Methods of inhibiting tumor growth by antagonizing il-6 receptor

a technology of il-6 receptor and tumor growth, which is applied in the field of compositions and methods for inhibiting or attenuating tumor growth or proliferation in subjects, can solve the problems of worse patient outcomes and increased serum il-6 levels, and achieve the effect of overcoming anti-vegf resistance and robust anti-tumor activity

Inactive Publication Date: 2013-05-16
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]The present invention is based, at least in part, on the surprising discovery that anti-VEGF-resistant tumors express elevated levels of IL-6 and that antagonism of IL-6 (e.g., by using an anti-IL-6R antibody), when combined with anti-VEGF therapy, is able to overcome anti-VEGF resistance in tumors and thus provides robust anti-tumor activity against tumors that heretofore were deemed unresponsive to VEGF antagonism.

Problems solved by technology

Clinical studies have shown that increased serum IL-6 levels are associated with worse patient outcomes.

Method used

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  • Methods of inhibiting tumor growth by antagonizing il-6 receptor
  • Methods of inhibiting tumor growth by antagonizing il-6 receptor

Examples

Experimental program
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Effect test

example 1

An Anti-IL-6R Monoclonal Antibody Inhibits Tumor Xenograft Growth as a Single Agent and in Combination with Other Anti-Tumor Agents

Therapeutic Agents

[0063]This example demonstrates the administration of an anti-IL-6R antibody, alone and in combination with a VEGF-Trap, an anti-EGFR antibody or an anti-ErbB3 antibody, to tumor bearing mice. The anti-IL-6R antibody used in this Example, also referred to herein as “anti-IL-6R mAb1,” is an antibody comprising heavy chain CDRs (HCDR1, HCDR2 and HCDR3) having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; and light chain CDRs (LCDR1, LCDR2 and LCDR3) having the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively (i.e., the anti-IL-6R antibody designated VQ8F11-21 in U.S. Pat. No. 7,582,298). The VEGF-Trap used in this Example is a dimer of two fusion polypeptides, each comprising: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:11; (2) a VEGFR2 component comprising amino acids 130 to 231 ...

example 2

An Anti-IL-6R Monoclonal Antibody in Combination with a VEGF Antagonist Inhibits the Growth of Anti-VEGF-Resistant Tumors

Introduction

[0074]A variant of the A431 human epidermoid carcinoma cell line that is resistant to the effects of VEGF Trap was isolated by serial passage in the presence of VEGF-Trap in vivo. The variant cell line is referred to herein as “A431-V2”, and the parental A431 cell line is referred to herein as “A431-P”.

[0075]Experiments were first conducted to assess the relative levels of IL-6 expressed from the A431-V2 cell line as compared to the A431-P cell line. For this purpose, conditioned medium was collected from cultured A431-P or A431-V2 cells and ELISA was performed to measure the concentration of human IL-6. As shown in FIG. 2(a), A431-V2, expresses much higher levels of IL-6 than does the parental A431 cell line (178 pg / ml vs 29 pg / ml).

[0076]Next, the levels of phospho-STAT3 were measured in the variant and parental A431 cells. Specifically, cultured A431...

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Abstract

The present invention provides methods for inhibiting or attenuating tumor growth in a subject by administering an IL-6 antagonist to the subject. In certain embodiments, the methods of the invention are used to inhibit the growth of an anti-VEGF-resistant tumor in a subject. The IL-6 antagonist may be, e.g., an antibody that specifically binds IL-6R. The IL-6 antagonist may be administered in combination with a VEGF antagonist, and / or an EGFR antagonist.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of U.S. provisional application Nos. 61 / 557,939, filed on Nov. 10, 2011; 61 / 609,968, filed on Mar. 13, 2012; and 61 / 613,538, filed on Mar. 21, 2012, the disclosures of which are herein incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to compositions and methods for inhibiting or attenuating tumor growth or proliferation in a subject. More specifically, the invention relates to methods comprising administering an interleukin-6 (IL-6) antagonist to a tumor-bearing subject.BACKGROUND[0003]Antagonists of vascular endothelial growth factor (VEGF) have been shown to effectively inhibit tumor growth in numerous experimental and clinical settings. VEGF antagonists exert their therapeutic effects by targeting the tumor vasculature. It has been observed, however, that tumors under certain circumstances can develop resistance to anti-VE...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28A61K39/395C07K19/00
CPCA61K39/39558C07K16/2866C07K19/00A61K39/3955C07K16/2863C07K16/32C07K16/22A61K2039/507C07K2317/73C07K2317/76A61K2039/505A61K2300/00A61P35/00A61P35/04A61P43/00C07K2317/56
Inventor ZHANG, LI
Owner REGENERON PHARM INC
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