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

增加单克隆抗体摄取、分布和治疗实体瘤疗效的药代动力学策略

• 批准号: 10397091
• 负责人: Joseph P Balthasar
• 金额: $ 35.54万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397091
• 关键词: Affinity; Antibodies; Antibody Affinity; Antibody Therapy; Antibody-drug conjugates; Antigens; Binding; Binding Sites; Biological; Blood Vessels; Breast; Bypass; Cancer Patient; Carcinoembryonic Antigen; Catabolism; Cell Surface Receptors; Cessation of life; Cetuximab; Characteristics; Chimeric Proteins; Clostridium; Collagen; Colorectal Cancer; Convection; Data; Development; Diffuse; Dissociation; Drug Kinetics; ERBB2 gene; Endosomes; Enzymes; Evaluation; Exocytosis; Extracellular Fluid; Extracellular Matrix; Extravasation; Gemtuzumab Ozogamicin; Health; Hematologic Neoplasms; Human; Immunoglobulin Fragments; In Vitro; Incidence; Injections; Intercellular Fluid; Investigation; Lung; Lymphangiogenesis; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Modeling; Monoclonal Antibodies; Oncology; Patients; Pharmaceutical Preparations; Physiological; Prevalence; Prostate; Safety; Site; Solid Neoplasm; Syndrome; Testing; Therapeutic Monoclonal Antibodies; Translations; Trastuzumab; Treatment Efficacy; Tumor Antibodies; Tumor Antigens; United States; Vascularization; Work; antagonist; anti-cancer; cancer diagnosis; cancer therapy; cell growth; chemotherapy; collagenase; design; human cancer mouse model; human model; improved; in silico; in vivo; malignant breast neoplasm; malignant stomach neoplasm; mathematical model; models and simulation; mouse model; nanobodies; neonatal Fc receptor; novel; novel strategies; pressure; prevent; receptor mediated endocytosis; research clinical testing; rituximab; side effect; targeted cancer therapy; targeted delivery; treatment optimization; tumor; uptake

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.

尽管在癌症的治疗方面取得了进展，但对许多患者来说，治疗是不够的，而且它 据预测，2019年美国将有超过60.7万人死于癌症。许多这样的死亡将会导致 从实体肿瘤发展而来的癌症，这种肿瘤特别难用化疗或 生物药物。抗癌单抗和抗体-药物结合物的次佳疗效 (ADC)的部分原因是这些药物在实体瘤中的摄取和分布较差。 实体瘤的病理生理特征包括细胞生长紊乱，细胞外致密。 基质，血管生成不良和紊乱，淋巴管生成减少，间质液体增多。 压力。这些特性限制了单抗和ADC在肿瘤内的对流和扩散传输， 导致肿瘤内分布差且不均匀。该提案测试了三个新的平台战略 旨在提高基于抗癌单抗的治疗的选择性和有效性 单抗和ADC在实体瘤中的分布。目标1介绍了一种新的战略，以克服 通过暂时抑制抗体与抗原的结合而在肿瘤内形成“结合部位屏障”，如共同实现的 给予抗独特型药物，允许mAb结合的短期和可逆拮抗。目标2 将研究使用依赖于pH的抗体，“捕捉并释放”结合来绕过分解代谢 Sink与受体介导的抗癌单抗内吞作用相关。在目标3中，有针对性地交付矩阵- 调节酶将被用来实现肿瘤中胶原的选择性消耗，并使 改善了单抗和ADC在肿瘤内的分布。每一个目标都有机械论的有力支持 并通过数学建模和初步数据论证了其实用性和可行性。药代动力学，疗效， 优化的抗HER2单抗和ADC治疗的安全性将使用HER2-小鼠模型进行评估。 阳性的人类癌症。在这项工作中开发的新的代理人可能适合立即翻译成 曲妥珠单抗和阿多曲妥珠单抗治疗HER2阳性乳腺和胃的疗效优化 癌症患者。此外，本提案中介绍的方法可以扩展以用于优化 应用All mAb和ADC治疗实体肿瘤，可能会使数百人受益 数以千计的病人。