Wagner Stefan, Krepler Clemens, Allwardt Dorothee, Latzka Julia, Strommer Sabine, Scheiner Otto, Pehamberger Hubert, Wiedermann Ursula, Hafner Christine, Breiteneder Heimo
Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria.
Clin Cancer Res. 2008 Dec 15;14(24):8178-83. doi: 10.1158/1078-0432.CCR-08-0371.
The high molecular weight melanoma-associated antigen (HMW-MAA) is an attractive target for immunotherapy of malignant melanoma. We have recently generated a vaccine based on the HMW-MAA mimotope 225D9.2+ that was able to induce anti-HMW-MAA antibodies with antitumor activity in vitro. Here, we investigated the antitumor activity of these antibodies in a human melanoma xenotransplant severe combined immunodeficient (SCID) mouse model.
Tumors were established by injecting the human melanoma 518A2 cells into C.B.17 SCID/SCID mice. In tumor prevention experiments, 200 microg purified total IgG antibodies were injected intravenously the same day or on day 5 in therapeutic experiments. Antibody administration was repeated every fourth day and tumor volumes were measured. Antibody specificity and tumor infiltration by macrophages were investigated by immunohistochemistry.
Within 35 days after cell inoculation, antibody treatment reduced tumor growth up to 40% in the therapeutic and up to 62% in the tumor prevention experiments compared with the control mice. In tumors of all groups, a similar distribution of the HMW-MAA and no differences in infiltration of macrophages were detected by immunohistochemistry.
Here, we showed that antibodies induced by the 225D9.2+ mimotope effectively inhibited melanoma tumor growth. Additional mechanisms besides antibody-dependent cell cytotoxicity like disruption of interactions of melanoma cells mediated by extracellular matrix components seem to be involved in tumor growth inhibition. Based on our findings, we suggest that active immunization with this mimotope might be a promising strategy for treatment of melanoma.
高分子量黑色素瘤相关抗原（HMW-MAA）是恶性黑色素瘤免疫治疗的一个有吸引力的靶点。我们最近基于HMW-MAA模拟表位225D9.2+研发了一种疫苗，该疫苗能够在体外诱导具有抗肿瘤活性的抗HMW-MAA抗体。在此，我们在人黑色素瘤异种移植严重联合免疫缺陷（SCID）小鼠模型中研究了这些抗体的抗肿瘤活性。
通过将人黑色素瘤518A2细胞注射到C.B.17 SCID/SCID小鼠体内建立肿瘤模型。在肿瘤预防实验中，于同一天静脉注射200微克纯化的总IgG抗体，在治疗实验中则于第5天注射。每四天重复一次抗体给药，并测量肿瘤体积。通过免疫组织化学研究抗体特异性和巨噬细胞的肿瘤浸润情况。
与对照小鼠相比，在细胞接种后35天内，抗体治疗在治疗实验中使肿瘤生长减少高达40%，在肿瘤预防实验中减少高达62%。通过免疫组织化学检测发现，所有组的肿瘤中HMW-MAA的分布相似，巨噬细胞浸润无差异。
在此，我们表明由225D9.2+模拟表位诱导的抗体有效抑制了黑色素瘤肿瘤生长。除了抗体依赖性细胞毒性外，其他机制如破坏由细胞外基质成分介导的黑色素瘤细胞相互作用似乎也参与了肿瘤生长抑制。基于我们的研究结果，我们认为用这种模拟表位进行主动免疫可能是治疗黑色素瘤的一种有前景的策略。
