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Combination of Aurora Kinase Inhibitors and Anti-CD20 Antibodies

a technology of aurora kinase inhibitors and anti-cd20 antibodies, which is applied in the field of methods for the treatment of hematological malignancies, can solve the problems of often subjected patients to disease relaps

Inactive Publication Date: 2010-07-22
MILLENNIUM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In some embodiments, such inhibition is selective, i.e., the Aurora kinase inhibitor reduces the ability of an Aurora kinase to phosphorylate a substrate peptide or protein at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect, e.g., reduction of the enzymatic activity of a different kinase. In some embodiments, the Aurora kinase inhibitor also reduces the enzymatic activity of another kinase, preferably one that is implicated in cancer.

Problems solved by technology

However, while anti-CD20 antibodies and, in particular, rituximab, have been reported to be effective for treatment of B-cell lymphomas, such as non-Hodgkin's lymphoma, the treated patients are often subject to disease relapse.
Additionally, combinations of anticancer agents may have additive, or even synergistic, therapeutic effects.

Method used

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  • Combination of Aurora Kinase Inhibitors and Anti-CD20 Antibodies
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  • Combination of Aurora Kinase Inhibitors and Anti-CD20 Antibodies

Examples

Experimental program
Comparison scheme
Effect test

example 1

Combination of Aurora A Kinase Specific Inhibitor (Compound III-1) and Rituximab in a Sub-Cutaneous Ly19 Lymphoma Model Grown in Female SCID Mice

Experimental Overview

[0164]This is an in vivo experiment looking at tumor volume after treatment with the combination of Compound III-1 and rituximab. Tumor growth was monitored with vernier calipers. The mean tumor volume was calculated using the formula V=W2×L / 2. When the mean tumor volume reached approximately 200 mm3, the animals were randomized into the following eight treatment groups, with each cohort made up of ten mice:

[0165]Vehicle

[0166]3 mg / kg Compound III-1 (qd)

[0167]10 mg / kg Compound III-1 (qd)

[0168]10 mg / kg Compound III-1 (bid)

[0169]10 mg / kg rituximab (qw)

[0170]3 mg / kg Compound III-1 (qd)+10 mg / kg rituximab (qw)

[0171]10 mg / kg Compound III-1 (qd)+10 mg / kg rituximab (qw)

[0172]10 mg / kg Compound III-1 (bid)+10 mg / kg rituximab (qw)

[0173]The animals were inoculated with 4.0×106 cells from cell line Ly-19 at implant site Flank (cell ...

example 2

Combination of Aurora A Kinase Specific Inhibitor (Compound III-1) and Rituximab in a Subcutaneous WSU-Luc Lymphoma Model Grown in Female SCID Mice

Experimental Overview

[0186]This is an in vivo experiment looking at tumor volume after treatment with the combination of Compound III-1 and rituximab. Tumor growth was monitored with vernier calipers. The mean tumor volume was calculated using the formula V=W2×L / 2. When the mean tumor volume reached approximately 250 mm3, the animals were randomized into the following six treatment groups, with each group made up of ten mice:

[0187]Vehicle

[0188]3 mg / kg Compound III-1 (P.O., qd)

[0189]10 mg / kg Compound III-1 (P.O., qd)

[0190]10 mg / kg rituximab (I.V., q7d)

[0191]3 mg / kg Compound III-4+10 mg / kg rituximab

[0192]10 mg / kg Compound III-1+10 mg / kg rituximab

[0193]The animals were inoculated with 4.0×106 cells from cell line WSU-DLCL2 at implant site Flank (cell suspension). Compounds were administered for 21 days, and tumor volumes were measured on day...

example 3

Combination of Aurora A Kinase Specific Inhibitor (Compound III-1) and Rituximab in a Sub-Cutaneous Primary Diffuse Large B-Cell Lymphoma Model (PHTX-22-06) Grown in Female SCID Mice

Experimental Overview

[0199]This is an in vivo experiment looking at tumor volume after treatment with the combination of Compound III-1, and rituximab. Tumor growth was monitored with vernier calipers. The mean tumor volume was calculated using the formula V=W2×L / 2. When the mean tumor volume reached approximately 200 mm3, the animals were randomized into the following six treatment groups, with each group made up of ten mice:

[0200]Vehicle

[0201]10 mg / kg Compound III-4 (P.O., bid)

[0202]20 mg / kg Compound III-1 (P.O., bid)

[0203]10 mg / kg rituximab (I.V., q7d)

[0204]10 mg / kg Compound III-1+10 mg / kg rituximab

[0205]20 mg / kg Compound III-1+10 mg / kg rituximab

[0206]The animals were inoculated with 2×5 mm3 tumor mass from primary PHTX-22L-6 tumor chunk at implant site Flank (trocar). Compounds were administered for ...

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Abstract

The present invention relates to methods for the treatment of hematological malignancies. In particular, the invention provides methods for treatment of hematological malignancies by administering Aurora kinase inhibitors in combination with anti-CD20 antibodies.

Description

RELATED APPLICATIONS[0001]The present application claims the benefit of U.S. Provisional Application Ser. No. 61 / 203,509, filed Dec. 22, 2008 (pending), the contents of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to methods for the treatment of hematological malignancies. In particular, the invention provides methods for treatment of hematological malignancies by administering Aurora kinase inhibitors in combination with anti-CD20 antibodies.BACKGROUND OF THE INVENTION[0003]According to the American Cancer Society, an estimated 1.4 million Americans were newly-diagnosed with cancer in 2004 and about 560,000 victims died from the disease. While medical advance have improved cancer survival rates, there is a continuing need for new and more effective treatment.[0004]Cancer is characterized by uncontrolled cell reproduction. Mitosis is a stage in the cell cycle during which a series of complex events ensure the fidelity of chromosome se...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00A61P35/02
CPCA61K31/55A61K39/00A61K39/395A61K45/06A61K39/3955C07K2317/24C07K16/2887A61K2039/505A61K2300/00A61P35/00A61P35/02
Inventor MANFREDI, MARK
Owner MILLENNIUM PHARMA INC
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