Combination therapy with an anti-axl antibody-drug conjugate

• US 10,544,223 B2
• Filed: 11/21/2018
• Issued: 01/28/2020
• Est. Priority Date: 04/20/2017
• Status: Active Grant

• Current Assignee: ADC Therapeutics SA, MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: ADC Therapeutics SA
• Inventors: Van Berkel, Patricius Hendrikus Cornelis, Wuerthner, Jens, Hartley, John, Zammarchi, Francesca
• Primary Examiner(s): Huff, Sheela J.
• Application Number:
  US16/197,891
• Publication Number:
  US 20190218291A1
• Time in Patent Office: 433 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer. In particular, the present disclosure relates to combination therapies comprising treatment with an Antibody Drug Conjugate (ADC) and a secondary agent.

Claims

1. A method for treating cancer in an individual, the method comprising administering to the individual an effective amount of ADC×

AXL and a secondary agent;

wherein ADC×

AXL has the chemical structure;

Ab-(DL)_p

wherein;

DL is;

2. A method according to claim 1, wherein the secondary agent is Fludarabine or Cytarabine.

3. A method according to claim 1, wherein the secondary agent is a PD1 antagonist.

4. A method according to claim 3, wherein the PD 1 antagonist is selected from the group consisting of pembrolizumab, nivolumab, MEDI0680, PDR001 (spartalizumab), Camrelizumab, AUNP12, Pidilizumab Cemiplimab (REGN-2810), AMP-224, BGB-A317 (Tisleizumab), and BGB-108.

5. A method according to claim 1, wherein the secondary agent is a PD-L1 antagonist.

6. A method according to claim 5, wherein the PD-L1 antagonist is selected from the group consisting of atezolizumab (Tecentriq), BMS-936559/MDX-1105, durvalumab/MEDI4736, and MSB0010718C (Avelumab).

7. A method according to claim 1, wherein the secondary agent is a GITR (Glucocorticoid-Induced TNFR-Related protein) agonist.

8. A method according to claim 7, wherein the GITR (Glucocorticoid-Induced TNFR-Related protein) agonist is selected from the group consisting of MEDI1873, TRX518, GWN323, MK-1248, MK 4166, BMS-986156 and INCAGN1876.

9. A method according to claim 1, wherein the secondary agent is an OX40 agonist.

10. A method according to claim 9, wherein the OX40 agonist is selected from the group consisting of MEDI0562, MEDI6383, MOXR0916, RG7888, OX40mAb24, INCAGN1949, GSK3174998, and PF-04518600.

11. A method according to claim 1, wherein the secondary agent is a CTLA-4 antagonist.

12. A method according to claim 11, wherein the CTLA-4 antagonist is ipilimumab or Tremelimumab.

13. A method according to claim 1, wherein the secondary agent is a hypomethylating agent.

14. A method according to claim 13, wherein the hypomethylating agent is azacitidine or decitabine.

15. A method according to claim 1, wherein the secondary agent is a PARP inhibitor (PARPi).

16. A method according to claim 15, wherein the PARPi is selected from the group consisting of Olaparib, CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib/SAR24-550/BSI-201, Veliparib (ABT-888), Niraparib/MK-4827, BGB-290, 3-aminobenzamide, and E7016.

17. A method according to claim 1, wherein the secondary agent is an agent that upregulates HER2 expression.

18. A method according to claim 17, wherein the agent that upregulates HER2 expression is gemcitabine or tamoxifen.

19. A method according to claim 1, wherein the secondary agent is an AXL-kinase inhibitor (AXLi), a BRAF inhibitor (BRAFi), or a MEK inhibitor (MEKi).

20. A method according to claim 19, wherein:

the AXLi is selected from the group consisting of BGB324 (bemcentinib), TP0903, Gilteritinib (ASP2215), Cabozantinib (XL184), SGI7079, Merestinib, amuvatinib (MP-470), bosutinib (SKI-606), MGCD265, and foretinib (GSK1363089/XL880);

the BRAFi is selected from the group consisting of vemurafenib, PLX4720, dabrafenib, Sorafenib, Encorafenib, and GDC0879; and

the MEKi is selected from the group consisting of Trametinib, Cobimetinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, and TAK-733.

21. A method according to claim 1, wherein the cancer comprises AXL+ve neoplastic cells, both AXL+ve and AXL−

ve neoplastic cells, or AXL−

ve neoplastic cells infiltrated with AXL+ve cells.