Hakim I, Levy S, Levy R
Division of Oncology, Department of Medicine, Stanford University Medical Center, CA 94305, USA.
J Immunol. 1996 Dec 15;157(12):5503-11.
The idiotypic determinants of B cell lymphoma provide a tumor-specific Ag and a target for immunotherapy. We have developed several generations of idiotype vaccines that were tested in an animal model, the 38C13 mouse B cell lymphoma. Initially we showed that effective tumor immunity was elicited by the syngeneic Id when it was conjugated to a carrier protein and mixed with an adjuvant. A subsequent generation of Id vaccines eliminated the need for a carrier protein and for an adjuvant by incorporating cytokines into fusion proteins containing the Id. A third generation of vaccines consisting of naked DNA encoding the Id-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins was equally effective in inducing tumor immunity. To determine whether Ig variable regions, in the absence of constant regions, could be immunotherapeutic in this model, we tested the use of single-chain Fv (scFv). scFv proteins, produced in bacteria, and naked DNA encoding scFv were used in this study. scFv was tested alone or fused to GM-CSF or an immunoenhancing peptide derived from IL-1beta. Here we demonstrate that scFv-GM-CSF was effective only when injected as a protein, not as a DNA vaccine. In contrast, both scFv-IL-1beta peptide fusion protein and naked DNA encoding it induced tumor immunity that protected mice from tumor challenge.
B细胞淋巴瘤的独特型决定簇可提供肿瘤特异性抗原，成为免疫治疗的靶点。我们已研发出几代独特型疫苗，并在动物模型38C13小鼠B细胞淋巴瘤中进行了测试。最初我们发现，当同基因独特型与载体蛋白偶联并与佐剂混合时，可引发有效的肿瘤免疫。随后一代的独特型疫苗通过将细胞因子掺入含独特型的融合蛋白中，不再需要载体蛋白和佐剂。第三代疫苗由编码独特型-粒细胞巨噬细胞集落刺激因子（GM-CSF）融合蛋白的裸DNA组成，在诱导肿瘤免疫方面同样有效。为了确定在缺乏恒定区的情况下，Ig可变区在该模型中是否具有免疫治疗作用，我们测试了单链Fv（scFv）的应用。本研究中使用了在细菌中产生的scFv蛋白以及编码scFv的裸DNA。单独测试scFv，或将其与GM-CSF或源自IL-1β的免疫增强肽融合。在此我们证明，scFv-GM-CSF仅在作为蛋白注射时有效，作为DNA疫苗则无效。相反，scFv-IL-1β肽融合蛋白及其编码的裸DNA均诱导了肿瘤免疫，保护小鼠免受肿瘤攻击。
