| 主权项 |
1. A method of treating a mammal having a proliferative disease comprising administering an effective amount of the conjugate of having formula I:
L-(LU-D)p (I)or a pharmaceutically acceptable salt thereof;wherein the proliferative disease treated is characterized by differential expression of a tumour-associated antigen selected from the group consisting of:
(1) BMPR1B (bone morphogenetic protein receptor-type IB); (2) E16 (LAT1, SLC7A5); (3) STEAP1 (six transmembrane epithelial antigen of prostate); (4) 0772P (CAl25, MUC16); (5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin); (6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b); (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B); (8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene); (9) ETBR (Endothelin type B receptor); (10) MSG783 (RNF124, hypothetical protein FLJ20315); (11) STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein); (12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4); (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor); (14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs 73792); (15) CD79b (CD79B, CD79β, IGb (immunoglobulin-associated beta), B29); (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C); (17) HER2; (18) NCA; (19) MDP; (20) IL20Rα; (21) Brevican; (22) EphB2R; (23) ASLG659; (24) PSCA; (25) GEDA; (26) BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3); (27) CD22 (B-cell receptor CD22-B isoform); (28) CD79a (CD79A, CD79a, immunoglobulin-associated alpha); (29) CXCR5 (Burkitt's lymphoma receptor 1); (30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen)); (31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5); (32) CD72 (B-cell differentiation antigen CD72, Lyb-2); (33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family); (34) FcRH1 (Fc receptor-like protein 1); (35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2); and (36) CD19; (37) CD20; (38) CD30; (39) CD33; (40) Glycoprotein NMB; (41) CanAg; (42) CD56 (NCAM); (43) CD70; (44) PSMA (prostate specific membrane antigen); (45) BCMA; (46) E-selectin; (47) Melanotransferin; (48) TMEFF2;wherein in formula I L is a Ligand unit selected from an antibody to said tumour-associated antigen and an antigen-binding fragment of an antibody to said tumour-associated antigen,
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 SON, 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 0, S, and NH, or an aromatic ring; Y and Y′ are selected from the group consisting of 0, 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. |
