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Methods of treating multiple myeloma and myeloma-induced bone resorption using integrin antagonists

a technology of integrin antagonists and multiple myeloma, which is applied in the field of multiple myeloma treatment, can solve the problems of inconclusive studies, inconclusive reports of myeloma cell factors, and pain in the bone, so as to improve the quality of life of patients and stop progressive bone destruction

Inactive Publication Date: 2010-07-22
MUNDY GREGORY R +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for treating multiple myeloma and bone disorders associated with tumors of bone marrow. The method involves administering an antagonist of an interaction between an integrin with an α4 subunit and a ligand for this integrin. This antagonist can be an antibody or a small molecule inhibitor of the interaction. By blocking this interaction, the method reduces the ability of myeloma cells to proliferate and survive in the marrow compartment, leading to a reduction in the production of osteolytic factors that promote bone resorption. The antagonist can be used alone or in combination with other compounds such as chemotherapy agents. The technical effect of this patent is to provide a novel approach for treating multiple myeloma and related bone disorders.

Problems solved by technology

This bone destruction can cause excruciating bone pain, pathologic fractures, spinal cord compression, and life-threatening hypercalcemia.
Although various mediators listed above have been implicated in the stimulation of osteoclast activity in patients with multiple myeloma, reports of factors produced by myeloma cells have not been consistent, and some studies have been inconclusive due to the presence of other contaminating cell types, including stromal cells and macrophages, in the multiple myeloma cell population.
Thus, the role of any of these factors in osteolytic bone disease in patients with myeloma has not been clearly demonstrated in vivo, so that known cytokines clearly do not totally account for the bone resorption seen in these patients.
Nevertheless, despite many laboratory advances, the fundamental mechanisms underlying increased osteoclastic bone destruction in myeloma in vivo remain poorly understood.
This is reflected in the inability to easily translate the data on adhesive interactions obtained in vitro to the in vivo setting.
These data show that the in vitro results were in fact unable to accurately predict in vivo relevance.
Furthermore, even when in vivo studies have been performed, the resultant data are inconsistent.
One major reason for the perplexing inconsistencies in the field of multiple myeloma is that currently available animal models are not good predictors of human disease.

Method used

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  • Methods of treating multiple myeloma and myeloma-induced bone resorption using integrin antagonists
  • Methods of treating multiple myeloma and myeloma-induced bone resorption using integrin antagonists
  • Methods of treating multiple myeloma and myeloma-induced bone resorption using integrin antagonists

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example 1

Materials and Methods

5TGM1 Myeloma Cells

[0159]5TGM1 myeloma cells were initially derived from a myeloma which arose spontaneously in aged C57BL / KaLwRij mice (Garrett 1997, Vanderkerken 1997). Cells were grown in Isocove's Modified Dulbecco's Medium (IMDM, Life Technologies Inc., Gaithersburg, Md.) supplemented with 10% fetal bovine serum (FBS, Summit, Fort Collins, Colo.) and 1% penicillin-streptomycin solution (GIBCO, Grand Island, N.Y.) at 37 C in 5% CO2 atmosphere. For in vitro experimentation described below, 5TGM1 cells between passage 25 and 30 were used.

Antibodies, Soluble VCAM-1

[0160]Neutralizing antibodies against murine VCAM-1 (M / K-2.7), integrin VLA-4 (PS / 2 mAb), and Intercellular Adhesion Molecule-1 (ICAM-1, YN1 / 1.7), were kindly gifted by Dr. Kensuke Miyake (Saga Medical University, Saga, Japan). Recombinant soluble VCAM-1 (Lobb et al., 1991), containing the 7 extracellular domains of human VCAM-1, was the gift of Dr. Roy Lobb, Biogen Inc., Cambridge, Mass.

Reverse Trans...

example 2

In Vivo Experiments

[0179]Our in vitro studies suggest that the interaction between VLA-4 on myeloma cells with VCAM-1 on marrow stromal cells may play a key role in the induction of bone resorbing activity by myeloma. We have taken the key step of testing this hypothesis in vivo in an animal model which accurately reflects human disease.

[0180]A. In this experiment, mice were injected with 1 e 5 5TGM1 myeloma cells, which were allowed to colonize the bone marrow. Mice were split into two groups of three, one serving as a control group, and the second treated biweekly beginning on day 8 with mAb PS / 2. Levels of IgG2b, the antibody isotype produced by 5TGM1 myeloma cells, were measured weekly from weeks 1 to 6. Treatment with mAb at a dose of 80 μg per injection (˜4 mg / kg) biweekly strongly inhibited IgG2b production, indicative of significant inhibition of myeloma cell survival and growth in vivo (FIG. 4). Further, the treated mice showed reduced incidence of paraplegia (all 3 untreat...

example 3

Other In Vivo Experiments

[0186]Based on the information presented herein for the first time, persons having ordinary skill in the art can readily confirm and extend the importance of the α4 integrins and their ligands in multiple myeloma using the murine animal model described.

[0187]The following series of experiments are well within the level of skill in the art based upon the present disclosure but serve merely to exemplify, and not limit, the types of work.[0188]1) Dose response to mAb PS / 2 to determine the optimal biweekly maintenance dose. 80 μg shows good efficacy, but 40 μg was without effect. One examines higher doses up to 20 mg / kg two or three times weekly to determine optimal dosing.[0189]2) Patients present with disease at different stages of severity, linked to increased tumor burden. One examines the efficacy of mAb PS / 2 given at different times after establishment of disease, i.e., one compares treatment initiation at 8 days (see for example FIG. 4) to initiation afte...

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Abstract

Antagonists of α4 integrin / α4 integrin ligand adhesion, which inhibit the biological effects of such adhesion are described and methods for their use are detailed. Such antagonists are useful in suppressing bone destruction associated with multiple myeloma. The homing of multiple myeloma cells to bone marrow and their α4 integrin-dependent release of bone-resorbing factors, resulting in bone destruction in patients with multiple myeloma, is inhibited.

Description

[0001]This utility application is a continuation-in-part of U.S. application Ser. No. 09 / 943,659, filed Aug. 31, 2001, which is a continuation-in-part of U.S. application Ser. No. 09 / 805,840, filed Mar. 13, 2001, which is a continuation of PCT application number PCT / US99 / 21170, filed Sep. 13, 1999, which claims benefit of U.S. provisional application No. 60 / 100,182, filed Sep. 14, 1998. The disclosures of U.S. application Ser. Nos. 09 / 943,659 and 09 / 805,840, PCT application number PCT / US99 / 21170 and U.S. provisional application No. 60 / 100,182 are incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to a treatment for multiple myeloma, and the release of bone-resorting factors by myeloma cells, resulting in severe bone loss, which is the major side-effect of myeloma in man. More particularly, this invention relates to integrin antagonists, such as antagonists of alpha4 containing integrins, which inhibit the biological effects of such a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61P35/00A61K38/00C07K14/705C07K16/28
CPCA61K38/00C07K14/70542C07K16/2842C07K16/2839C07K16/2836A61P35/00
Inventor MUNDY, GREGORY R.YONEDA, TOSHIYUKI
Owner MUNDY GREGORY R
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