# US 10,117,953 B2 · Antibody drug conjugates

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- Number: US 10,117,953 B2
- Document ID: US10117953B2
- Status: Granted
- Kind: B2
- Application number: 15/284,444
- Filed: 2016-10-03
- Published: 2017-02-09
- Granted: 2018-11-06
- Earliest claimed: 2013-03-15
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Tinya Abrams; Steven Bruce Cohen; Christie P. Fanton; Thomas Huber; Kathy Miller; Siew Ho Schleyer; Kathrin Ulrike Tissot-Daguette; Catrin Finner
- Web page: https://patentgrep.com/patent/US10117953B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 31/537: spiro-condensed or forming part of bridged ring systems
- A61K 39/39591: {Stabilisation, fragmentation}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/6801: {Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent}
- A61K 47/68033: {the drug being a maytansine}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6857: {the tumour determinant being from lung cancer cell}
- A61K 47/6865: {the tumour determinant being from skin, nerves or brain cancer cell}
- A61K 47/6867: {the tumour determinant being from a cell of a blood cancer}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61K 47/6921: {the form being a particulate, a powder, an adsorbate, a bead or a sphere}
- A61K 49/00: Preparations for testing in vivo
- A61K 51/103: {against receptors for growth factors or receptors for growth regulators}
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61P 35/00: Antineoplastic agents
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/32: against translation products of oncogenes
- G01N 33/53: Immunoassay; Biospecific binding assay; Materials therefor
- G01N 33/532: Production of labelled immunochemicals
- G01N 33/575: for cancer
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/55: Fab or Fab'
- 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 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to anti-cKIT antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.

## Claims

### Claim 1

An antibody drug conjugate of the formula
Ab—(L—(D)m)n
or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 22, (b) a VH CDR2 of SEQ ID NO: 23, (c) a VH CDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 31, (e) a VL CDR2 of SEQ ID NO: 32, and (f) a VL CDR3 of SEQ ID NO: 33 and specifically binds to an epitope of human cKIT at domains 1-3 (SEQ ID NO:155);
L is a linker;
D is a drug moiety;
m is an integer from 1 to 8; and
n is an integer from 1 to 10.

### Claim 2 (depends on 1)

The antibody drug conjugate of claim 1, wherein said n is 3 or 4.

### Claim 3 (depends on 1)

The antibody drug conjugate of claim 1, wherein said linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, a procharged linker and a dicarboxylic acid based linker.

### Claim 4 (depends on 3)

The antibody drug conjugate of claim 3, wherein the linker is derived from a cross-linking reagent selected from the group consisting of N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC), N-sulfosuccinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (sulfo-SMCC) or 2,5-dioxopyrrolidin-1-yl 17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-1-oate (CX1-1).

### Claim 5 (depends on 4)

The antibody drug conjugate of claim 4, wherein said linker is derived from the cross-linking reagent N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC).

### Claim 6 (depends on 1)

The antibody drug conjugate of claim 1, wherein the drug moiety is a maytansinoid.

### Claim 7 (depends on 6)

The antibody drug conjugate of claim 6, wherein the maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).

### Claim 8

An antibody drug conjugate of the formula
or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 22, (b) a VH CDR2 of SEQ ID NO: 23, (c) a VH CDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 31, (e) a VL CDR2 of SEQ ID NO: 32, and (f) a VL CDR3 of SEQ ID NO: 33 and specifically binds to human cKIT, and comprises at least n number of primary amines; and n is an integer from 1 to 10.

### Claim 9 (depends on 8)

The antibody drug conjugate of claim 8, wherein said n is 3 or 4.

### Claim 10 (depends on 1, 8)

The antibody drug conjugate of claim 1 or claim 8, wherein said antibody is a humanized antibody.

### Claim 11 (depends on 1, 8)

The antibody drug conjugate of claim 1 or claim 8, wherein said antibody is a monoclonal antibody.

### Claim 12 (depends on 1, 8)

A pharmaceutical composition comprising the antibody drug conjugate of claim 1 or claim 8 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12 wherein said composition is prepared as a lyophilisate.

### Claim 14 (depends on 1, 13)

The pharmaceutical composition of claim 13, wherein said lyophilisate comprises the antibody drug conjugate of claim 1, sodium succinate, and polysorbate 20.

### Claim 15 (depends on 1, 8)

The antibody drug conjugate of claim 1 or 8, wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region (vH) that comprises SEQ ID NO: 28, and a light chain variable region (vL) that comprises SEQ ID NO:37.