Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-001262.
Some patients with cancer treated with anticancer monoclonal antibodies (mAbs) develop antidrug antibodies (ADAs) that recognize and bind the therapeutic antibody. This response may neutralize the therapeutic mAb, interfere with mAb effector function or cause toxicities. We investigated the potential influence of ADA to modify the tumor-binding capability of a tumor-reactive 'immunocytokine' (IC), namely, a fusion protein (hu14.18-IL2) consisting of a humanized, tumor-reactive, anti-GD2 mAb genetically linked to interleukin 2. We characterize the role of treatment delivery of IC (intravenous vs intratumoral) on the impact of ADA on therapeutic outcome following IC treatments in an established antimelanoma (MEL) regimen involving radiotherapy (RT) +IC.
C57BL/6 mice were injected with human IgG or the hu14.18-IL2 IC to develop a mouse anti-human antibody (MAHA) response (MAHA). In vitro assays were performed to assess ADA binding to IC using sera from MAHA and MAHA mice. In vivo experiments assessed the levels of IC bound to tumor in MAHA and MAHA mice, and the influence of IC route of delivery on its ability to bind to B78 (GD2+) MEL tumors.
MAHA is inducible in C57BL/6 mice. In vitro assays show that MAHA is capable of inhibiting the binding of IC to GD2 antigen on B78 cells, resulting in impaired ADCC mediated by IC. When B78-bearing mice are injected intravenously with IC, less IC binds to B78-MEL tumors in MAHA mice than in MAHA mice. In contrast, when IC is injected intratumorally in tumor-bearing mice, the presence of MAHA does not detectibly impact IC binding to the tumor. Combination therapy with RT+IT-IC showed improved tumor regression compared with RT alone in MAHA mice. If given intratumorally, IC could be safely readministered in tumor-bearing MAHA mice, while intravenous injections of IC in MAHA mice caused severe toxicity. Histamine levels were elevated in MAHA mice compared with MAHA mice after reintroduction of IC.
Intratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.
一些接受抗癌单克隆抗体（mAbs）治疗的癌症患者会产生针对药物的抗体（ADAs），这些抗体能够识别并结合治疗性抗体。这种反应可能会中和治疗性 mAb，干扰 mAb 的效应功能或引起毒性。我们研究了 ADA 对肿瘤反应性“免疫细胞因子”（IC）的肿瘤结合能力的潜在影响，即由与人源化、肿瘤反应性、抗 GD2 mAb 基因融合的白细胞介素 2 组成的融合蛋白（hu14.18-IL2）。我们描述了 IC 治疗方法（静脉内 vs 肿瘤内）对 ADAs 对既定抗黑色素瘤（MEL）方案（包括放疗[RT]+IC）中 IC 治疗后治疗结果的影响。
C57BL/6 小鼠注射人 IgG 或 hu14.18-IL2 IC 以产生针对人抗体的抗体（MAHA）反应（MAHA）。进行体外试验以评估来自 MAHA 和 MAHA 小鼠的血清中 ADA 与 IC 的结合。体内实验评估了 MAHA 和 MAHA 小鼠中 IC 与肿瘤的结合水平，以及 IC 给药途径对其与 B78（GD2+）MEL 肿瘤结合的影响。
MAHA 可在 C57BL/6 小鼠中诱导。体外试验表明，MAHA 能够抑制 IC 与 B78 细胞上 GD2 抗原的结合，从而削弱了由 IC 介导的 ADCC。当 B78 荷瘤小鼠静脉内注射 IC 时，MAHA 小鼠中与 B78-MEL 肿瘤结合的 IC 少于 MAHA 小鼠。相比之下，当 IC 瘤内注射到荷瘤小鼠中时，MAHA 的存在并不会明显影响 IC 与肿瘤的结合。与单独 RT 相比，RT+IT-IC 联合治疗可改善 MAHA 小鼠的肿瘤消退。如果瘤内给药，IC 可安全地重新给予荷瘤 MAHA 小鼠，而 MAHA 小鼠静脉内注射 IC 则会引起严重毒性。重新引入 IC 后，MAHA 小鼠的组胺水平高于 MAHA 小鼠。
肿瘤内注射可能是克服针对肿瘤反应性 mAb 或 IC 的 ADA 中和治疗活性的一种手段，并且可以降低全身毒性，这可能具有重要的转化意义。
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