Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma.
Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma.
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DOI：
10.1158/1078-0432.ccr-08-0285
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发表时间：
2008-11-01
期刊：
影响因子：
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通讯作者：
Melero I
中科院分区：
文献类型：
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作者：
Murillo O;Arina A;Hervas-Stubbs S;Gupta A;McCluskey B;Dubrot J;Palazón A;Azpilikueta A;Ochoa MC;Alfaro C;Solano S;Pérez-Gracia JL;Oyajobi BO;Melero I
Eradication of post-treatment residual myeloma cells is needed to prevent relapses and immunostimulatory monoclonal antibodies (mAbs) such as anti-CD137, CTLA-4, CD40, etc, that enhance the immune response against malignancies represent a means of achieving this purpose. This study explores anti-CD137 mAbs for mutiple myeloma (MM) treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers. The anti-tumor effect of anti-CD137 mAb on mouse plasmacytomas derived from HOPC and NS0 cell lines was studied and compared with that of anti-CTLA-4, anti-CD40 and anti-ICAM-2 mAbs. The anti-tumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human MM. Depletions of specific cell populations and gene-targeted mice were used to unravel the requirements for tumor rejection. Agonistic mAb against CD137 and blocking anti-CTLA-4 mAb showed activity against intra-peritoneal HOPC tumors, resulting in extended survival of mice that also became immune to re-challenge. Anti-CD137 mAbs induced complete eradications of established subcutaneous NS0-derived tumors that were dependent on IFN-γ, NK cells and CD8+ T lymphocytes. NK cells accumulated in tumor draining lymph nodes (TDLNs) and showed increased IFN-γ production. Anti-tumor efficacy of anti-CD137 mAb was preserved in CD28-deficient mice, despite the fact that CD28 signaling increases the expression of CD137 on CD8+ T cells. Importantly, anti-CD137 mAb treatment significantly decreased systemic tumor burden in the disseminated 5TGM1 model. Anti-CD137 mAb's immune-mediated anti-tumor activity in mouse models holds promise for myeloma treatment in humans.
