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Combination therapy of an anti cd20 antibody with a btk inhibitor

Inactive Publication Date: 2015-05-07
ONO PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text explains that a combination of a type I or a type II anti-CD20 antibody with a BTK inhibitor has significantly better effects in stopping the growth of cancer cells than using either antibody alone. This combination is more powerful than using either antibody individually, and can provide a better treatment for cancer.

Problems solved by technology

Surprisingly, this combination is more than additive, i.e. highly synergistic.

Method used

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  • Combination therapy of an anti cd20 antibody with a btk inhibitor
  • Combination therapy of an anti cd20 antibody with a btk inhibitor
  • Combination therapy of an anti cd20 antibody with a btk inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0157]Antitumor efficacy study of BTK inhibitor in combination with anti-CD20 Abs in SCID mice subcutaneously xenografted with TMD8 (ABC-DLBCL) cells

1. Materials and Methods

1.1. Test Substances

[0158]The test substance, 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one hydrochloride (hereinafter referred to as “compound A”), was stored in sealed containers at ambient temperature, protected from light.

[0159]GA101 (obinutuzumab, sold under the tradename Gazyva® or Gazyvaro®): 500 mg, Rituximab (RTX, sold under the tradenames Rituxan® and MabThera®): 200 mg, were supplied by Roche Glycart A G, and stored at 4° C.

1.2. Substance Vehicle

[0160]Compound A was weighed out and suspended in a 0.5 w / v % methyl cellulose 400 cP solution (Wako Pure Chemical Industries, Ltd., hereinafter referred to as “0.5% MC”), using a mortar and pestle, to obtain a 1 mg / mL suspension. The suspension was used within 7 days of preparation. The suspension was confirmed t...

example 2

[0178]The experiment in Example 2 was performed according to the method described in Example 1 except for the following “substance vehicle” and “treatment schedule”.

1. 1. Substance Vehicle

[0179]Compound A was weighed out and suspended in a 0.5 w / v % methyl cellulose 400 cP solution (Wako Pure Chemical Industries, Ltd., hereinafter referred to as “0.5% MC”), using a mortar and pestle, to obtain a 1 mg / mL (10 mg / kg) suspension. The suspension was used within 7 days of preparation. The suspension was confirmed to be stable and uniform for 7 days under refrigeration, protected from light, and for a further 24 hours at ambient temperature exposed to indoor lighting.

[0180]The stock solutions of both GA101 (25 mg / mL) and Rituximab (10 mg / mL) were kept at 4° C. Before administration to mice, the stock solutions were diluted in NaCl 0.9% at 0.3 mg / mL (3 mg / kg) for this study.

1.2. Treatment Schedule

[0181]When the mean tumor volume reached 400 to 450 mm3 mice were randomized in groups of 6 acc...

example 3

[0187]The experiment in Example 3 was performed according to the method described in Example 1 except for the following “substance vehicle”, “route of drug administration” and “treatment schedule”

1.1 Test Substance

[0188]The comparative substance, ibrutinib (hereinafter referred to as “compound B”), was stored in sealed containers at ambient temperature, protected from light.

1.2 Route of Drug Administration

[0189]Mice were fed a commercial diet (CRF1, Oriental Yeast Co., Ltd.) supplemented with either 0.0037% (wt / wt incorporated in the pellets) of compound A or 0.012% (wt / wt incorporated in the pellets) of compound B, respectively. The dose of compound A or compound B corresponds to a daily intake of 6 or 20 mg / kg of body weight. This calculation was based on the mean daily food intakes ranged from 160 to 180 mg / g of body weight.

1.3 Treatment Schedule

[0190]Two groups (vehicle and RTX): Mice fed a normal diet (CRF1). Treatment groups: Mice fed the same diet containing compound A or com...

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Abstract

The present invention is directed to the combination therapy of an anti-CD20 antibody with a BTK inhibitor for the treatment of cancer, especially to the combination therapy of CD20 expressing cancers with a type I anti-CD20 antibody or an afucosylated humanized B-Ly1 antibody and a BTK inhibitor.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is based upon and claims the benefit of priority from European Patent Application No. 13192006.8, filed on Nov. 7, 2013, the entire contents of which are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention is directed to the combination therapy of an anti CD20 antibody with a BTK inhibitor for the treatment of cancer.BACKGROUND OF THE INVENTIONAfucosylated Antibodies[0003]Cell-mediated effector functions of monoclonal antibodies can be enhanced by engineering their oligosaccharide component as described in Umaña, P., et al., Nature Biotechnol. 17 (1999) 176-180; and U.S. Pat. No. 6,602,684. IgG1 type antibodies, the most commonly used antibodies in cancer immunotherapy, are glycoproteins that have a conserved N-linked glycosylation site at Asn297 in each CH2 domain. The two complex biantennary oligosaccharides attached to Asn297 are buried between the CH2 domains, forming extensive contacts with th...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/522A61K45/06
CPCA61K39/39558A61K2039/505A61K31/522A61K45/06A61K39/3955A61K2039/585A61K2300/00C07K16/2887C07K2317/24A61P35/00A61P35/02A61P43/00
Inventor KLEIN, CHRISTIANYOSHIZAWA, TOSHIOYASUHIRO, TOMOKO
Owner ONO PHARMA CO LTD
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