碳酸酐酶IX (carbonic anhydrase IX，CA9)是肾细胞癌(Renal Cell Carcinoma，RCC)特异细胞膜蛋白，与RCC的致死性有关，在80％的原发性、转移性特别是常见的透明细胞型（common clear cell variant）RCC中都有表达。热休克蛋白（Heat shock proteins ，HSP's）结合和保护部分变性蛋白，有时会用于发展疫苗。疫苗Oncophage（vitespen）是一种将HSP's作为提呈肿瘤特异抗原平台的策略。Roswell Park癌症研究所Hyung L.Kim与其同事在其临床前研究中利用RENCA模型，检测HSP 110:CA9疫苗配方治疗RCC的效果。
研究人员在表达CA9的遗传工程小鼠体内，利用RCC的RENCA模型，检测3种CA9 DNA疫苗配方（formulations）：①全长CA9＋hsp110②一段CA9＋hsp110③CA9＋HSP grp170的疗效。实验过程中，研究人员首先用3种疫苗配方免疫小鼠，然后注射肿瘤细胞，监控小鼠肿瘤生长情况（效仿佐剂治疗模型）。第①种配方免疫的小鼠40天内没有肿瘤生长，体内有抗CA9抗体，Elispot检测中出现CA-9特异性IFNγ反应；第②种配方免疫的小鼠抑制但不能阻止肿瘤生长，第③种配方没有抗肿瘤效果。另一组实验中，研究人员为已经出现RENCA肿瘤的小鼠注射全长CA9：hsp110，结果与对照组相比，实验组小鼠的肿瘤生长得到抑制（p＝0.0001），但肿瘤没有衰退。
CA9是一种RCC特异性分子靶标，已经应用于多种RCC治疗策略中，包括抗体策略和最近的以这些分子为靶标的疫苗策略。此次临床前研究结果说明全长CA9+hsp110的疫苗也许是临床研究中靶向CA9的有效策略，不足之处是研究所用模型不能检测表达CA9的正常组织（如胆管上皮）反应中出现毒性的可能，这些毒性会阻碍此策略的临床发展。（引自生物通）
原始出处：
Cancer Immunology, Immunotherapy，Volume 56, Number 7 / 2007年7月
Evaluation of renal cell carcinoma vaccines targeting carbonic anhydrase IX using heat shock protein 110
Hyung L. Kim1  , Xiaolei Sun1, John R. Subjeck2 and Xiang-Yang Wang1, 2
| (1) |
Department of Urologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA |
| (2) |
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA |
Received: 3 October 2006 Accepted: 10 November 2006 Published online: 5 December 2006
Abstract Carbonic anhydrase IX (CA9) is a renal cell carcinoma (RCC)-specific tumor protein that is targeted using heat shock protein 110 (hsp110). The chaperoning ability of hsp110 can be utilized to form a complex with CA9 (hsp110 + CA9) in vitro, which can be administered as a highly concentrated tumor vaccine. In a tumor prevention model, hsp110 + CA9 prevented the growth of RENCA tumors in BALB/c mice, and produced IFN-γ response measured using ELISPOT and an antibody response measured using ELISA. To test a second vaccine strategy, hsp110 complexed to a previously described CA9 peptide prevented tumor growth and produced a very weak IFN-γ response, but no antibody response. A plasmid vector containing grp170, a member of the hsp110 family, linked to CA9 did not produce an antitumor response and produced no IFN-γ response or antibodies. In a model of metastatic RCC, RENCA cells were injected intradermally prior to vaccination. Hsp110 + CA9 decreased tumor growth compared to control vaccinations. These studies suggest that recombinant hsp110 complexed to CA9 should be evaluated for treatment of RCC.
Keywords Renal cell carcinoma - Carbonic anhydrase IX - Heat shock protein - Tumor vaccine - RENCA - Heat shock protein 110 |
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