IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4.

中文翻译：

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在免疫能力强的大鼠模型中，CSPG4导向的IgE抗体的体内安全性。

IgE单克隆抗体在癌症治疗中具有巨大潜力。临床前的体内系统，尤其是其中抗体识别宿主物种的目标抗原并结合相关Fc受体的临床前系统，通常是最接近人体暴露的体内系统，并且是评估基于抗体的疗法安全性的关键挑战。我们试图开发一种免疫功能大鼠系统，以评估啮齿动物抗肿瘤IgE的安全性，作为人类治疗候选药物的替代品。我们产生了针对人类肿瘤相关抗原硫酸软骨素蛋白聚糖4（CSPG4）的大鼠IgE，并且对大鼠抗原具有交叉反应性。我们分析了在正常大鼠和人体组织中CSPG4的分布，并通过对免疫活性大鼠进行全身给药后监测临床体征和分子生物标记物来研究抗体的体内安全性。人和大鼠CSPG4在正常组织中的表达相当。接受抗体的动物表现出短暂的轻度至中度不良事件，并伴有血清类胰蛋白酶的轻度升高，但未出现与过敏反应或细胞因子风暴有关的血管紧张素II或细胞因子。从长远来看，重复施用抗体的耐受性良好，动物体重，肝肾功能或血细胞计数无变化。该模型为IgE治疗性抗体的安全性分析提供了临床前支持。由于人类和大鼠的抗原组织分布相当，