Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors

尽管癌症治疗已取得进展，但对于许多患者来说治疗还不够，而且 预计 2019 年美国将有超过 607,000 人因癌症死亡。其中许多死亡将因 来自发展为实体瘤的癌症，这些肿瘤特别难以用化疗或其他方法治疗 生物药物。抗癌单克隆抗体 (mAb) 和抗体药物偶联物的功效不佳 (ADC) 的部分原因是实体瘤内这些药物的摄取和分布不良。 实体瘤的病理生理学特征包括其细胞生长混乱、细胞外致密 基质、血管化不良和紊乱、淋巴管生成减少、间质液含量高 压力。这些特性限制了 mAb 和 ADC 在肿瘤内的对流和扩散运输， 导致瘤内分布不良且不均匀。该提案测试了三种新的平台策略 旨在通过增强抗癌单克隆抗体疗法的选择性和功效 mAb 和 ADC 在实体瘤内的分布。目标 #1 引入了一种新颖的策略来克服 通过暂时抑制抗体与抗原的结合，在肿瘤内形成“结合位点屏障”， 施用抗独特型药物，可短期且可逆地拮抗 mAb 结合。目标#2 将研究使用具有 pH 依赖性、“捕获并释放”结合的抗体来绕过分解代谢 与受体介导的抗癌单克隆抗体内吞作用相关的水槽。在目标#3中，有针对性地递送基质- 将采用调节酶来实现肿瘤中胶原蛋白的选择性消耗，并使得 改善 mAb 和 ADC 的肿瘤内分布。每个目标都有机制的有力支持 数学建模并通过初步数据证明实用性和可行性。药代动力学、功效、 优化的抗 HER2 mAb 和 ADC 疗法的安全性将使用 HER2-小鼠模型进行评估 人类癌症呈阳性。这项工作中开发的新型药物可能适合立即转化为 曲妥珠单抗和 ado-曲妥珠单抗 emtansine 治疗 HER2 阳性乳腺和胃病的优化 癌症患者。此外，本提案中引入的方法可以扩展用于优化 将所有 mAb 和 ADC 应用于实体瘤治疗，可能为数百人带来益处 数以千计的患者。

Although advances have been made in the treatment of cancer, therapy is inadequate for many patients, and it is projected that there will be over 607,000 cancer deaths in the US in 2019. Many of these deaths will result from cancers that develop as solid tumors, which are particularly difficult to treat with chemotherapy or with biological drugs. Sub-optimal efficacy of anti-cancer monoclonal antibodies (mAb) and antibody-drug conjugates (ADC) has been explained, in part, by poor uptake and distribution of these agents within solid tumors. Pathophysiologic characteristics of solid tumors include their chaotic cellular growth, dense extracellular matrices, poor and disorganized vascularization, decreased lymphangiogenesis, and high interstitial fluid pressure. These characteristics limit the convective and diffusive transport of mAb and ADC within tumors, leading to poor and heterogeneous intra-tumoral distribution. This proposal tests three new platform strategies designed to improve the selectivity and efficacy of anti-cancer monoclonal antibody-based therapy by enhancing the distribution of mAb and ADCs within solid tumors. Aim #1 introduces a novel strategy for overcoming the “binding-site barrier” within tumors through transient inhibition of antibody binding to antigen, as achieved co- administration of anti-idiotypic agents that allow short-term and reversible antagonism of mAb binding. Aim #2 will investigate the use of antibodies with pH-dependent, “catch-and-release” binding to bypass the catabolic sink associated with receptor-mediated endocytosis of anti-cancer mAb. In Aim #3, targeted delivery of matrix- modulating enzymes will be employed to achieve selective depletion of collagen in tumors, and to enable improved intra-tumoral distribution of mAb and ADC. Each aim is strongly supported by mechanistic mathematical modeling and by preliminary data demonstrating utility and feasibility. Pharmacokinetics, efficacy, and safety of optimized anti-HER2 mAb and ADC therapy will be assessed using mouse models of HER2- positive human cancer. The novel agents developed in this work may be suitable for immediate translation toward optimization of trastuzumab and ado-trastuzumab emtansine treatment of HER2-positive breast and gastric cancer patients. Additionally, the approaches introduced in this proposal may be extended for use in optimizing therapy with all mAb and ADC applied to the treatment of solid tumors, potentially providing benefit to hundreds of thousands of patients.