Claims for Patent: 9,695,240

Summary for Patent: 9,695,240

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:	Genentech, Inc. (South San Francisco, CA) Nerviano Medical Sciences S.R.L. (Milan, IT)
Application Number:	14/528,142
Patent Claims:	1. A method of making an antibody-drug conjugate compound comprising reacting an anthracycline derivative and an antibody (Ab) to form the antibody-drug conjugate compound, wherein the anthracycline derivative is selected from the structures: ##STR00113## ##STR00114## where R is H, C.sub.1-C.sub.12 alkyl, or C.sub.6-C.sub.20 aryl; and R.sup.1 and R.sup.2 are independently selected from an amino acid side chain; the antibody (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_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); and the antibody-drug conjugate compound is selected from the structures: ##STR00115## ##STR00116## 2. The method of claim 1 wherein Ab is a cysteine-engineered antibody. 3. The method of claim 1 wherein Ab is trastuzumab. 4. The method of claim 1 wherein the antibody-drug conjugate compound comprises 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. 5. The method of claim 4 wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 3 to about 4. 6. The method of claim 1 wherein R is --CH.sub.3. 7. The method 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. 8. The method of claim 1 wherein R.sup.1 is --(CH.sub.2).sub.3NHCONH.sub.2 and R.sup.2 is isopropyl. 9. The method of claim 1 wherein the anthracycline derivative has the structure: ##STR00117## and the antibody-drug conjugate compound has the structure: ##STR00118##

Details for Patent 9,695,240

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