Novel Transgenic Mouse Models Addressing Outstanding Translational Barriers in Antibody-Based Therapeutics

摘要 近二十年来，单克隆抗体在癌症的诊断和治疗中发挥了举足轻重的作用 并继续以指数级的速度增长。最初是因为其针对肿瘤的特殊能力而开发的 抗原和引发抗体依赖性细胞毒性（ADCC），它们最近已被用于 调节患者的免疫系统用于抗癌免疫疗法。而产生和发展的 靶向各种细胞表面蛋白的抗体已经迅速发展，用于前 这类疗法的临床试验已经滞后。这是因为人抗体i）不能完全与鼠抗体结合， 或非人灵长类Fc受体（Fcγ R），ii）是在同种异体宿主中迅速排斥的外源蛋白 和iii）通常在缺乏适应性免疫细胞的免疫缺陷异种移植模型中进行不适当的测试， 同源FcγR。因此，我们的研究集中在临床相关模型的生成和测试上， 更好地了解诊断和治疗抗体的体内活性。目前的提案旨在 生成并充分表征新型鼠模型，其允许更好地进行人抗体的临床前测试， 工程化我们先前开发的人源化FcγR小鼠品系以表达人FcRn和IgG 1。 人FcRn的表达将允许更准确地分析人抗体的药代动力学， 评估旨在产生具有延长的体内半衰期的抗体的方法。通过更换鼠标 由于人IgG 1的恒定区与人重链互补，该模型也将允许长期施用人IgG 1。 基于IgG的治疗剂，而不产生抗药抗体反应。通过解决两个主要障碍， 在抗体治疗领域，这些模型将允许更快速和有效的临床前毒理学测试 并可能揭示Fc工程抗体的新机制。此外，鉴于越来越多的兴趣 在免疫治疗中，具有免疫活性模型提供了优于当前异种移植物的额外优势 模型最后，由于最近的数据表明Fc-FcγR在放射性标记的抗体诊断中具有重要作用，因此， 模型将提供一个临床相关的模型，以帮助改善创新的开发和测试， 用于肿瘤的体内检测和定位的基于抗体的分子。

ABSTRACT Monoclonal antibodies have played a pivotal role in the diagnosis and treatment of cancer for nearly two decades and continue to grow at an exponential pace. Initially developed for their exceptional ability to target tumor antigens and elicit antibody-dependent cellular cytotoxicity (ADCC), they have more recently been used to modulate a patient’s immune system for anti-cancer immunotherapy. While the generation and development of antibodies targeting various cell surface proteins has rapidly progressed, appropriate model systems for pre- clinical testing of such therapeutics has lagged. This is because human antibodies i) don’t fully engage murine or non-human primate Fc receptors (FcγRs), ii) are foreign proteins that are rapidly rejected in allogeneic hosts and iii) are often inappropriately tested in immunodeficient xenograft models lacking adaptive immune cells or homologous FcγR. Thus, our studies have focused on the generation and testing of clinically relevant models to better understand the in vivo activity of diagnostic and therapeutic antibodies. The current proposal aims to now generate and fully characterize novel murine models that allow better preclinical testing of human antibodies by engineering our previously developed humanized FcγR mouse strains to express human FcRn and IgG1. Expression of human FcRn will allow more accurate pharmacokinetic analysis of human antibodies and assessment of methods aimed at generating antibodies with extended in vivo half-life. By replacing the mouse heavy chain with the constant regions of human IgG1, this model will also allow chronic administration of human IgG-based therapeutics without developing anti-drug antibody responses. By addressing two major hurdles in the field of antibody therapeutics, these models will allow more rapid and efficient pre-clinical toxicology testing and potentially uncover novel mechanisms of Fc-engineered antibodies. Additionally, given the growing interest in immunotherapy, having an immunocompetent model provides an additional advantage over current xenograft models. Finally, as recent data suggest an important role for Fc-FcγR in radiolabeled antibody diagnostics, these models will provide a clinically relevant model to help improve the development and testing of innovative antibody-based molecules for the in vivo detection and localization of neoplasms.