Antibody-drug conjugates and the use of same in therapy
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.
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,
X 1 is a C═O or an NH group or a single bond
X 2 is an NH group or a C═O or a single bond
X 3 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
n 1 is an integer equal to 0 or 1; n 2 is an integer equal to 1, 2 or 3 and n 3 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 n 5 amino acids, which is identical or different, natural or non-natural, wherein n 5 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.
2. 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.
3. The product according to claim 1 in which the
radical is such that n 5 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.
4. The product according to claim 2 , wherein T is a nitrogen atom, and Y and Z represent CH.