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

尽管在癌症的治疗方面已经取得了进展，但对于许多患者来说，治疗是不够的， 预计2019年美国将有超过607，000人死于癌症。许多死亡将导致 从发展为实体瘤的癌症，这是特别难以治疗的化疗或 生物药物抗癌单克隆抗体（mAb）和抗体-药物偶联物的次优疗效 (ADC)部分原因是这些药物在实体瘤中的吸收和分布较差。 实体瘤的病理生理特征包括其混乱的细胞生长，致密的细胞外基质， 基质、不良和紊乱的血管形成、淋巴管生成减少和高间质液 压力这些特征限制了mAb和ADC在肿瘤内的对流和扩散转运， 导致肿瘤内分布差和不均匀。该提案测试了三个新的平台战略 旨在通过增强抗肿瘤单克隆抗体治疗的选择性和有效性， mAb和ADC在实体瘤中的分布。目标#1介绍了一种新的策略来克服 通过瞬时抑制抗体与抗原的结合，实现肿瘤内的"结合位点屏障"， 给予允许mAb结合的短期和可逆拮抗作用的抗独特型剂。目标2 将研究使用抗体与pH值依赖性，"捕捉和释放"结合，以绕过分解代谢 与抗癌mAb受体介导的内吞作用相关的接收器。在目标#3中，基质的靶向递送- 调节酶将用于实现肿瘤中胶原的选择性消耗， 改善mAb和ADC的肿瘤内分布。每一个目标都得到了机械的有力支持。 数学模型和初步数据证明实用性和可行性。药代动力学、疗效， 将使用HER2 - 1的小鼠模型评估优化的抗HER2 mAb和ADC疗法的安全性。 阳性人类癌症在这项工作中开发的新药物可能适合于立即翻译为 曲妥珠单抗和ado-曲妥珠单抗-美坦新偶联物治疗HER2阳性乳腺癌和胃癌的优化 癌症患者。此外，在该建议中介绍的方法可以扩展用于优化 使用所有mAb和ADC的治疗应用于实体瘤的治疗，可能为数百人提供益处。 成千上万的病人。

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.