Miederer Matthias, McDevitt Michael R, Sgouros George, Kramer Kim, Cheung Nai-Kong V, Scheinberg David A
Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Nucl Med. 2004 Jan;45(1):129-37.
Short-lived alpha-emitting isotopes individually conjugated to monoclonal antibodies have now reached human use, but little is still known about their toxicity. Use of antibody targetable (225)Ac nanogenerators is a new approach in the field of alpha-immunotherapy offering the advantage of a 10-d half-life (t(1/2)) and increased potency due to generation of 3 new atoms, yielding a total of 4 alpha-particles. However, the 3 alpha-emitting daughter elements generated have the potential for significant toxicity as these nuclides are no longer bound to the carrier IgG.
Cynomolgus monkeys were used to evaluate the toxicity of prototype (225)Ac nanogenerators. Monoclonal antibody HuM195 (anti-CD33) is the carrier for planned human clinical trials of (225)Ac; there are no CD33 sites in cynomolgus monkeys. In one experiment, 2 monkeys received a single intravenous dose of (225)Ac-HuM195 at 28 kBq/kg. This dose level is approximately the planned initial human dose. In another experiment, 2 animals received a dose escalation schedule of 3 increasing (225)Ac-HuM195 doses with a cumulative activity of 377 kBq/kg. The whole-blood t(1/2) of (225)Ac, ratios of (225)Ac to its ultimate alpha-emitting daughter nuclide (213)Bi, generation of monkey anti-HuM195 antibodies (MAHA), hematologic indices, serum biochemistries, and clinical parameters were measured. Monkeys were euthanized and examined histopathologically when the dose escalation reached toxicity.
The blood t(1/2) of (225)Ac-HuM195 was 12 d, and 45% of generated (213)Bi daughters were cleared from the blood. MAHA production was not detected. Approximately 28 kBq/kg of (225)Ac caused no toxicity at 6 mo, whereas a cumulative dose of approximately 377 kBq/kg caused severe toxicity. In the cumulative dosing schedule, single doses of approximately 37 kBq/kg resulted in no toxicity at 6 wk. After approximately 130 kBq/kg were administered, no toxicity was observed for 13 wk. However, 28 wk after this second dose administration, mild anemia and increases of blood urea nitrogen and creatinine were detected. After administration of an additional 185 kBq/kg, toxicity became clinically apparent. Monkeys were euthanized 13 and 19 wk after the third dose administration (cumulative dose was 377 kBq/kg). Histopathologic evaluation revealed mainly renal tubular damage associated with interstitial fibrosis.
(225)Ac nanogenerators may result in renal toxicity and anemia at high doses. The longer blood t(1/2) and the lack of target cell antigens in cynomolgus monkeys may increase toxicity compared with human application. Therefore, a dose level of at least 28 kBq/kg may be a safe starting dose in humans. Hematologic and renal function will require close surveillance during clinical trials.
与单克隆抗体单独偶联的短寿命发射α粒子的同位素现已应用于人体，但对其毒性仍知之甚少。使用可靶向抗体的（225）锕纳米发生器是α免疫疗法领域的一种新方法，其优点是半衰期为10天（t(1/2)），并且由于产生3个新原子，产生总共4个α粒子，从而提高了效力。然而，产生的3种发射α粒子的子元素具有显著毒性的可能性，因为这些核素不再与载体免疫球蛋白结合。
食蟹猴用于评估原型（225）锕纳米发生器的毒性。单克隆抗体HuM195（抗CD33）是计划用于（225）锕人体临床试验的载体；食蟹猴体内没有CD33位点。在一项实验中，2只猴子接受了28 kBq/kg的单次静脉注射（225）锕-HuM195。该剂量水平大约是计划的人体初始剂量。在另一项实验中，2只动物接受了3次递增的（225）锕-HuM195剂量的剂量递增方案，累积活度为377 kBq/kg。测量了（225）锕的全血t(1/2)、（225）锕与其最终发射α粒子的子核素（213）铋的比率、猴抗HuM195抗体（MAHA）的产生、血液学指标、血清生化指标和临床参数。当剂量递增达到毒性时，对猴子实施安乐死并进行组织病理学检查。
（225）锕-HuM195的血液t(1/2)为12天，产生的（213）铋子元素中有45%从血液中清除。未检测到MAHA产生。大约28 kBq/kg的（225）锕在6个月时未引起毒性，而累积剂量约377 kBq/kg则引起严重毒性。在累积给药方案中，单次剂量约37 kBq/kg在6周时未引起毒性。在给予约130 kBq/kg后，13周内未观察到毒性。然而，在第二次给药后28周，检测到轻度贫血以及血尿素氮和肌酐升高。在额外给予185 kBq/kg后，毒性在临床上变得明显。在第三次给药后13周和19周（累积剂量为377 kBq/kg）对猴子实施安乐死。组织病理学评估显示主要是与间质纤维化相关的肾小管损伤。
（225）锕纳米发生器在高剂量时可能导致肾毒性和贫血。与人体应用相比，食蟹猴较长的血液t(1/2)和缺乏靶细胞抗原可能会增加毒性。因此，至少28 kBq/kg的剂量水平可能是人体安全的起始剂量。在临床试验期间需要密切监测血液学和肾功能。
