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

摘要 近二十年来，单抗在癌症的诊断和治疗中发挥了关键作用。 并继续以指数级的速度增长。最初是因为它们具有针对肿瘤的非凡能力而开发的 抗原和诱导抗体依赖的细胞毒性(ADCC)，它们最近被用于 调节患者的免疫系统以进行抗癌免疫治疗。虽然它的产生和发展 针对各种细胞表面蛋白的抗体进展迅速，合适的模型系统可用于前 这种疗法的临床测试一直滞后。这是因为人类抗体不能与小鼠完全结合 或非人类灵长类Fc受体(FcγRs)，II是异体宿主迅速排斥的外来蛋白 和iii)经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，我们的研究集中于临床相关模型的生成和测试 更好地了解诊断和治疗抗体的体内活性。目前的提案旨在现在 建立和充分描述新的小鼠模型，允许通过以下方式更好地进行人类抗体的临床前测试 改造我们之前开发的人源化FcγR小鼠品系，以表达人FcRN和IgG1. 人FcRN的表达将使人抗体和 体内半衰期延长的抗体产生方法的评价。通过更换鼠标 重链与人类免疫球蛋白G1区的恒定区，该模型还将允许慢性给药人类 以免疫球蛋白为基础的治疗，不会产生抗药抗体反应。通过解决以下两个主要障碍 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 并有可能发现Fc工程抗体的新机制。此外，鉴于越来越多的人对 在免疫治疗中，拥有免疫活性模型比目前的异种移植提供了额外的优势。 模特们。最后，由于最近的数据表明Fc-FCγR在放射性标记抗体诊断中发挥了重要作用，这些 模型将提供临床相关的模型，以帮助改进创新的开发和测试 基于抗体的分子，用于体内肿瘤的检测和定位。

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.