Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds

Patent metadata

Field	Value
Publication number	US-9695240-B2
Application number	US-201414528142-A
Country	US
Kind code	B2
Filing date	Oct 30, 2014
Priority date	Jul 15, 2008
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

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.

First claim

We claim:

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:

where R is H, C 1 -C 12 alkyl, or C 6 -C 20 aryl; and
R 1 and R 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 , CD79β, 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) IL20Rα (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, CD79α, 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:

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 3 .

7. The method of claim 1 wherein R 1 and R 2 are independently selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 SCH 3 , —CH 2 CONH 2 , —CH 2 COOH, —CH 2 CH 2 CONH 2 , —CH 2 CH 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 3 NH 2 , —(CH 2 ) 3 NHCOCH 3 , —(CH 2 ) 3 NHCHO, —(CH 2 ) 4 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 4 NHCOCH 3 , —(CH 2 ) 4 NHCHO, —(CH 2 ) 3 NHCONH 2 , —(CH 2 ) 4 NHCONH 2 , —CH 2 CH 2 CH(OH)CH 2 NH 2 .

8. The method of claim 1 wherein R 1 is —(CH 2 ) 3 NHCONH 2 and R 2 is isopropyl.

9. The method of claim 1 wherein the anthracycline derivative has the structure:

and the antibody-drug conjugate compound has the structure:

Assignees

• Genentech Inc
• Nerviano Medical Sciences Srl

Inventors

• Beria Italo
• Caruso Michele
• Flygare John A
• Lupi Vittoria
• Perego Rita
• Polakis Paul
• Polson Andrew
• Salsa Matteo
• Spencer Susan D
• Valsasina Barbara
• Cohen Robert L

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title