Folate-targeted dinitrophenyl hapten immunotherapy: Effect of linker chemistry on antitumor activity and allergic potential
Folate-targeted dinitrophenyl hapten immunotherapy: Effect of linker chemistry on antitumor activity and allergic potential
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DOI：
10.1021/mp070050b
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Leamon, Christopher P.
中科院分区：
文献类型：
--
作者：
Lu, Yingjuan;You, Fei;Leamon, Christopher P.
由于叶酸受体（FR）在人类肿瘤上的优先表达，叶酸相关疗法靶向恶性肿瘤已被证明是一项有前途的奋进。我们已经表明，叶酸（蝶酰谷氨酸）可用于提供一种抗原半抗原，荧光素，肿瘤细胞的表面，以促进其调理素内的荧光素免疫的主机。在这里，我们调查的另一类叶酸-半抗原缀合物（EC 57，EC 63，EC 0293和EC 0294），即那些含有二硝基苯基（DNP）基团的抗原半抗原的成员之间的结构-活性关系。我们报道，尽管对FIR表现出相似的亲和力，但这些DNP缀合物的抗肿瘤活性和过敏潜力根据其接头化学和结合抗DNP IgG/IgE抗体的能力而变化。与EC 57和EC 63不同，EC 0293和EC 0294（i）都具有与匙孔血蓝蛋白（KLH）-DNP中发现的相同的DNP桥接化学（即，免疫原），（ii）有效识别DNP特异性IgG，和（iii）介导更显著的抗肿瘤应答。然而，还发现EC 0293和EC 0294识别DNP特异性IgE，并且当在被动皮肤过敏反应试验中进行评价时，它们显示出更大的过敏风险。尽管如此，在与适当的细胞因子（IL-2/IFN-a）共刺激后，叶酸靶向的“半抗原化”过程允许肿瘤排斥和保护性抗肿瘤免疫，而不会在免疫小鼠中引起任何可见的过敏。我们的数据进一步支持叶酸半抗原靶向免疫疗法可能为FR阳性癌症的治疗提供有效的治疗选择，但考虑到潜在过敏反应的风险，这种治疗应谨慎进行。
Targeting of malignancies with folate-linked therapeutics has proven to be a promising endeavor due to the preferential expression of folate receptors (FR) on human tumors. We have shown that folic acid (pteroyl-glutamate) can be used to deliver an antigenic hapten, fluorescein, to the surface of tumor cells to promote their opsonization within a fluorescein-immunized host. Here, we investigate structure-activity relationships among members of another class of folate-hapten conjugates (EC57, EC63, EC0293, and EC0294), namely, those containing the dinitrophenyl (DNP) group as the antigenic hapten. We report that despite exhibiting similar affinities for the FIR, the antitumor activity and allergic potential of these DNP conjugates varied depending on their linker chemistries and abilities to bind anti-DNP lgG/lgE antibodies. Unlike EC57 and EC63, both EC0293 and EC0294 (i) share the identical DNP bridging chemistry to that found in keyhole limpet hemocyanin (KLH)-DNP (i.e., the immunogen), (ii) efficiently recognize DNP-specific IgG, and (iii) mediate more pronounced antitumor responses. However, EC0293 and EC0294 were also found to recognize DNP-specific IgE, and they displayed a greater risk of allergy when evaluated in a passive cutaneous anaphylaxis assay. Nonetheless, upon co-stimulation with the appropriate cytokines (lL-2/lFN-alpha), the folate-targeted "haptenization" process allowed for tumor rejection and protective antitumor immunity without causing any visible allergy in immunized mice. Our data further support the concept that folate-hapten-targeted immunotherapy may offer an effective therapeutic option for treatment of FR-positive cancers, but such treatment should proceed with caution given the risk of a potential allergic reaction.