SILVESTROL ANTIBODY-DRUG CONJUGATES AND METHODS OF USE
First Claim
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1. An antibody-drug conjugate compound comprising an antibody covalently attached through a linker to a silvestrol drug moiety, selected from Formulas Ia and Ib:
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Abstract
The invention relates generally to a silvestrol molecule activated with a leaving group. The invention further relates generally to an antibody-drug conjugate comprising an antibody conjugated by a linker to one or more silvestrol drug moieties and methods of treatment.
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Citations
53 Claims
- 1. An antibody-drug conjugate compound comprising an antibody covalently attached through a linker to a silvestrol drug moiety, selected from Formulas Ia and Ib:
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2. The antibody-drug conjugate compound of claiml wherein the antibody which binds to one or more tumor-associated antigens or cell-surface receptors is selected from (1)-(53):
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(1) BMPR1B (bone morphogenetic protein receptor-type IB); (2) E16 (LAT1, SLC7A5); (3) STEAP1 (six transmembrane epithelial antigen of prostate); (4) MUC16 (0772P, CA125); (5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin); (6) Napi2b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b); (7) Sema 5b (F1110372, 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 F1120315); (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, F1120041, 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, CD7913, 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, CD79α
, immunoglobulin-associated alpha);(29) CXCR5 (Burkitt'"'"'s lymphoma receptor
1);(30) HLA-DOB (Beta subunit of MEW 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) FcRH5 (IRTA2, Immunoglobulin superfamily receptor translocation associated
2);(36) TENB2 (putative transmembrane proteoglycan); (37) PMEL17 (silver homolog;
SILV;
D12S53E;
PMEL17;
SI;
SIL);(38) TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1;
Tomoregulin-1);(39) GDNF-Ra1 (GDNIF family receptor alpha 1;
GFRA1;
GDNFR;
GDNFRA;RETL1;
TRNR1;
RET1L;
GDNFR-alphal;
GFR-ALPHA-1);(40) Ly6E (lymphocyte antigen 6 complex, locus E;
Ly67,RIG-E,SCA-2,TSA-1);(41) TMEM46 (shisa homolog 2 (Xenopus laevis);
SHISA2);(42) Ly6G6D (lymphocyte antigen 6 complex, locus G6D;
Ly6-D, MEGT1);(43) LGRS (leucine-rich repeat-containing Ci protein-coupled receptor 5;
GPR49, GPR67);(44) RET (ret proto-oncogene;
MEN2A;
HSCR1;
MEN2B;
MTC1;
PTC;
CDHF12;
Hs.168114;
RET51;
RET-ELE1);(45) LY6K (lymphocyte antigen 6 complex, locus K;
LY6K;
HSJ001348;
FLJ35226);(46) GPR19 (G protein-coupled receptor 19;
Mm.4787);(47) GPR54 (KISS1 receptor;
KISS1R;
GPR54;
HOT7T175;
AXOR12);(48) ASPHD1 (aspartate beta-hydroxylase domain containing 1;
LOC253982);(49) Tyrosinase (TYR;
OCAIA;
OCA1A;
tyrosinase;
SHEP3);(50) TMEM118 (ring finger protein, transmembrane 2;
RNFT2;
FLJ14627);(51) GPR172A (G protein-coupled receptor 172A;
GPCR41;
FLJ11856;
D15Ertd747e);(52) CD33; and (53) CLL-1. - View Dependent Claims (3)
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- 37. A silvestrol-linker intermediate compound of Formula II:
Specification