A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy
A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy
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DOI：
10.1186/1471-2407-13-195
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发表时间：
2013-04-17
期刊：
影响因子：
3.8
通讯作者：
Penichet, Manuel L.
中科院分区：
文献类型：
--
作者：
Daniels-Wells, Tracy R.;Helguera, Gustavo;Penichet, Manuel L.
背景：前列腺癌（PCa）是美国男性癌症死亡的第二大原因。前列腺特异性抗原（PSA）通常在PCa患者的血清中以高水平存在，已被用作PCa检测的标志物和免疫治疗的靶点。鼠IgG 1单克隆抗体AR 47.47对人PSA具有特异性，已显示与PSA复合时可增强人树突状细胞的抗原呈递，并诱导CD 4和CD 8 T细胞活化。在这项研究中，我们探讨了一种新的小鼠/人嵌合抗PSA IgE的特性，含有AR47.47的可变区作为一个潜在的治疗前列腺癌。我们的目标是利用IgE的独特性质，以触发对PCa.Methods免疫激活抗体的结合特性，通过ELISA和流式细胞仪测定。通过从效应细胞释放β-氨基己糖苷酶来测定体外脱粒。使用被动皮肤过敏试验监测人Fc ε RI α转基因小鼠的体内脱粒。这些小鼠也用于疫苗接种研究，以确定该抗体的体内抗癌作用。使用对数秩检验确定存活率的显著差异。在体外T细胞活化进行了研究，使用人树突状细胞和自体T cells.Results：抗PSA IgE，在小鼠骨髓瘤细胞中表达，正确组装和分泌，并结合抗原和Fc γ RI。此外，当人工交联时，该抗体能够在体外和体内触发效应细胞脱粒，但在存在天然可溶性抗原的情况下不会，表明这种相互作用不会触发全身性过敏反应。重要的是，抗PSA IgE与PSA组合也触发免疫激活在体外和体内，并显着延长人FceRIa转基因小鼠的生存攻击与PSA表达的肿瘤在预防性vaccination setting.Conclusions：抗PSA IgE表现出预期的生物学特性，并能够触发免疫激活和抗肿瘤保护。这种抗体作为潜在的PCa治疗的进一步研究是必要的。
Background: Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 and CD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa.Methods: Binding characteristics of the antibody were determined by ELISA and flow cytometry. In vitro degranulation was determined by the release of beta-hexosaminidase from effector cells. In vivo degranulation was monitored in human Fc epsilon RI alpha transgenic mice using the passive cutaneous anaphylaxis assay. These mice were also used for a vaccination study to determine the in vivo anti-cancer effects of this antibody. Significant differences in survival were determined using the Log Rank test. In vitro T-cell activation was studied using human dendritic cells and autologous T cells.Results: The anti-PSA IgE, expressed in murine myeloma cells, is properly assembled and secreted, and binds the antigen and Fc epsilon RI. In addition, this antibody is capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis. Importantly, the anti-PSA IgE combined with PSA also triggers immune activation in vitro and in vivo and significantly prolongs the survival of human FceRIa transgenic mice challenged with PSA-expressing tumors in a prophylactic vaccination setting.Conclusions: The anti-PSA IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection. Further studies on this antibody as a potential PCa therapy are warranted.