Chen Z J, Yang H, Ferrone S
Department of Microbiology and Immunology, New York Medical College, Valhalla 10595.
J Immunol. 1991 Aug 1;147(3):1082-90.
Previous studies have shown that the mouse antiidiotypic mAb MK2-23 elicited with the syngeneic anti-human high molecular weight melanoma-associated Ag (HMW-MAA) mAb 763.74 elicits anti-HMW-MAA antibodies in syngeneic hosts and in patients with melanoma. The present investigation has characterized the fine specificity of antibodies elicited by mAb MK2-23, tested its ability to induce delayed-type hypersensitivity reaction to HMW-MAA-bearing melanoma cells and analyzed the variables that influence the immunogenicity of mAb MK2-23. The anti-HMW-MAA antibodies elicited by mAb MK2-23 recognize the same population of molecules recognized by mAb 763.74, react with the same (or spatially close) determinant(s) and express the idiotopes recognized by mAb MK2-23 in their Ag-combining sites. The antiidiotypic antibodies that bind to HMW-MAA have a lower titer than those that do not. These results in conjunction with those obtained in mice using a suboptimal immunization schedule suggest that the idiotope(s) that mimic(s) the mAb 763.74-defined determinant of the HMW-MAA is less immunogenic than those that do not. mAb MK2-23 induces a delayed-type hypersensitivity reaction to HMW-MAA-bearing melanoma cells. Therefore, mAb MK2-23 represents the first example of mouse antiidiotypic mAb that induces a cellular and humoral immunity to a human tumor-associated Ag (TAA), because the previously described mouse antiidiotypic mAb that bear the mirror image of TAA have been shown to induce only humoral anti-TAA immunity. The immunogenicity of mAb MK2-23 is markedly enhanced by its conjugation to keyhole limpet hemocyanin and its administration with FA. Furthermore, the number of immunizations and the doses of mAb MK2-23 injected influence its immunogenicity, although to a lower extent than conjugation to a carrier and mixing with an adjuvant. The information derived from the present investigation represents a useful background to optimize the immunization schedule with mAb MK2-23 in patients with melanoma.
先前的研究表明，用同基因抗人高分子量黑色素瘤相关抗原（HMW-MAA）单克隆抗体763.74诱导产生的小鼠抗独特型单克隆抗体MK2-23，能在同基因宿主和黑色素瘤患者体内诱导产生抗HMW-MAA抗体。本研究对单克隆抗体MK2-23诱导产生的抗体的精细特异性进行了表征，测试了其诱导对携带HMW-MAA的黑色素瘤细胞的迟发型超敏反应的能力，并分析了影响单克隆抗体MK2-23免疫原性的变量。单克隆抗体MK2-23诱导产生的抗HMW-MAA抗体识别与单克隆抗体763.74识别的相同分子群体，与相同（或空间上接近）的决定簇发生反应，并在其抗原结合位点表达被单克隆抗体MK2-23识别的独特型表位。与HMW-MAA结合的抗独特型抗体的效价比不与HMW-MAA结合的抗体低。这些结果与使用次优免疫方案在小鼠中获得的结果相结合，表明模拟单克隆抗体763.74定义的HMW-MAA决定簇的独特型表位的免疫原性低于不模拟的独特型表位。单克隆抗体MK2-23诱导对携带HMW-MAA的黑色素瘤细胞的迟发型超敏反应。因此，单克隆抗体MK2-23代表了小鼠抗独特型单克隆抗体诱导对人肿瘤相关抗原（TAA）产生细胞免疫和体液免疫的首个实例，因为先前描述的具有TAA镜像的小鼠抗独特型单克隆抗体已被证明仅诱导体液抗TAA免疫。单克隆抗体MK2-23与钥孔戚血蓝蛋白偶联并与弗氏佐剂一起给药后，其免疫原性显著增强。此外，免疫次数和注射的单克隆抗体MK2-23剂量会影响其免疫原性，尽管其影响程度低于与载体偶联和与佐剂混合。从本研究中获得的信息为优化黑色素瘤患者使用单克隆抗体MK2-23的免疫方案提供了有用的背景。
