Site-specific antibody-drug conjugates

A conjugate of formula L-(DL)p, where DL is of formula I or II:

• wherein:
• L is an antibody (Ab) which binds CD22, and which comprises:
• heavy chains comprising an amino acid substitution of each of HC226 and HC229 according to the EU index as set forth in Kabat,
• light chains each having an amino acid substitution of the interchain cysteine residue κLC214 or λLC213 according to the EU index as set forth in Kabat, and
• heavy chains each retaining the unsubstituted interchain cysteine HC220 according to the EU index as set forth in Kabat;
• when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of:
• (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising:
• halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;
• (ib) C1-5 saturated aliphatic alkyl;
• (ic) C3-6 saturated cycloalkyl;
• (id)
• wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5;
• (ie)
• wherein one of R25a and R25b is H and the other is selected from:
• phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy;
• pyridyl;
• and thiophenyl;
• and
• (if)
• where R24 is selected from:
• H;
• C1-3 saturated alkyl;
• C2-3 alkenyl;
• C2-3 alkynyl;
• cyclopropyl;
• phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy;
• pyridyl;
• and thiophenyl;
• when there is a single bond present between C2′ and C3′,
• R12 is
• where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester;
• or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester;
• R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;
• R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;
• R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine;
• Y and Y′ are selected from O, S, or NH;
• R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively;
• [Formula I]
• RL1′ is a linker for connection to the antibody (Ab);
• R11a is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
• R20 and R21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
• R20 is selected from H and RC, where RC is a capping group;
• R21 is selected from OH, ORA and SOzM;
• when there is a double bond present between C2 and C3, R2 is selected from the group consisting of:
• (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising:
• halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;
• (ib) C1-5 saturated aliphatic alkyl;
• (ic) C3-6 saturated cycloalkyl;
• (id)
• wherein each of R11, R12 and R13 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5;
• (ie)
• wherein one of R15a and R1b is H and the other is selected from:
• phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy;
• pyridyl;
• and thiophenyl;
• and
• (if)
• where R14 is selected from:
• H;
• C1-3 saturated alkyl;
• C2-3 alkenyl;
• C2-3 alkynyl;
• cyclopropyl;
• phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy;
• pyridyl;
• and thiophenyl;
• when there is a single bond present between C2 and C3,
• R2 is
• where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester;
• or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester;
• [Formula I]
• R22 is of formula IIIa, formula IIIb or formula IIIc:
• (a)
• where A is a C5-7 aryl group, and either
• (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond, O, S and NH and n is from 1 to 3;
• or
• (ii) Q1 is —CH═CH—, and Q2 is a single bond;
• (b)
• where;
• RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl;
• (c)
• where Q is selected from O—RL2′, S—RL2′, and NRN—RL2′, and RN is selected from H, methyl and ethyl
• X is selected from the group comprising:
• O—RL2′, CO2—RL2′, CO—RL2′, NH—C(═O)—RL2′, NHNH—RL2′, CONHNH—RL2′,
• NRNRL2′, wherein RN is selected from the group comprising H and C1-4 alkyl;
• RL2′ is a linker for connection to the antibody (Ab);
• R10 and R11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
• R10 is H and R11 is selected from OH, ORA and SOzM;
• R30 and R31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
• R30 is H and R31 is selected from OH, ORA and SOzM;
• [Formula I and II]
• wherein the conjugation of the drug moiety to the antibody is at HC220 according to the EU index as set forth in Kabat.