Maytansinoid derivatives, conjugates thereof, and methods of use

Patent metadata

Field	Value
Publication number	US-10463749-B2
Application number	US-201815907142-A
Country	US
Kind code	B2
Filing date	Feb 27, 2018
Priority date	Jan 25, 2016
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

Provided herein are maytansinoid compounds, derivatives thereof, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A is arylene or heteroarylene;
L is a linker;
BA is a binding agent; and
k is an integer from 1 to 8.

2. A method of treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein:
A is arylene or heteroarylene;
L is a linker;
BA is a binding agent; and
k is an integer from 1 to 30.

3. The method of claim 2 , comprising administering to a patient having cancer, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I), and a pharmaceutically acceptable excipient.

4. The method of claim 2 , wherein the cancer is renal cell carcinoma, pancreatic carcinoma, head and neck cancer, prostate cancer, malignant gliomas, osteosarcoma, colorectal cancer, gastric cancer, malignant mesothelioma, multiple myeloma, ovarian cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, breast cancer, or melanoma.

5. The method of claim 2 , wherein the binding agent interacts with or binds to a tumor antigen.

6. The method of claim 5 , wherein the tumor antigen is specific for a type of tumor or is shared, overexpressed, or modified on a particular type of tumor.

7. The method of claim 5 , wherein the tumor antigen is selected from the group consisting of prolactin receptor (PRLR), prostate-specific membrane antigen (PSMA), MUC16, STEAP2, and EGFRvIII.

8. The method of claim 5 , wherein the tumor antigen is selected from the group consisting of AFP, ALK, B7H4, BAGE proteins, β-catenin, brc-ab1, BRCA1, BORIS, CA9 (carbonic anhydrase IX), caspase-8, CD20, CD40, CD123, CDK4, CEA, CLEC12A, c-kit, cMET, CTLA4, cyclin-B1, CYP1B1, EGFR, EGFRvIII, endoglin, Epcam, EphA2, ErbB2/Her2, ErbB3/Her3, ErbB4/Her4, ETV6-AML, Fra-1, FOLR1, GAGE proteins, GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/EBNA1, HLA/k-ras, HLA/MAGE-A3, hTERT, IGF1R, LGR5, LMP2, MAGE proteins, MART-1, mesothelin, ML-IAP, Muc1, Muc16, CA-125, MUM1, NA17, NGEP, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PDGFR-α, PDGFR-β, PDGF-A, PDGF-B, PDGF-C, PDGF-D, PLAC1, PRLR, PRAME, PSCA, PSGR, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, Steap-1, Steap-2, STn, survivin, TAG-72, TGF-β, TMPRSS2, Tn, TNFRSF17, TRP-1, TRP-2, tyrosinase, and uroplakin-3, alpha-actinin-4 with lung cancer, ARTC1 with melanoma, BCR-ABL fusion protein with chronic myeloid leukemia, B-RAF, CLPP or Cdc27 with melanoma, CASP-8 with squamous cell carcinoma, and hsp70-2 with renal cell carcinoma, BAGE-1, GAGE, GnTV, KK-LC-1, MAGE-A2, NA88-A, and TRP2-INT2, BCMA, SLAMF7, B7H4, GPNMB, UPK3A, and LGR5, and fragments thereof.

9. The method of claim 2 , wherein the binding agent is an antibody selected from the group consisting of an anti-PSMA antibody, anti-MUC16 antibody, anti-HER2 antibody, anti-EGFRvIII antibody, and anti-STEAP-2 antibody.

10. The method of claim 2 , wherein k is an integer from 1 to 8.

11. The method of claim 2 , wherein the compound is:

wherein:
Ab is an antibody or an antigen binding fragment thereof;
S is a bond to a cysteine of the antibody or the antigen binding fragment thereof;
N is a bond to a lysine of the antibody or the antigen binding fragment thereof;
k is an integer from 1 to 30;
t is an integer from 1 to 8; and
Gln is a bond to a glutamine of the antibody or the antigen binding fragment thereof.

12. The method of claim 2 , wherein the compound is:

13. The method of claim 2 , wherein the compound is:

wherein:
Ab is an antibody or an antigen binding fragment thereof;
S is a bond to a cysteine of the antibody or the antigen binding fragment thereof;
N is a bond to a lysine of the antibody or the antigen binding fragment thereof;
k is an integer from 1 to 30;
t is an integer from 1 to 8; and
Gln is a bond to a glutamine of the antibody or the antigen binding fragment thereof.

14. The method of claim 2 , wherein the compound is:

15. A pharmaceutical composition comprising a compound selected from the group consisting of:

and a pharmaceutically acceptable excipient;

Assignees

• Regeneron Pharma

Inventors

• Nittoli Thomas
• Markotan Thomas P

Classifications

• A61K47/6851 Primary

  the antibody targeting a determinant of a tumour cell · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title

• C07D498/18

  Bridged systems · CPC title

• A61K47/68 Primary

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C07K16/40

  against enzymes · CPC title