Combination treatment with antibody-drug conjugates and cytarabine

Patent metadata

Field	Value
Publication number	US-2019160089-A1
Application number	US-201816175165-A
Country	US
Kind code	A1
Filing date	Oct 30, 2018
Priority date	Oct 31, 2017
Publication date	May 30, 2019
Grant date	—

Abstract

The present invention provides a method of treating a cancer in a subject comprising administering to the subject an effective amount of a CD33-targeted antibody-drug conjugate (ADC) and an effective amount of cytarabine. Also provided are pharmaceutical compositions comprising an effective amount of a CD33-targeted ADC and an effective amount of cytarabine.

First claim

1 . A method of treating a cancer in a subject comprising administering to the subject an effective amount of cytarabine and an effective amount of an antibody-drug conjugate of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is hydrogen, when it is a single bond, X is hydrogen and Y is —SO 3 H;
Ab is an anti-CD33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ) complementary determining region (CDR)1 sequence of SEQ ID NO:1, a V H CDR2 sequence of SEQ ID NO:2, and a V H CDR3 sequence of SEQ ID NO:3, and a light chain variable region (V L ) CDR1 sequence of SEQ ID NO:4, a V L CDR2 sequence of SEQ ID NO:5, and a V L CDR3 sequence of SEQ ID NO:6; and
r is an integer from 1 to 10.

2 . The method of claim 1 , wherein the antibody-drug conjugate is represented by the following formula:

or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 , wherein the antibody-drug conjugate is represented by the following formula:

or a pharmaceutically acceptable salt thereof; and wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

4 . (canceled)

5 . The method of claim 1 , wherein the antibody-drug conjugate is represented by the following formula:

6 . The method of claim 1 , wherein the anti-CD33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:7 or 9; and a light chain variable region comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:8 or 10.

7 . (canceled)

8 . The method of claim 1 , wherein the anti-CD33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the sequence of SEQ ID NO:9 and a light chain variable region comprising the sequence of SEQ ID NO:10.

9 . The method of claim 1 , wherein Ab is an anti-CD33 antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO:11 and a light chain having the amino acid sequence set forth in SEQ ID NO:12.

10 . The method of claim 1 , wherein the antibody is a CDR-grafted or resurfaced antibody.

11 . The method of claim 1 , wherein the antibody-drug conjugate is represented by the following formula:

or a pharmaceutically acceptable salt thereof; and wherein the pharmaceutically acceptable salt is sodium salt.

12 . (canceled)

13 . The method of claim 1 , wherein the cancer is selected from the group consisting of leukemia, lymphoma and myeloma.

14 . The method of claim 13 , wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell lineage acute lymphoblastic leukemia (B-ALL), T-cell lineage acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), myelodysplastic syndrome (MDS), blastic plasmacytoid DC neoplasm (BPDCN) leukemia, non-Hodgkin lymphomas (NHL), mantle cell lymphoma, eosinophilic leukemia, B myelomonocytic leukemia and Hodgkin's leukemia (HL).

15 . The method of claim 14 , wherein the cancer is acute myeloid leukemia (AML).

16 . The method of claim 15 , wherein the acute myeloid leukemia (AML) is refractory or relapse acute myeloid leukemia.

17 . The method of claim 14 , wherein the subject is a fit AML subject.

18 . The method of claim 14 , wherein the subject is an unfit AML subject.

21 . The method of claim 14 , wherein the acute myeloid leukemia (AML) is characterized by overexpression of P-glycoprotein, overexpression of EVI1, a p53 alteration, DNMT3A mutation, FLT3 internal tandem duplication, a complex karyotype, decreased expression in BRCA1, BRCA2, or PALB2, or mutations in BRCA1, BRCA2, or PALB2.

26 . The method of claim 1 , wherein a total daily dose of 20-3000 mg/m 2 of cytarabine is administered to the subject.

27 . The method of claim 26 , wherein cytarabine is administered to the subject daily or every other day.

28 - 29 . (canceled)

30 . The method of claim 1 , wherein: (i) a total daily dose of 110 mg/m 2 of cytarabine is administered to the subject every day for 7 days, (ii) a total daily dose of 3000 mg/m 2 of cytarabine is administered to the subject every other day for 5 days, (iii) a total daily dose of 20 mg/m 2 of cytarabine is administered to the subject every day for 10 days, or (iv) a total daily dose of 200 mg/m 2 of cytarabine is administered to the subject every day for 7 days.

31 - 34 . (canceled)

35 . A pharmaceutical composition comprising: i) an effective amount of cytarabine; ii) an effective amount of an antibody-drug conjugate of Formula (I):

or a pharmaceutically acceptable salt thereof; and iii) a pharmaceutically acceptable carrier or diluent; wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is hydrogen, when it is a single bond, X is hydrogen, Y is —SO 3 H;
Ab is an anti-CD33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ) complementary determining region (CDR)1 sequence of SEQ ID NO:1, a V H CDR2 sequence of SEQ ID NO:2, and a V H CDR3 sequence of SEQ ID NO:3, and a light chain variable region (V L ) CDR1 sequence of SEQ ID NO:4, a V L CDR2 sequence of SEQ ID NO:5, and a V L CDR3 sequence of SEQ ID NO:6; and
r is an integer from 1 to 10.

36 - 46 . (canceled)

Assignees

• Immunogen Inc

Inventors

• Adams Sharlene
• Sloss Callum M
• Zweidler-Mckay Patrick

Classifications

• A61K31/7068 Primary

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title