Targeted pyrrolobenzodiazapine conjugates

A conjugate having formula I:

• L-(LU-D)p (I)
• or a pharmaceutically acceptable salt thereof;
• wherein L is a Ligand unit selected from an antibody, an antigen-binding fragment of an antibody or a Fc fusion protein,
• LU is a Linker unit which is of formula 1a:
• -A1-L1-, (1a)
• wherein:
• -A1- is selected from the group consisting of:
• wherein the asterisk indicates the point of attachment to L1, the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;
• wherein the asterisk indicates the point of attachment to L1, the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30;
• and
• wherein the asterisk indicates the point of attachment to L1, the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30;
• L1 is an amino acid sequence, and is cleavable by the action of an enzyme;
• p is 1 to 20;
• and
• D is a Drug unit wherein the Drug unit is a PBD dimer having the following formula II:
• wherein:
• R2 is of formula III:
• wherein A is a C5-7 aryl group, X is connected to the Linker unit and is selected from the group consisting of —O—, —S—, —C(O)O—, —C(O)—, —NH(C═O)—, and —N(RN)—, wherein RN is selected from the group consisting of H, C1-4 alkyl and (C2H4O)mCH3, where m is 1 to 3, and either:
• (i) Q1 is a single bond, and Q2 is selected from the group consisting of a single bond and —Z—(CH2)n—, wherein Z is selected from the group consisting of 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;
• R12 is a C5-10 aryl group optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C1-7 alkoxy, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;
• R6 and R9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• R7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;
• wherein R and R′ are independently selected from the group consisting of optionally substituted C1-12 alkyl, C3-20 heterocyclyl, and C5-20 aryl groups;
• either:
• (a) R10 is H, and R11 is OH, ORA, wherein RA is C1-4 alkyl, or
• (b) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound, or
• (c) R10 is H and R11 is SOzM, wherein z is 2;
• R″ is a C3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms selected from the group consisting of O, S, and NH, or an aromatic ring;
• Y and Y′ are selected from the group consisting of O, S, and NH;
• R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively, and R10′ and R11′ are the same as R10 and R11, and each M is a monovalent pharmaceutically acceptable cation or both M groups together are a divalent pharmaceutically acceptable cation;
• wherein C3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S;
• and
• wherein C3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.