Pyrrolobenzodiazepine antibody drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-10632196-B2
Application number	US-201815899612-A
Country	US
Kind code	B2
Filing date	Feb 20, 2018
Priority date	Oct 2, 2015
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.

First claim

We claim:

1. An antibody-drug conjugate compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
X Y is selected from the group consisting of CH 2 —CH 2 , CH═CH, C(═O)—NH and CH 2 —NH;
A is a 5-membered or 6-membered heterocyclic ring, optionally substituted with a group selected from F, C 1 -C 6 alkyl, or ═C(R) 2 where R is independently selected from H, F, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 1 and R 2 are independently selected from H or C 1 -C 6 alkyl, or R 1 and R 2 form a 3, 4, 5, or 6-membered cycloalkyl or heterocyclyl group;
p is an integer from 1 to 8; and
Ab is an antibody.

2. The antibody-drug conjugate compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(53):
(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 (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, 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) 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 (GDNF 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) LGR5 (leucine-rich repeat-containing G 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; or
(53) CLL-1.

3. The antibody-drug conjugate compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula IIa:

4. The antibody-drug conjugate compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula IIb:

5. The antibody-drug conjugate compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula IIc:

wherein R 4 and R 5 are each H, or R 4 and R 5 are ═O.

6. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 wherein R 4 and R 5 are each H.

7. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 wherein R 4 and R 5 are ═O.

8. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 having Formula IId:

9. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, of claim 5 having Formula IIe:

10. The antibody-drug conjugate compound of claim 5 , or a pharmaceutically acceptable salt thereof, having Formula IIf:

11. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said Ab is a cysteine-engineered antibody.

12. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 11 , wherein the cysteine-engineered antibody comprises K149C substitution in the light chain according to Kabat numbering; or A118C substitution in the heavy chain according to EU numbering as the site of drug conjugation.

13. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein Ab is selected from anti-HER2, anti-CD 22, anti-CD33, anti-Napi2b, or anti-CLL-1.

14. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein p is 1, 2, 3, or 4.

15. The antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody, p, in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

16. A pharmaceutical composition comprising the antibody-drug conjugate compound, or a pharmaceutically acceptable salt thereof, according to claim 1 and a pharmaceutically acceptable diluent, carrier or excipient.

17. A method of making an antibody-drug conjugat

Assignees

• Genentech Inc

Inventors

• DRAGOVICH Peter
• Pillow Thomas
• Sadowsky Jack
• Sliwkowski Mark X
• Wei Binqing

Classifications

• C07K2317/40

  characterized by post-translational modification · CPC title

• C07K2317/522

  CH1 domain · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title