McCabe R P, Peters L C, Haspel M V, Pomato N, Carrasquillo J A, Hanna M G
Bionetics Research, Inc., Rockville, MD 20850-4373.
Cancer Res. 1988 Aug 1;48(15):4348-53.
We studied the pharmacokinetic properties of two human monoclonal antibodies to colon carcinoma cells and their ability to detect tumors in nude mice bearing primary human colon carcinoma xenografts. The 16-88 and 28A32 monoclonal antibodies are immunoglobulin M class human antibodies produced by cell lines derived from peripheral blood lymphocytes from patients with colon carcinoma. The patients received an autologous tumor cell vaccine as part of an active specific immunotherapy protocol. The 125I-labeled antibodies were cleared from the circulation of non-tumor-bearing and tumor-bearing nude mice with a 6-8-h half-life. The half-life of the antibodies in tumor tissue was 48 to 72 h compared to 8 to 12 h for normal tissues. Tumor:normal tissue ratios were highest 4 to 7 days postinjection with tumor:blood ratios of 12:1 for 16-88 and 10:1 for 28A32 antibody. Experiments with a control human immunoglobulin M myeloma protein confirmed the specificity of the human monoclonal antibodies. Radioimmunoscintigraphic studies using nude mice bearing contralateral antibody-reactive and nonreactive colon tumor xenografts further confirmed that the antibodies specifically localized in tumor tissues. The antibody-reactive tumors were clearly visible by radioimmunoscintigraphy within 4 days of injection. These experiments, undertaken as a preliminary step to clinical trials, demonstrated for the first time that i.v. administered human immunoglobulin M monoclonal antibodies could be taken up by human colon tumor tissue and retained to a sufficient extent to easily permit tumor detection by external radioimmunoscintigraphy. These studies also demonstrated that the nude mouse human colon tumor xenograft model is a useful in vivo system for comparison studies of human monoclonal antibodies as part of a selection process for clinical trials and for evaluating immunoconjugates containing these antibodies for relative pharmacokinetic properties and potential diagnostic or therapeutic efficacy.
我们研究了两种抗结肠癌细胞的人单克隆抗体的药代动力学特性，以及它们在携带原发性人结肠癌异种移植瘤的裸鼠中检测肿瘤的能力。16 - 88和28A32单克隆抗体是免疫球蛋白M类人抗体，由源自结肠癌患者外周血淋巴细胞的细胞系产生。这些患者接受了自体肿瘤细胞疫苗，作为主动特异性免疫治疗方案的一部分。125I标记的抗体在无肿瘤和有肿瘤的裸鼠循环中的清除半衰期为6 - 8小时。抗体在肿瘤组织中的半衰期为48至72小时，而在正常组织中为8至12小时。注射后4至7天，肿瘤与正常组织的比值最高，16 - 88抗体的肿瘤与血液比值为12:1，28A32抗体为10:1。用对照人免疫球蛋白M骨髓瘤蛋白进行的实验证实了人单克隆抗体的特异性。使用携带对侧抗体反应性和非反应性结肠肿瘤异种移植瘤的裸鼠进行的放射免疫闪烁成像研究进一步证实，抗体特异性定位于肿瘤组织中。注射后4天内，通过放射免疫闪烁成像可清晰看到抗体反应性肿瘤。作为临床试验的初步步骤进行的这些实验首次证明，静脉注射的人免疫球蛋白M单克隆抗体可被人结肠肿瘤组织摄取并保留到足够程度，以便通过外部放射免疫闪烁成像轻松检测肿瘤。这些研究还表明，裸鼠人结肠肿瘤异种移植模型是一种有用的体内系统，可用于作为临床试验选择过程一部分的人单克隆抗体比较研究，以及评估含有这些抗体的免疫缀合物的相对药代动力学特性和潜在诊断或治疗效果。
