A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement
A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement
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DOI：
10.1158/1078-0432.ccr-15-3111
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发表时间：
2016-09-01
影响因子：
11.5
通讯作者：
Braendlein, Stephanie
中科院分区：
文献类型：
--
作者：
Rasche, Leo;Menoret, Emmanuelle;Braendlein, Stephanie
目的：葡萄糖调节蛋白（GRP）78在多发性骨髓瘤中过表达，其表面表达及其作为未折叠蛋白反应的关键传感器的生物学意义使GRP 78成为免疫干预的理想候选者。单克隆抗体PAT-SM 6靶向表面GRP 78，并在临床试验中作为单一药物使用时导致疾病稳定。在这篇文章中，我们评估了GRP 78在复发难治性疾病中的表达，并探讨了PAT-SM 6联合治疗方案。实验设计：在多发性骨髓瘤的不同阶段，在疾病进展和耐药性发展过程中，对GRP 78的表达进行了化学分析。在体外评估PAT-SM 6与抗多发性骨髓瘤剂来那度胺、硼替佐米和地塞米松的组合的活性。最后，我们报告的多发性骨髓瘤患者复发难治性疾病治疗PAT-SM 6与硼替佐米和来那度胺。结果：虽然sGRP 78的表达存在于所有阶段，它增加了疾病的进展，甚至强烈升高的耐药和髓外疾病的患者。用地塞米松预处理以及PAT-SM 6/来那度胺的双重组合进一步增加sGRP 78表达，并且在增殖测定中连续显示与PAT-SM 6的协同抗多发性骨髓瘤作用。作为概念的证据，一名62岁的男性患有三重耐药的多发性骨髓瘤与PAT-SM 6，硼替佐米，和来那度胺治疗经历了部分缓解的intra-and extramalidomide lesions.Conclusions：PAT-SM 6联合治疗方案在复发难治性多发性骨髓瘤显示出疗效。(C)2016年AACR。
Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra-and extramedullary lesions.Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. (C) 2016 AACR.