Enzymatic conjugation of polypeptides
AssigneesInnate Pharma, Paul Scherrer Institut
InventorsDelphine Bregeon, Patrick Dennler, Christian Belmant, Eliane Fischer, Laurent Gauthier, Francois Romagné, Roger Schibli
Life of this patent
Estimating the term…
Abstract
The present application relates to methods for the functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.
Claims40
A composition comprising a population of antibodies or antibody fragments, wherein each member of the population has the same primary amino acid sequence, and wherein at least 90% of the antibodies or antibody fragments in the composition have (m) functionalized acceptor glutamine residues (Q) per antibody or fragment, wherein m is an integer selected from 2 or 4, and wherein each of the functionalized acceptor glutamine residues has the structure of Formula IVb,
- (Q)-NH-(C)n-X-L-(V—(Y-(M)z)q)r Formula IVb
- or a pharmaceutically acceptable salt or solvate thereof,
- wherein:
- Q is a glutamine residue present within or substituted into the primary amino acid sequence of a constant region of the antibodies or antibody fragments;
- (C)n is a substituted alkyl chain, an unsubstituted alkyl chain, a substituted heteroalkyl chain, or an unsubstituted heteroalkyl chain;
- n is an integer selected from among the range of 2 to 20;
- X is NH, O, S, absent, or a bond;
- L is independently absent, a bond or a continuation of a bond, or a carbon comprising framework of 1 to 200 atoms substituted at one or more atoms;
- r is an integer selected from among 1, 2, 3 or 4;
- q is an integer selected from among 1, 2, 3 or 4;
- z is an integer selected from among 1, 2, 3 or 4;
- V is independently absent, a bond or a continuation of a bond, a non-cleavable moiety or a conditionally-cleavable moiety;
- Y is independently absent, a bond or a continuation of a bond, or a spacer system which is comprised of 1 or more spacers;
- M is (RR′)-L′-(V′—(Y′—(Z)z′)q′)r′, wherein
- R is a reactive moiety;
- (RR′) is an addition product between R and a complementary reactive moiety R′;
- L′ is independently a carbon comprising framework of 1 to 200 atoms substituted at one or more atoms;
- V′ is independently absent, a bond or a continuation of a bond, a non-cleavable moiety or a conditionally-cleavable moiety;
- Y′ is independently absent, a bond or a continuation of a bond, or a spacer system which is comprised of 1 or more spacers;
- Z is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, nitrogen mustards, maytansinoids, calicheamycins, duocarmycins, tubulysines, amatoxins, dolastatins, auristatins, enediynes, pyrrolobenzodiazepines, and ethylenimines;
- and
- z′, q′ and r′ are each independently an integer selected from among 1, 2, 3 or 4,
- wherein the antibodies or antibody fragments specifically bind to a tumor antigen.
A composition comprising a population of antibodies or antibody fragments, wherein at least 90% of the antibodies or antibody fragments in the composition comprise on each heavy chain at least one functionalized acceptor glutamine residues having the structure of Formula IVb,
- (Q)-NH—(C)n-X-L-(V—(Y-(M)z)q)r Formula IVb
- or a pharmaceutically acceptable salt or solvate thereof,
- wherein:
- Q is a glutamine residue present within or substituted into the primary amino acid sequence of a constant region of the antibodies or antibody fragments;
- (C)n is a substituted alkyl chain, an unsubstituted alkyl chain, a substituted heteroalkyl chain, or an unsubstituted heteroalkyl chain;
- n is an integer selected from among the range of 2 to 20;
- X is NH, O, S, absent, or a bond;
- L is independently absent, a bond or a continuation of a bond, or a carbon comprising framework of 1 to 200 atoms substituted at one or more atoms;
- r is an integer selected from among 1, 2, 3 or 4;
- q is an integer selected from among 1, 2, 3 or 4;
- z is an integer selected from among 1, 2, 3 or 4;
- V is independently absent, a bond or a continuation of a bond, a non-cleavable moiety or a conditionally-cleavable moiety;
- Y is independently absent, a bond or a continuation of a bond, or a spacer system which is comprised of 1 or more spacers;
- M is (RR′)-L′-(V′—(Y′—(Z)z′)q′)r′, wherein
- R is a reactive moiety;
- (RR′) is an addition product between R and a complementary reactive moiety R′;
- L′ is independently a carbon comprising framework of 1 to 200 atoms substituted at one or more atoms;
- V′ is independently absent, a bond or a continuation of a bond, a non-cleavable moiety or a conditionally-cleavable moiety;
- Y′ is independently absent, a bond or a continuation of a bond, or a spacer system which is comprised of 1 or more spacers;
- Z is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, nitrogen mustards, maytansinoids, calicheamycins, duocarmycins, tubulysines, amatoxins, dolastatins and auristatins, enediynes, pyrrolobenzodiazepines, and ethylenimines;
- and
- z′, q′ and r′ are each independently an integer selected from among 1, 2, 3 or 4 wherein at least 90% of the antibodies or antibody fragments in the composition have (m) functionalized acceptor glutamine residues (Q) per antibody or fragment, wherein m is an integer selected from 2 or 4,
- wherein the antibodies or antibody fragments specifically bind to a tumor antigen and wherein each member of the population has the same primary amino acid sequence.
A composition comprising a population of antibodies or antibody fragments, wherein each member of the population has the same primary amino acid sequence, and wherein at least 90% of the antibodies or antibody fragments in the composition have (m) functionalized acceptor glutamine residues (Q) per antibody or fragment, wherein m is an integer selected from 2 or 4, and wherein each of the functionalized acceptor glutamine residues has the structure:
- (Q)-L″-RR′—Y—Z
- or a pharmaceutically acceptable salt or solvate thereof,
- wherein:
- Q is a glutamine residue present within or substituted into the primary amino acid sequence of a constant region of the antibodies or antibody fragments;
- L″ is a lysine-based linker in which the nitrogen atom is covalently bonded to the y carbon of Q as a secondary amine;
- (RR′) is an addition product between a reactive moiety R and a complementary reactive moiety R′;
- Y is a spacer system;
- and
- Z is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, nitrogen mustards, maytansinoids, calicheamycins, duocarmycins, tubulysines, amatoxins, dolastatins, auristatins, enediynes, pyrrolobenzodiazepines, and ethylenimines,
- wherein the antibodies or antibody fragments specifically bind to a tumor antigen.
Dependencies are inferred from the claim text.