TRIOXACARCINS, TRIOXACARCIN-ANTIBODY CONJUGATES, AND USES THEREOF

• US 20150297747A1
• Filed: 11/26/2013
• Published: 10/22/2015
• Est. Priority Date: 11/26/2012
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Myers, Andrew G, Smaltz, Daniel J., Schumacher, Andreas
• Granted Patent: US 9,775,915 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/6807 the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6829 Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/18 against material from animals or humans

Abstract

Provided herein are trioxacarcin-antibody drug conjugates of Formula (A): and pharmaceutically acceptable salts thereof, comprising at least one instance of the group -L¹-(A-L²)a-B attached thereto, wherein a is an integer between 1 and 10, inclusive, L¹ is absent or is a linking group, A is a moiety formed from the reaction of two complimentary groups (X and Y), L² is absent or is another linking group, and B is an antibody or antibody fragment. Also provided are methods of preparing these antibody-drug conjugates, pharmaceutically acceptable compositions thereof, and methods of their use and treatment. Further provided are precursors to the trioxacarcin-antibody drug conjugates, novel trioxacarcins without an antibody conjugated thereto, pharmaceutical compositions thereof, and methods of their use and treatment.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein L¹ is absent or is a linking group consisting of a combination of one or more groups of the formula:

3. The compound of claim 2, wherein L² is absent or is a linking group consisting of a combination of one or more groups of the formula:

4. The compound of claim 1, wherein L² is absent or is a linking group consisting of a combination of one or more groups of the formula:

6. The compound of claim 1, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f):

19. The compound of claim 1, wherein R¹ is hydrogen or —

OR^A1 and R² is hydrogen.

21. The compound of claim 1, wherein R¹ and R² are joined to form ═

O.

22. The compound of claim 1, wherein R³ is hydrogen.

24. The compound of claim 1, wherein R¹, R², and R³ are each hydrogen.

25. The compound of claim 1, wherein R⁴ is —

OR^D1.

26. The compound of claim 1, wherein R⁵ is —

OR^E1.

27. The compound of claim 1, wherein R⁶ is substituted or unsubstituted alkyl or —

OR^F1.

28. The compound of claim 1, wherein R⁷ is hydrogen.

30. The compound of claim 1, wherein R⁸ is hydrogen, —

CH₂(OR^I1), —

CH(OR^I1)₂, or —

CH₂OC(═

O)R^I2.

31. The compound of claim 1, wherein B is an antibody selected from the group consisting of Adecatumumab, Afutuzumab, Alemtuzumab (CAMPATH), Bavituximab, Belimumab, Bevacizumab (AVASTIN), Brentuximab, Cantuzumab, Cetuximab (ERBITUX), Citatuzumab, Cixutumumab, Conatumumab, Dacetuzumab, Elotuzumab, Etaracizumab, Farletuzumab, Figitumumab, Gemtuzumab, Ibritumomab, Inotuzumab, Ipilimumab (YERVOY), Iratumumab, Labetuzumab, Lexatumumab, Lintuzumab, Lucatumumab, Mapatumumab, Matuzumab, Milatuzumab, Necitumumab, Nimotuzumab, Ofatumumab (ARZERRA), Olaratumab, Oportuzumab, Panitumumab (VECTIBIX), Pertuzumab (PERJETA), Pritumumab, Rituximab (RITUXAN), Robatumumab, Sibrotuzumab, Siltuximab, Tacatuzumab, Tigatuzumab, Tositumomab (BEXXAR), Trastuzumab (HERCEPTIN), Tucotuzumab, Veltuzumab, Votumumab, and Zalutumumab, or an antibody fragment thereof.

32. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. A method of treating a condition selected from the group consisting of cardiovascular diseases, proliferative diseases, diabetic retinopathy, inflammatory diseases, autoimmune diseases, and infectious diseases from which a subject is suffering from, comprising administering to the subject an amount of a compound of claim 1 or pharmaceutically acceptable salt thereof, effective to treat the condition.

34. The method of claim 33, wherein the proliferative disease is a cancer.

5. (canceled)

7-18. -18. (canceled)

20. (canceled)

23. (canceled)

29. (canceled)

35-36. -36. (canceled)

37. A compound of Formula (P-I):

38. A method of preparing a compound of Formula (I):