Anti-OX40 (CD134) administration to nonhuman primates: Immunostimulatory effects and toxicokinetic study
Anti-OX40 (CD134) administration to nonhuman primates: Immunostimulatory effects and toxicokinetic study
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DOI：
10.1097/01.cji.0000211319.00031.fc
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发表时间：
2006-11-01
影响因子：
3.9
通讯作者：
Urba, Walter J.
中科院分区：
文献类型：
--
作者：
Weinberg, Andrew D.;Thalhofer, Colin;Urba, Walter J.
抗CD134(OX40)抗体的免疫刺激特性已经在啮齿动物中得到了很好的证明，包括它们增强抗肿瘤免疫的能力。在这项研究中，一种已知在体外共刺激猕猴T细胞的抗OX40抗体(Ab)被注入恒河猴体内。猴子免疫猴免疫缺陷病毒蛋白gp130。免疫猴注射抗OX40抗体后，引流淋巴结较注射小鼠Ig免疫猴的引流淋巴结增大。与对照组相比，接受抗OX40治疗的猴子增加了gp130特异性抗体效价，并增加了长寿T细胞反应。在接受抗OX40治疗的猴子中，没有明显的毒性迹象。令人鼓舞的免疫刺激作用导致了用于癌症患者临床试验的抗OX40抗体的良好生产实践。用抗OX40在非人灵长类动物中进行了详细的毒理学研究。三组8只猴子分别接受3个剂量水平(0.4、2.0和10 mg/kg)之一的抗OX40，对照组注射生理盐水。没有观察到临床毒性，但在抗OX40治疗的动物中观察到急性脾肿大和肠道相关淋巴结增大；脾肿大和淋巴结病在第28天消失。这些研究证明了抗OX40在灵长类动物中的免疫刺激特性和安全性，并为在人类身上进行临床试验提供了强有力的科学依据。
The immune-stimulatory properties of anti-CD134 (OX40) antibodies have been well documented in rodents, including their ability to enhance antitumor immunity. In this study, an anti-OX40 antibody (Ab) known to costimulate monkey T cells in vitro, was infused into rhesus macaque. monkeys during immunization with the simian immunodeficiency virus protein, gp130. The draining lymph nodes from immunized monkeys treated with anti-OX40 were enlarged compared with immunized monkeys injected with mouse Ig. Anti-OX40-treated monkeys had increased gp130-specific Ab titers, and increased long-lived T-cell responses, compared with controls. There were no overt signs of toxicity in the anti-OX40-treated monkeys. The encouraging immune-stimulatory effects led to the good manufacturing practice production of an anti-OX40 Ab for clinical trials in cancer patients. A detailed toxicology study was performed with anti-OX40 in nonhuman primates. Three groups of 8 monkeys received anti-OX40 at 1 of 3 dose levels (0.4, 2.0, and 10 mg/kg) and a control group received saline. No clinical toxicity was observed, but acute splenomegaly and enlarged gut-associated lymph nodes were observed in the anti-OX40-treated animals; splenomegaly and lymphadenopathy resolved by day 28. These studies demonstrate the immune-stimulatory properties and safety of anti- OX40 in primates and provide a strong scientific rationale to pursue clinical trials in humans.