Wikstrand C J, Fredman P, Svennerholm L, Bigner D D
Department of Pathology, Duke University Medical Center, Durham, NC 27710.
Prog Brain Res. 1994;101:213-23. doi: 10.1016/s0079-6123(08)61951-2.
In this study, MAbs to the 'conventional' gangliosides expressed by human gliomas were generated and used to detect ganglioside species previously unisolated or defined in normal adult CNS tissue. Despite the marked phenotypic and genotypic heterogeneity shown by glioma cell lines (Bigner et al., 1981), the ganglioside phenotype of these cell lines is remarkably consistent qualitatively, if not quantitatively, in the ganglioside species expressed (Table V). The majority of cell lines and tumor samples express GM2, GD2 and GD3; this does not provide a diagnostic advantage (Vick et al., 1992). Nevertheless, as the relative amounts of these gangliosides in tumor as compared with normal adult CNS tissue is considerable, such reagents might be considered in compartmental immunotherapeutic approaches. Since GD2 and GD3 have been determined to mediate tumoricidal activity with human effector cells via specific antiganglioside epitope MAbs (Thurin et al., 1987; Kushner and Cheung, 1991; Barker et al., 1991; Reisfeld, 1993), cell-mediated approaches, as well as targeted immunoglobulin therapies, are also possible. The prospect of a more targeted approach with little or no effect on normal CNS tissue is now possible via the 'oncofetal' epitopes characteristic of 3'-isoLM1 and 3',6'-isoLD1. Several factors recommend the use of these moieties for compartmental immunotherapy; the inability to detect them within the adult CNS; the relatively high frequency of expression of 3'-isoLM1 and 3',6'-isoLD1, especially in human tumor samples (50-100%, depending upon the series and assay); and the existence of specific MAbs reactive with these epitopes. Current technology is being applied to these MAbs to transfer the specific recognition capacity of existing murine MAbs into various human framework structures of any desired immunoglobulin class, and thereby, biologic function. The variety of effector functions, the stability in affinity, labeling capacity, and the exquisite sensitivity of these MAbs for these glioma-distinctive epitopes is an exciting and promising approach for immunotherapy of human CNS tumors.
在本研究中，制备了针对人胶质瘤表达的“常规”神经节苷脂的单克隆抗体，并用于检测先前在正常成人中枢神经系统组织中未分离或未定义的神经节苷脂种类。尽管胶质瘤细胞系表现出明显的表型和基因型异质性（Bigner等人，1981年），但这些细胞系的神经节苷脂表型在表达的神经节苷脂种类上，即使数量上不一致，质量上也非常一致（表V）。大多数细胞系和肿瘤样本表达GM2、GD2和GD3；这并没有提供诊断优势（Vick等人，1992年）。然而，由于与正常成人中枢神经系统组织相比，这些神经节苷脂在肿瘤中的相对含量相当可观，因此在分区免疫治疗方法中可以考虑使用此类试剂。由于已确定GD2和GD3通过特异性抗神经节苷脂表位单克隆抗体与人效应细胞介导杀肿瘤活性（Thurin等人，1987年；Kushner和Cheung，1991年；Barker等人，1991年；Reisfeld，1993年），细胞介导的方法以及靶向免疫球蛋白疗法也是可行的。通过3'-isoLM1和3'，6'-isoLD1特有的“癌胚”表位，现在有可能实现对正常中枢神经系统组织影响很小或没有影响的更有针对性的方法。有几个因素推荐使用这些部分进行分区免疫治疗；在成人中枢神经系统中无法检测到它们；3'-isoLM1和3'，6'-isoLD1的表达频率相对较高，特别是在人类肿瘤样本中（50%-100%，取决于系列和检测方法）；以及存在与这些表位反应的特异性单克隆抗体。当前技术正在应用于这些单克隆抗体，以将现有鼠单克隆抗体的特异性识别能力转移到任何所需免疫球蛋白类别的各种人框架结构中，从而实现生物学功能。这些单克隆抗体对这些胶质瘤独特表位的多种效应功能、亲和力稳定性、标记能力以及极高的敏感性，是人类中枢神经系统肿瘤免疫治疗中一种令人兴奋且有前景的方法。
