Ludwig Collaborative Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY;
Blood. 2014 Apr 3;123(14):2172-80. doi: 10.1182/blood-2013-12-544742. Epub 2014 Feb 20.
Immunotherapy for cancer using antibodies to enhance T-cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4(+) T cells, B cells, and interleukin-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific immunoglobulin G1 (IgG1), can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet-activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies.
利用抗体增强 T 细胞功能的癌症免疫疗法在最近的临床试验中取得了成功。许多能够改善 T 细胞激活和效应功能的分子已被研究为免疫调节抗体的潜在新靶点，包括肿瘤坏死因子受体超家族成员 GITR 和 OX40。与 GITR 或 OX40 结合的抗体在临床前模型中可显著保护肿瘤。在这项研究中，我们观察到 GITR 激动剂抗体 DTA-1 在重复腹腔给药后会引起小鼠过敏反应。DTA-1 诱导的过敏反应需要 GITR、CD4(+)T 细胞、B 细胞和白细胞介素-4。从接受 DTA-1 治疗的小鼠中转移血清抗体，其中含有高水平的 DTA-1 特异性免疫球蛋白 G1（IgG1），在给予额外剂量的 DTA-1 后可在幼稚小鼠中诱导过敏反应，表明过敏反应是由抗 DTA-1 抗体引起的。嗜碱性粒细胞耗竭和血小板激活因子（过敏反应 IgG1 途径的关键成分）的阻断可挽救 DTA-1 诱导的过敏反应小鼠。这些结果表明，重复给予激动剂免疫调节抗体可导致以前未描述的致命副作用，并深入了解毒性机制，这可能为未来使用抗 GITR 或其他激动剂抗体作为免疫疗法的临床试验中预防不良反应提供一种手段。
