McLendon R E, Archer G E, Larsen R H, Akabani G, Bigner D D, Zalutsky M R
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):491-9. doi: 10.1016/s0360-3016(99)00206-0.
The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide 211At is of interest as an endoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of 211At-labeled chimeric 81C6 in patients, the long-term radiotoxicity of this radiopharmaceutical has been evaluated.
Antibody labeling was performed using N-succinimidyl 3-[211At]astato-benzoate. After an initial dose-finding experiment, a second toxicity study was carried out at 4 dose levels in groups of 30 nonthyroid blocked B6C3F1 mice per group (15 males, 15 females). Male mice received either saline or 15-81 kBq/g and females received either saline or 16-83 kBq/g of 211At-labeled antibody. Ten animals (5 males, 5 females) were followed for 6 months and the remainder for 1 year.
The lethal dose in 10% of animals (LD10) for 211At-labeled chimeric 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects--perivascular fibrosis of the intraventricular septum of the heart, bone marrow suppression, splenic white pulp atrophy, and spermatic maturational delay--generally were confined to a few animals receiving the highest doses of labeled antibody.
The LD10 of 211At-labeled chimeric 81C6 in this mouse strain was about half that of [211At]astatide. These results establish the preclinical maximum tolerated dose of 211At-labeled chimeric 81C6 and define in the mouse the target organs for toxicity. These studies will be useful for determining starting doses for clinical studies with 211At-labeled chimeric 81C6.
用发射α粒子的放射性核素砹-211标记的抗腱生蛋白人/鼠嵌合单克隆抗体作为一种用于治疗脑肿瘤的内放射治疗剂备受关注。为便于在患者中研究砹-211标记的嵌合体81C6，已对这种放射性药物的长期放射毒性进行了评估。
使用N-琥珀酰亚胺基3-[砹-211]阿替苯甲酸酯进行抗体标记。在初始剂量探索实验之后，在4个剂量水平上进行了第二项毒性研究，每组30只未进行甲状腺阻断的B6C3F1小鼠（15只雄性，15只雌性）。雄性小鼠接受生理盐水或每克体重15 - 81千贝可的砹-211标记抗体，雌性小鼠接受生理盐水或每克体重16 - 83千贝可的砹-211标记抗体。10只动物（5只雄性，5只雌性）随访6个月，其余动物随访1年。
砹-211标记的嵌合体81C6在10%动物中的致死剂量（LD10），雌性为每克体重46千贝可，雄性为每克体重102千贝可。毒性效应——心脏室内间隔的血管周围纤维化、骨髓抑制、脾白髓萎缩以及精子成熟延迟——通常局限于少数接受最高剂量标记抗体的动物。
在该小鼠品系中，砹-211标记的嵌合体81C6的LD10约为[砹-211]砹化物的一半。这些结果确定了砹-211标记的嵌合体81C6的临床前最大耐受剂量，并在小鼠中确定了毒性靶器官。这些研究将有助于确定砹-211标记的嵌合体81C6临床研究的起始剂量。
