# US 10,307,488 B2 · Antibody-drug conjugates and the use of same in therapy

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- Number: US 10,307,488 B2
- Document ID: US10307488B2
- Status: Granted
- Kind: B2
- Application number: 14/904,353
- Filed: 2014-07-11
- Published: 2016-06-02
- Granted: 2019-06-04
- Earliest claimed: 2013-07-11
- Assignees: Universite Francois Rabelais
- Applicants: Universite Francois Rabelais
- Inventors: Nicolas Joubert; Marie Claude Viaud-Massuard; Renaud Respaud
- Web page: https://patentgrep.com/patent/US10307488B2

## CPC

- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6871: {the antibody targeting an enzyme}
- 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 49/00: Preparations for testing in vivo
- A61K 51/02: characterised by the carrier {, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 207/456: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07K 16/2887: {against CD20}
- C07K 16/32: against translation products of oncogenes
- C07K 16/40: against enzymes
- C12N 9/1077: {Pentosyltransferases (2.4.2)}
- C12N 9/24: acting on glycosyl compounds (3.2)
- C12N 9/2497: {hydrolysing N- glycosyl compounds (3.2.2)}
- C12Y 204/02036: NAD(+)--diphthamide ADP-ribosyltransferase (2.4.2.36)
- C12Y 302/00: Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y 302/02022: rRNA N-glycosylase (3.2.2.22)
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Disclosed are novel antibody-drug conjugates and use thereof in therapy, in particular in anticancer or anti-inflammatory therapy, as well as synthetic products useful as linkers, composed of a linker head and a linker body, and also a method for preparing the linkers and the antibody-drug conjugates.

## Claims

### Claim 1

A product that corresponds to formula I selected from formulae IB:
where in formula IB:
A represents either an aryl or cycloalkyl radical, said aryl or cycloalkyl radical is carbocyclic or heterocyclic,
X1 is a C═O or an NH group or a single bond
X2 is an NH group or a C═O or a single bond
X3 is an oxygen or a single bond
s is equal to 1, 2 or 3
r is equal to 0, 1 or 2
wherein the sum r+s is equal to 3
n1 is an integer equal to 0 or 1; n2 is an integer equal to 1, 2 or 3 and n3 is an integer equal to 1, 2 or 3, and
W represents:
an -L radical which represents a linker comprising a terminal reactive function corresponding to general formula III:
wherein:
K represents a
radical representing a sequence of n5 amino acids, which is identical or different, natural or non-natural, wherein n5 represents an integer from 1 to 6,
Z represents a leaving group selected from the group consisting of para cyano phenyloxy,
and a chlorine atom
a cytotoxic drug M which is a chemotherapeutic agent or a toxin selected from the group consisting of methotrexate, Ilomedin, an IMIDs, Duocarmycin, combretastatin, calicheamicin, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansine, DM1, DM4, SN38, Amanitin, a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, a pyrrolopyridodiazepine, a pyrrolopyridodiazepine dimer, a histone deacetylase inhibitor, a tyrosine kinase inhibitor, and ricin,
an -L-M radical in which L and M have the meanings given above,
an -FL fluorophore group selected from the group consisting of rhodamine B, fluorescein isothiocyanate (FITC), a Cy dye selected from the group consisting of Cy5, Cy5.5, and Cy7, an Alexa fluor dye selected from the group consisting of Alexa Fluor 647, Alexa Fluor 700 and Alexa Fluor 750, Texas Red, Nile Blue A, allophycocyanin (APC), and phycoerythrin (PE),
P is an antibody or an antibody fragment, a fusion protein comprising an antibody or an antibody fragment,
wherein:
the antibody is a chimeric monoclonal antibody, humanized or human, monospecific or bispecific,
the antibody fragment is selected from the group consisting of Fab, F(ab)′2, Fc, F′c, pFc′, ScFv, Fv, Fd, Fabc, diabody, minibody, ScFv-Fc and ScFv-Fv,
or
P is an albumin,
and
t represents an integer from 1 to 15.

### Claim 2 (depends on 1)

The product according to claim 1, wherein the
group is a radical selected from the group consisting of:
wherein each of T, Y and Z independently represents a carbon or nitrogen,
wherein CA is a cycloalkyl group, and
wherein Het is a heterocycle, heteroaryl, or aryl.

### Claim 3 (depends on 1)

The product according to claim 1 in which the
radical is such that n5 is equal to 1, 2, 3, 4 or 6, and AA represents a valine and a citrulline; or a phenylalanine and a lysine; or a valine and an aspartic acid; or a lysine and a methionine; or a lysine and an asparagine; or a proline and an isoleucine; or a proline and a lysine; or a lysine and a methionine; or a lysine and an asparagine; or a valine and a lysine; or an alanine and a lysine; or a phenylalanine and a lysine; or two phenylalanines and a lysine; or an alanine, a phenylalanine and a lysine; two arginines; a lysine and an arginine; a glutamic acid, a glycine and an arginine; two glycines and an arginine.

### Claim 4 (depends on 2)

The product according to claim 2, wherein T is a nitrogen atom, and Y and Z represent CH.