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Last Updated: March 29, 2024

Claims for Patent: 8,900,589


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Summary for Patent: 8,900,589
Title:Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds
Abstract: The present invention relates to conjugates of therapeutically useful anthracyclines with carriers such as polyclonal and monoclonal antibodies, proteins or peptides of natural or synthetic origin; methods for their preparation, pharmaceutical composition containing them and use thereof in treating certain mammalian tumors.
Inventor(s): Beria; Italo (Milan, IT), Caruso; Michele (Milan, IT), Flygare; John A. (Burlingame, CA), Lupi; Vittoria (Milan, IT), Perego; Rita (Milan, IT), Polakis; Paul (Mill Valley, CA), Polson; Andrew (San Francisco, CA), Salsa; Matteo (Milan, IT), Spencer; Susan D. (Tiburon, CA), Valsasina; Barbara (Milan, IT), Cohen; Robert L. (San Mateo, CA)
Assignee: Genetech, Inc. (South San Francisco, CA)
Application Number:12/502,433
Patent Claims:1. An antibody-drug conjugate compound comprising an antibody covalently attached by a linker L and an optional spacer Z to one or more anthracycline derivative drug moieties D, the compound having the formula (D-L-(Z).sub.m).sub.p-Ab or a pharmaceutically acceptable salt thereof, wherein: Ab is an antibody; D is an anthracycline derivative selected from the structures A and B: ##STR00113## where the wavy line indicates the attachment to L; L is a linker selected from --CH.sub.2O--, --N(R)(C.sub.1-C.sub.12 alkylene)-X.sup.1, --N(R)--, --N(R).sub.m(C.sub.1-C.sub.12 alkylene)-, --N(R)(C.sub.2-C.sub.8 alkenylene)-, --N(R)(C.sub.2-C.sub.8 alkynylene)-, --N(R)(CH.sub.2CH.sub.2O).sub.n--, and the structures: ##STR00114## where the wavy lines indicate the attachments to D and Z; and Z is an optional spacer selected from --CH.sub.2C(O)--, --CH.sub.2C(O)NR(C.sub.1-C.sub.12 alkylene)-, and the structures: ##STR00115## R is H, C.sub.1-C.sub.12 alkyl, or C.sub.6-C.sub.20 aryl; R.sup.1 and R.sup.2 are independently selected from an amino acid side chain; Z.sup.1 is selected from X.sup.1, --S--, --CH.sub.2C(O)--, --(CH.sub.2CH.sub.2O).sub.nCH.sub.2C(O)--, --(CH.sub.2CH.sub.2O).sub.nCH.sub.2--X.sup.1--, --(C.sub.1-C.sub.12 alkylene)-X.sup.1, and --(C.sub.1-C.sub.12 alkylene); X.sup.1 is ##STR00116## m is 0 or 1; n is 1 to 6; and p is an integer from 1 to 8, wherein Ab is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(36): (1) BMPR1B (bone morphogenetic protein receptor-type IB); (2) E16 (LAT1, SLC7A5); (3) STEAP1 (six transmembrane epithelial antigen of prostate); (4) 0772P (CA125, 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.sub.--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, CD79.beta., IGb (immunoglobulin-associated beta), B29); (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C); (17) HER2 (ErbB2); (18) NCA (CEACAM6); (19) MDP (DPEP1); (20) IL20R.alpha. (IL20Ra, ZCYTOR7); (21) Brevican (BCAN, BEHAB); (22) EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5); (23) ASLG659 (B7h); (24) PSCA (Prostate stem cell antigen precursor); (25) GEDA (lipoma HMGIC fusion-partner-like protein); (26) BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3); (27) CD22 (B-cell receptor CD22-B isoform); (28) CD79a (CD79A, CD79.alpha., 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 (Fc receptor-like protein 1, Immunoglobulin superfamily receptor translocation associated 2); and (36) TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR, putative transmembrane proteoglycan).

2. The antibody-drug conjugate compound of claim 1 wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, --CH.sub.2OH, --CH(OH)CH.sub.3, --CH.sub.2CH.sub.2SCH.sub.3, --CH.sub.2CONH.sub.2, --CH.sub.2COOH, --CH.sub.2CH.sub.2CONH.sub.2, --CH.sub.2CH.sub.2COOH, --(CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, --(CH.sub.2).sub.3NH.sub.2, --(CH.sub.2).sub.3NHCOCH.sub.3, --(CH.sub.2).sub.3NHCHO, --(CH.sub.2).sub.4NHC(.dbd.NH)NH.sub.2, --(CH.sub.2).sub.4NH.sub.2, --(CH.sub.2).sub.4NHCOCH.sub.3, --(CH.sub.2).sub.4NHCHO, --(CH.sub.2).sub.3NHCONH.sub.2, --(CH.sub.2).sub.4NHCONH.sub.2, --CH.sub.2CH.sub.2CH(OH)CH.sub.2NH.sub.2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, and the following structures: ##STR00117##

3. The antibody-drug conjugate compound of claim 1 wherein spacer Z comprises a para-aminobenzyloxycarbonyl (PAB) group.

4. The antibody-drug conjugate compound of claim 1 wherein linker-spacer unit L-Z comprises a maleimidocaproyl (MC) group.

5. The antibody-drug conjugate compound of claim 4 wherein Z comprises a valine-citrulline (vc) group.

6. The antibody-drug conjugate compound of claim 1 wherein Ab is a cysteine-engineered antibody.

7. The antibody-drug conjugate of claim 1 wherein Ab is trastuzumab.

8. The antibody-drug conjugate compound of claim 1 wherein p is 1, 2, 3, or 4.

9. The antibody-drug conjugate compound of claim 1 comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

10. The antibody-drug conjugate compound of claim 9 wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 3 to about 4.

11. A pharmaceutical composition comprising the antibody-drug conjugate compound of claim 1 and a pharmaceutically acceptable diluent, carrier or excipient.

12. The pharmaceutical composition of claim 11 further comprising a therapeutically effective amount of a chemotherapeutic agent.

13. An article of manufacture comprising an antibody-drug conjugate compound of claim 1; a container; and a package insert or label indicating that the compound can be used to treat cancer.

14. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to STEAP1.

15. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to HER2.

16. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to CD22.

17. The antibody-drug conjugate compound of claim 1 selected from the structures: ##STR00118##

18. The antibody-drug conjugate compound of claim 1 having the structure: ##STR00119##

19. The antibody-drug conjugate compound of claim 5 having the structure: ##STR00120##

20. The antibody-drug conjugate compound of claim 5 having the structure: ##STR00121##

Details for Patent 8,900,589

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 09/25/1998 ⤷  Try a Trial 2039-02-26
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 02/10/2017 ⤷  Try a Trial 2039-02-26
Genentech, Inc. HERCEPTIN HYLECTA trastuzumab and hyaluronidase-oysk Injection 761106 02/28/2019 ⤷  Try a Trial 2039-02-26
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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