# US 2024/0199748 A1 · Combination therapies with bispecific anti-egfr/c-met antibodies and third generation egfr tyrosine kinase inhibitors

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- Number: US 2024/0199748 A1
- Document ID: US20240199748A1
- Status: Published application
- Kind: A1
- Application number: 18/510,412
- Filed: 2023-11-15
- Published: 2024-06-20
- Earliest claimed: 2019-05-14
- Assignees: Janssen Biotech, Inc.
- Applicants: Janssen Biotech, Inc.
- Inventors: Sylvie LAQUERRE; Matthew LORENZI; Sheri MOORES
- Web page: https://patentgrep.com/patent/US20240199748A1

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61K 2039/505: {comprising antibodies}
- C07K 2317/31: multispecific
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to combination therapies with bispecific anti-EGFR/c-Met antibodies and 3rd generation EGFR tyrosine kinase inhibitors.

## Claims

### Claim at position 1

1-45. (canceled)

### Claim 46

A pharmaceutical combination comprising:
a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody; and
a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof.

### Claim 47 (depends on 46)

The pharmaceutical combination of claim 46, wherein the isolated bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody comprises a first domain that binds EGFR comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, the HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, the 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 the LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; and a second domain that binds c-Met comprising 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 48 (depends on 46)

The pharmaceutical combination of claim 46, wherein the compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

### Claim 49 (depends on 46)

The pharmaceutical combination of claim 46, wherein the compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof is a mesylate salt of formula (I).

### Claim 50 (depends on 46)

The pharmaceutical combination of claim 46, comprising between about 350 mg and about 1400 mg of the bispecific EGFR/c-Met antibody and between about 160 mg and about 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

### Claim 51 (depends on 49)

The pharmaceutical combination of claim 49, wherein the mesylate salt of formula (I) is represented by formula (II)

### Claim 52 (depends on 46)

The pharmaceutical combination of claim 46, wherein the pharmaceutical combination is a non-fixed combination.

### Claim 53 (depends on 47)

The pharmaceutical combination of claim 47, wherein the first domain that binds EGFR comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (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 54 (depends on 43)

The pharmaceutical combination of claim 43, wherein the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 17, a first light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 18, a second heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 19, and a second light chain (LC2) comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 55 (depends on 46)

The pharmaceutical combination of claim 46, wherein the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype.

### Claim 56 (depends on 46)

The pharmaceutical combination of claim 46, wherein the bispecific anti-EGFR/c-Met antibody has a biantennary glycan structure with a fucose content of between about 1% to about 15%.

### Claim 57 (depends on 46)

The pharmaceutical combination of claim 46, wherein the bispecific EGFR/c-Met antibody and the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof are formulated in separate compositions.

### Claim 58

A pharmaceutical combination comprising:
a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody; and
a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof;
wherein the bispecific anti-EGFR/c-Met antibody comprises:
(a) a first domain that binds EGFR comprising the first heavy chain complementarity determining region 1 (HCDR1), the first HCDR2, and the first HCDR3 of the heavy chain variable region (VH) of SEQ ID NO: 13 and the first light chain complementarity determining region 1 (LCDR1), the first LCDR2, and the first LCDR3 of the light chain variable region (VL) of SEQ ID NO: 14; and
(b) a second domain that binds c-Met comprising the second HCDR1, the second HCDR2, and the second HCDR3 of the VH of SEQ ID NO: 15 and the second LCDR1, the second LCDR2, and the second LCDR3 of the VL of SEQ ID NO: 16.

### Claim 59 (depends on 58)

The pharmaceutical combination of claim 58, wherein
(a) the first HCDR1 comprises the amino acid sequence of SEQ ID NO: 1, the first HCDR2 comprises the amino acid sequence of SEQ ID NO: 2, the first HCDR3 comprises the amino acid sequence of SEQ ID NO: 3, the first LCDR1 comprises the amino acid sequence of SEQ ID NO: 4, the first LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and the first LCDR3 comprises the amino acid sequence of SEQ ID NO: 6; and
(b) the second HCDR1 comprises the amino acid sequence of SEQ ID NO: 7, the second HCDR2 comprises the amino acid sequence of SEQ ID NO: 8, the second HCDR3 comprises the amino acid sequence of SEQ ID NO: 9, the second LCDR1 comprises the amino acid sequence of SEQ ID NO: 10, the second LCDR2 comprises the amino acid sequence of SEQ ID NO: 11, and the second LCDR3 comprises the amino acid sequence of SEQ ID NO: 12.

### Claim 60 (depends on 59)

The pharmaceutical combination of claim 59, wherein
(a) 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
(b) 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 61 (depends on 60)

The pharmaceutical combination of claim 60, wherein
(a) the first domain that binds EGFR comprises the VH of SEQ ID NO:13 and the VL of SEQ ID NO: 14; and
(b) the second domain that binds c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

### Claim 62 (depends on 58)

The pharmaceutical combination of claim 58, wherein the compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof is a mesylate salt of formula (I).

### Claim 63 (depends on 62)

The pharmaceutical combination of claim 62, wherein the mesylate salt of formula (I) is represented by formula (II)

### Claim 64 (depends on 58)

The pharmaceutical combination of claim 58, wherein the bispecific EGFR/c-Met antibody and the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof are formulated in separate compositions.

### Claim 65

A pharmaceutical combination comprising:
a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody; and
a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof;
wherein the bispecific anti-EGFR/c-Met antibody comprises:
(a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a first light chain comprising the amino acid sequence of SEQ ID NO: 18; and
(b) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a second light chain comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 66 (depends on 65)

The pharmaceutical combination of claim 65, comprising:
(a) the first heavy chain of SEQ ID NO: 17 and the first light chain of SEQ ID NO: 18; and
(b) the second heavy chain of SEQ ID NO: 19 and the second light chain of SEQ ID NO: 20.

### Claim 67 (depends on 65)

The pharmaceutical combination of claim 65, comprising between about 350 mg and about 1400 mg of the bispecific EGFR/c-Met antibody and between about 160 mg and about 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

### Claim 68 (depends on 65)

The pharmaceutical combination of claim 65, wherein the compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof is a mesylate salt of formula (I).

### Claim 69 (depends on 68)

The pharmaceutical combination of claim 68, wherein the mesylate salt of formula (I) is represented by formula (II)

### Claim 70 (depends on 65)

The pharmaceutical combination of claim 65, wherein the bispecific EGFR/c-Met antibody and the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof are formulated in separate compositions.