Pyrrolobenzodiazepine antibody drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-10639373-B2
Application number	US-201816036575-A
Country	US
Kind code	B2
Filing date	Jul 16, 2018
Priority date	Oct 2, 2015
Publication date	May 5, 2020
Grant date	May 5, 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. A method of treating cancer comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising an antibody-drug conjugate 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;
and a pharmaceutically acceptable diluent, carrier or excipient.

2. The method of claim 1 wherein the patient is administered a chemotherapeutic agent, in combination with the pharmaceutical composition, or a pharmaceutically acceptable salt thereof.

3. A method of treating cancer comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising 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 anti-HER2 antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21;
and a pharmaceutically acceptable diluent, carrier or excipient.

4. The method of claim 3 , wherein the cancer is a HER2-positive cancer.

5. The method of claim 4 , wherein the HER2-positive cancer is breast cancer or gastric cancer.

6. A method of treating cancer comprising administering to a patient a therapeutically effective amount of 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 anti-HER2 antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

7. The method of claim 6 , wherein the cancer is a HER2-positive cancer.

8. The method of claim 7 , wherein the HER2-positive cancer is breast cancer or gastric cancer.

9. The method of claim 6 , further comprising administering to a patient an additional therapeutic agent.

10. The method of claim 9 , wherein the additional therapeutic agent is a chemotherapeutic agent.

11. The method of claim 9 , wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2.

12. The method of claim 11 , wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2.

13. The method of claim 11 , wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C 4 , and/or (ii) an antibody or immunoconjugate that binds to epitope 4D5.

14. The method of claim 11 , wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), or pertuzumab.

15. The method of claim 11 , further comprising administering to the patient (1) trastuzumab or T-DM1, and (2) pertuzumab.

16. The method of claim 1 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 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, 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, CD79a, 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

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

• C07K16/2803

  against the immunoglobulin superfamily · CPC title

• C07K2317/522

  CH1 domain · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title

• A61P15/00

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