Stein R, Blumenthal R, Sharkey R M, Goldenberg D M
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, New Jersey 07103.
Cancer. 1994 Feb 1;73(3 Suppl):816-23. doi: 10.1002/1097-0142(19940201)73:3+<816::aid-cncr2820731311>3.0.co;2-t.
RS7 is a murine monoclonal antibody immunoglobulin G1 with pan-carcinoma reactivity, which was raised against human squamous cell carcinoma of the lung. To optimize the use of monoclonal antibody RS7 as a carrier of radionuclides for tumor targeting and therapeutic applications, whole RS7 immunoglobulin G and its F(ab')2 fragment were radiolabeled, and their biodistribution and effectiveness as radioimmunotherapeutic agents in nude mice bearing established human tumor xenografts were evaluated. The contributions of the tumor model, monoclonal antibody form (fragment vs. intact), radioisotope (131I, 111In, 90Y, and 188Re), and antigen target were evaluated.
Cumulative absorbed radiation doses were calculated from biodistribution data, and doses were normalized to blood to estimate expected relative toxicities. Two tumor models expressing different levels of RS7-antigen were studied: ME180, a cervical carcinoma cell line, and Calu-3, an adenocarcinoma of the lung cell line. In addition, the therapeutic effectiveness of 131I-RS7-F(ab')2 was compared to that of 131I-RS7-IgG.
Doses delivered to tumor (normalized to blood) calculated for 131I-RS7-F(ab')2 and 90Y-RS7-IgG were 4.7 times and 1.8 times greater, respectively, than 131I-RS7-IgG, and therefore would be expected to yield greater therapeutic efficacy when equitoxic doses are administered. This expectation was confirmed in the radioimmunotherapy study with 131I-RS7-F(ab')2. At equivalent absorbed dose to tumor, 131I-RS7-F(ab')2 was found to effect a slightly longer suppression of tumor growth than the intact 131I-RS7 IgG, and a 50% dose escalation yielded tumor regression for a prolonged period with the fragment, whereas a similar 50% dose escalation with 131I-RS7-IgG could not be tolerated.
RS7是一种具有泛癌反应性的鼠单克隆抗体免疫球蛋白G1，它是针对人肺鳞状细胞癌产生的。为了优化单克隆抗体RS7作为放射性核素载体用于肿瘤靶向和治疗应用，对完整的RS7免疫球蛋白G及其F(ab')2片段进行了放射性标记，并评估了它们在荷人肿瘤异种移植瘤裸鼠中的生物分布以及作为放射免疫治疗剂的有效性。评估了肿瘤模型、单克隆抗体形式（片段与完整形式）、放射性同位素（131I、111In、90Y和188Re）以及抗原靶点的作用。
根据生物分布数据计算累积吸收辐射剂量，并将剂量归一化至血液以估计预期的相对毒性。研究了两种表达不同水平RS7抗原的肿瘤模型：ME180，一种宫颈癌细胞系；以及Calu-3，一种肺腺癌细胞系。此外，比较了131I-RS7-F(ab')2与131I-RS7-IgG的治疗效果。
计算得出，131I-RS7-F(ab')2和90Y-RS7-IgG输送至肿瘤（归一化至血液）的剂量分别比131I-RS7-IgG高4.7倍和1.8倍，因此当给予等毒性剂量时，预计会产生更大的治疗效果。在使用131I-RS7-F(ab')2的放射免疫治疗研究中证实了这一预期。在肿瘤等效吸收剂量下，发现131I-RS7-F(ab')2对肿瘤生长的抑制作用比完整的131I-RS7 IgG稍长，并且片段剂量增加50%可使肿瘤长期消退，而131I-RS7-IgG类似的50%剂量增加则无法耐受。
