The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78.
The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78.
复制标题
DOI：
10.1371/journal.pone.0063414
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Brändlein S
中科院分区：
文献类型：
--
作者：
Rasche L;Duell J;Morgner C;Chatterjee M;Hensel F;Rosenwald A;Einsele H;Topp MS;Brändlein S
与其他血液系统恶性肿瘤相比，靶向免疫治疗尚未进入新发或复发性多发性骨髓瘤（MM）的标准治疗方案。虽然目前正在MM的临床试验中评估许多IgG形式的单克隆抗体，但我们的研究旨在研究靶向热休克蛋白GRP 78的肿瘤特异性变体的全人源IgM单克隆抗体PAT-SM 6是否可能成为未来免疫治疗方法的有吸引力的候选者。我们在这里表明，GRP 78是稳定和一致的表达在肿瘤细胞的表面上从患者的从头，但也复发MM和PAT-SM 6 MM细胞的结合可以特异性地发挥对恶性浆细胞的细胞毒性作用，而非恶性细胞不被靶向。我们证明，诱导细胞凋亡，并在较小程度上，补体依赖性细胞毒性是PAT-SM 6的主要作用模式，而抗体依赖性细胞毒性似乎并不有助于这种抗体的细胞毒性特性。鉴于PAT-SM 6在猴中的有利安全性特征，以及最近在恶性黑色素瘤患者中的I期试验，我们的结果形成了计划在复发性MM患者中进行I期研究的基础。
In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.
登录
查看更多内容
影响因子：
11.2
作者：
Gonzalez-Gronow, Mario;Cuchacovich, Miguel;Pizzo, Salvatore V.
通讯作者：
Pizzo, Salvatore V.
影响因子：
20.3
作者：
MacMillan, Margaret L.;Couriel, Daniel;Blazar, Bruce R.
通讯作者：
Blazar, Bruce R.
DOI：
10.1182/asheducation-2011.1.184
发表时间：
2011-12-01
期刊：
HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM
影响因子：
--
作者：
Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
11.2
作者：
Pohle, T;Brändlein, S;Vollmers, HP
通讯作者：
Vollmers, HP
影响因子：
3.9
作者：
MORDOH, J;SILVA, C;KAIRIYAMA, C
通讯作者：
KAIRIYAMA, C