Ma D, McDevitt M R, Barendswaard E, Lai L, Curcio M J, Pellegrini V, Brechbiel M W, Scheinberg D A
Department of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Leukemia. 2002 Jan;16(1):60-6. doi: 10.1038/sj.leu.2402320.
In recent years, radioimmunotherapy (RIT) with beta(-) particle emitting radionuclides targeting the CD20 antigen on B cells in the treatment of non-Hodgkin's lymphoma has provided the most compelling human clinical data for the success of RIT. CD19, like CD20, is an antigen expressed on the surface of cells of the B lineage, and CD19 may provide an alternative target for radioimmunotherapy of B cell neoplasms. CD19 has been largely overlooked as a target for conventional 131I RIT, because the antigen rapidly internalizes upon binding of antibody, resulting in catabolism and significant release of 131I. Such modulation may be an advantage to RIT with radiometals such as 90Y, 177Lu, 213Bi and 225Ac. Herein, we have compared beta(-) particle RIT with antibodies targeting either CD19 or CD20. The anti-CD19 and anti-CD20 antibodies, B4 or C2B8, respectively, were appended with the SCN-CHX-A''-DTPA bifunctional chelating agent and labeled with 90Y. In the tumor model used, there were three times as many CD20 target sites on lymphoma cells as compared to CD19 sites (62000 vs 20000 binding sites, respectively). We compared the efficacy of the 90Y-labeled antibodies to reduce lymphoma in a nude mouse xenograft solid tumor model, after measurable lymphoma appeared. Reduction in tumor size began at day 3 in all three 90Y-treated groups, but tumor began to recur in many animals 9 days after the treatments. There was one cure in each specific treatment group. In contrast, the tumor in the two control groups showed no regression. There was a significant prolongation of median survival time from xenograft (P < 0.0001) in all the 90Y-labeled antibody construct-treated groups (32 days for 0.15 mCi 90Y-B4; 26 days for 0.20 mCi 90Y-C2B8, and 23 days for 0.15 mCi 90Y-C2B8) in comparison to the two control groups (11 days for 0.02 mg of C2B8 and 9 days for untreated growth controls). Specificity of the radioimmunotherapy was also shown. In conclusion, 90Y-labeled anti-CD19 antibody has efficacy comparable to 90Y-labeled anti-CD20 antibody in the treatment of mice bearing human lymphoma xenografts. These data suggest that CD19-targeted RIT merits further study.
近年来，用发射β⁻粒子的放射性核素靶向B细胞上的CD20抗原进行放射免疫治疗（RIT），已为RIT的成功提供了最令人信服的人体临床数据。与CD20一样，CD19是B淋巴细胞系细胞表面表达的一种抗原，CD19可能为B细胞肿瘤的放射免疫治疗提供一个替代靶点。作为传统¹³¹I RIT的靶点，CD19在很大程度上被忽视了，因为该抗原在抗体结合后会迅速内化，导致分解代谢并大量释放¹³¹I。这种调节对于用诸如⁹⁰Y、¹⁷⁷Lu、²¹³Bi和²²⁵Ac等放射性金属进行的RIT可能是一个优势。在此，我们比较了靶向CD19或CD20的β⁻粒子RIT。抗CD19和抗CD20抗体，分别为B4或C2B8，与SCN-CHX-A''-DTPA双功能螯合剂连接并标记上⁹⁰Y。在所用的肿瘤模型中，淋巴瘤细胞上的CD20靶点数量是CD19靶点数量的三倍（分别为62000个和20000个结合位点）。在可测量的淋巴瘤出现后，我们在裸鼠异种移植实体瘤模型中比较了⁹⁰Y标记抗体减少淋巴瘤的疗效。所有三个⁹⁰Y治疗组在第3天开始肿瘤体积缩小，但在治疗后9天许多动物的肿瘤开始复发。每个特定治疗组都有1只治愈的动物。相比之下，两个对照组的肿瘤没有消退。与两个对照组（0.02 mg C2B8组为11天，未治疗的生长对照组为9天）相比，所有⁹⁰Y标记抗体构建体治疗组（0.15 mCi⁹⁰Y-B4组为32天；0.20 mCi⁹⁰Y-C2B8组为26天，0.15 mCi⁹⁰Y-C2B8组为23天）的异种移植瘤中位生存时间显著延长（P < 0.0001）。放射免疫治疗的特异性也得到了证实。总之，在治疗荷人淋巴瘤异种移植瘤的小鼠中，⁹⁰Y标记的抗CD19抗体与⁹⁰Y标记的抗CD20抗体疗效相当。这些数据表明，靶向CD19的RIT值得进一步研究。
