has a newly diagnosed EGFR, c-Met, or EGFR and c-Met expressing cancer.

### Claim 44 (depends on 41)

The method of claim 41, wherein the subject is resistant or has acquired resistance to treatment with a prior anti-cancer therapy.

### Claim 45 (depends on 44)

The method of claim 44, wherein the prior anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

### Claim 46 (depends on 45)

The method of claim 45, wherein the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

### Claim 47 (depends on 46)

The method of claim 46, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 48 (depends on 42)

The method of claim 42, wherein the cancer cell expressing EGFR, c-Met, or EGFR and c-Met is derived from epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, cancer of the nose, pancreatic cancer, skin cancer, oral cancer, cancer of the tongue, esophageal cancer, vaginal cancer, cervical cancer, cancer of the spleen, testicular cancer, gastric cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, HCC, or sporadic or hereditary papillary renal cell carcinoma PRCC.

### Claim 49 (depends on 48)

The method of claim 48, wherein the cancer cell expressing EGFR, c-Met, or EGFR and c-Met is derived from non-small cell lung cancer (NSCLC).

### Claim 50 (depends on 48)

The method of claim 48, comprising further administering one or more anti-cancer therapies to the subject.

### Claim 51 (depends on 50)

The method of claim 50, wherein the one or more anti-cancer therapies comprise a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

### Claim 52 (depends on 51)

The method of claim 51, wherein the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

### Claim 53 (depends on 52)

The method of claim 52, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 54 (depends on 53)

The method of claim 53, wherein the kinase inhibitor is lazertinib.

### Claim 55

A method of inducing trogocytosis from a donor cancer cell that expresses EGFR, c-Met, or EGFR and c-Met to an acceptor macrophage cell or an acceptor monocyte cell, the method comprising contacting the donor cancer cell with a bispecific anti-EGFR/c-Met antibody for a time sufficient to induce trogocytosis from the donor cancer cell to the acceptor macrophage cell or the acceptor monocyte cell,
wherein the bispecific anti-EGFR/c-Met antibody comprises:
a HC1 comprising the amino acid sequence of SEQ ID NO: 17, a LC1 comprising the amino acid sequence of SEQ ID NO: 18, a HC2 comprising the amino acid sequence of SEQ ID NO: 19, and a LC2 comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 56 (depends on 55)

The method of claim 55, wherein the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype.

### Claim 57 (depends on 55)

The method of claim 55, wherein the acceptor cell is the macrophage cell.

### Claim 58 (depends on 55)

The method of claim 55, wherein the acceptor cell is the monocyte cell.

### Claim 59 (depends on 55)

The method of claim 55, wherein the donor cancer cell has a wild-type EGFR, an EGFR activating mutation, an EGFR gene amplification, increased levels of circulating HGF, a wild-type c-Met, a c-Met activating mutation, a c-Met gene amplification, or a mutant KRAS.

### Claim 60 (depends on 55)

The method of claim 55, wherein the EGFR activating mutation comprises a L718Q, G719A, G719X (X being any amino acid), L861X (X being any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M substitution, deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, Val, and Ala (SVA) between S768 and V769, insertion of Asn and Ser (NS) between P772 and H773, insertion of one or more amino acids between D761 and E762, A763 and Y764, Y764 and Y765, M766 and A767, A767 and V768, S768 and V769, V769 and D770, D770 and N771, N771 and P772, P772 and H773, H773 and V774, V774 and C775, one or more deletions in EGFR exon 20, one or more insertions in EGFR exon 20, or any combination thereof.

### Claim 61 (depends on 60)

The method of claim 60, wherein the EGFR activating mutation comprises one or more insertions in EGFR exon 20.

### Claim 62 (depends on 60)

The method of claim 60, wherein the EGFR activating mutation comprises L858R, deletion of E746-A750, or deletion of R748-P753.

### Claim 63 (depends on 62)

The method of claim 62, wherein the EGFR activating mutation comprises L858R.

### Claim 64 (depends on 62)

The method of claim 62, wherein the EGFR activating mutation comprises deletion of E746-A750, or deletion of R748-P753.

### Claim 65 (depends on 59)

The method of claim 59, wherein the mutant KRAS comprises a G12V, G12C, or G12A substitution.

### Claim 66 (depends on 55)

The method of claim 55, wherein the contacting step is done in vitro.

### Claim 67 (depends on 55)

The method of claim 55, wherein the contacting step comprises administering the bispecific anti-EGFR/c-Met antibody to a subject.

### Claim 68 (depends on 67)

The method of claim 67, wherein the subject has an EGFR, c-Met, or EGFR and c-Met expressing cancer.

### Claim 69 (depends on 67)

The method of claim 67, wherein the subject has a newly diagnosed EGFR, c-Met, or EGFR and c-Met expressing cancer.

### Claim 70 (depends on 67)

The method of claim 67, wherein the subject is resistant or has acquired resistance to treatment with a prior anti-cancer therapy.

### Claim 71 (depends on 70)

The method of claim 70, wherein the prior anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

### Claim 72 (depends on 71)

The method of claim 71, wherein the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

### Claim 73 (depends on 72)

The method of claim 72, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 74 (depends on 69)

The method of claim 69, wherein the cancer cell expressing EGFR, c-Met, or EGFR and c-Met is derived from epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, cancer of the nose, pancreatic cancer, skin cancer, oral cancer, cancer of the tongue, esophageal cancer, vaginal cancer, cervical cancer, cancer of the spleen, testicular cancer, gastric cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, HCC, or sporadic or hereditary papillary renal cell carcinoma PRCC.

### Claim 75 (depends on 74)

The method of claim 74, wherein the cancer cell expressing EGFR, c-Met, or EGFR and c-Met is derived from non-small cell lung cancer (NSCLC).

### Claim 76 (depends on 74)

The method of claim 74, comprising further administering one or more anti-cancer therapies to the subject.

### Claim 77 (depends on 76)

The method of claim 76, wherein the one or more anti-cancer therapies comprise a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

### Claim 78 (depends on 77)

The method of claim 77, wherein the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

### Claim 79 (depends on 78)

The method of claim 78, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 80 (depends on 79)

The method of claim 79, wherein the kinase inhibitor is lazertinib.