Novel anti-CD70-VEGF-trap fusion antibodies as a next-generation therapeutic approach for renal cancer

新型抗 CD70-VEGF-trap 融合抗体作为下一代肾癌治疗方法

基本信息

批准号：
10065500
负责人：
Petr B. Makhov
金额：
$ 9.35万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-05 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065500
关键词：
Affinity Antibodies Binding Biochemical Biological Clear Cell Clear cell renal cell carcinoma Clinical Development Disease Dose Endothelial Growth Factors Receptor Human Immunotherapeutic agent Immunotherapy Incidence Interruption Ligands Malignant Neoplasms Metastatic Renal Cell Cancer Molecular Target Mus Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Positioning Attribute Progression-Free Survivals Property Renal Cell Carcinoma Renal carcinoma Temperature Testing Therapeutic Time Toxic effect Tumor Antibodies Tyrosine Kinase Inhibitor VEGF Trap Variant Vascular Endothelial Growth Factors Vegf inhibition Xenograft Model base bevacizumab combinatorial design experimental study human model novel novel strategies novel therapeutics patient derived xenograft model pharmacokinetics and pharmacodynamics response side effect therapeutic evaluation treatment strategy tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Renal cell carcinoma (RCC) is a lethal disease whose incidence is on the rise. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. Current targeted molecular strategies, including tyrosine kinase inhibitors (TKIs), have resulted in a doubling of progression-free survival and significant gains in overall survival in ccRCC patients. Despite the therapeutic progress, complete and durable responses have been noted in only a few cases. The landscape of therapeutic approaches for advanced RCC has expanded rapidly in recent years as a result of significant progress in the development of immunotherapeutic drugs. The combination of VEGFR-targeting and immunotherapies has shown significant clinical promise and opened the possibility of a cure for this lethal disease. However, such therapies have also conferred additional toxicities ranging from moderate to adverse, requiring dose interruptions or reductions, thereby limiting the efficacy. We have developed novel bi-specific anti-CD70-VEGF trap fusion antibodies (FA) for dual targeting of CD27/CD70 and VEGFR pathways, critical for ccRCC development and progression. This antibody does simultaneously bind CD70, a ligand, specifically expressed in ccRCC, and neutralize VEGF. It is expected that intra-tumoral depletion of VEGF by anti-CD70-VEGF trap FA will overcome side-effects arising from off-target VEGF inhibition seen with systemic anti-VEGF approaches. The proposed studies will test the hypothesis that novel bi-specific anti-CD70-VEGF trap FA have two major advantages over existing VEGF neutralizing agents. By targeting the VEGF Trap to tumors, it will (i) achieve higher intra-tumoral concentrations of the VEGF Trap; and (ii) limit side-effects arising from off-target VEGF inhibition seen with systemic anti- VEGF approaches. To test our hypothesis and to validate the therapeutic value of anti-CD70-VEGF Trap FA, we propose the following Specific Aims: (1) Biochemical, biological and pharmacological characterization of newly developed anti-CD70-VEGF trap fusion antibodies, and (2) To evaluate the anti-tumor efficacy of anti- CD70-VEGF trap FA using direct human-to-mouse xenograft model of RCC.

项目概要/摘要肾细胞癌（RCC）是一种致命疾病，其发病率呈上升趋势。它分为各种亚型，其中透明细胞 RCC (ccRCC) 约占所有 RCC 肿瘤的 85%。目前的目标分子包括酪氨酸激酶抑制剂 (TKI) 在内的策略已使无进展生存期加倍 ccRCC 患者的总体生存率显着提高。尽管治疗取得了进展，但仍完全且仅在少数情况下取得了持久的反应。治疗方法的前景近年来，由于农村信用社发展取得重大进展，高级农村信用社迅速扩张。免疫治疗药物。 VEGFR 靶向疗法和免疫疗法的结合已显示出显着的效果临床前景并开启了治愈这种致命疾病的可能性。然而，此类疗法也产生从中度到不良的额外毒性，需要中断或减少剂量，从而限制功效。我们开发了新型双特异性抗 CD70-VEGF 陷阱融合抗体 (FA) 用于 CD27/CD70 和 VEGFR 通路的双重靶向，对于 ccRCC 的发生和进展至关重要。这抗体同时结合 CD70（一种在 ccRCC 中特异性表达的配体）并中和 VEGF。这是预计通过抗 CD70-VEGF trap FA 进行肿瘤内 VEGF 的耗竭将克服所产生的副作用系统性抗 VEGF 方法中观察到的脱靶 VEGF 抑制。拟议的研究将测试假设新型双特异性抗 CD70-VEGF trap FA 比现有 VEGF 有两大优势中和剂。通过将 VEGF Trap 靶向肿瘤，它将 (i) 实现更高的肿瘤内浓度 VEGF 陷阱； (ii) 限制系统性抗血管生成药物脱靶 VEGF 抑制所产生的副作用 VEGF 逼近。为了检验我们的假设并验证抗 CD70-VEGF Trap FA 的治疗价值，我们提出以下具体目标：（1）生化、生物学和药理学表征新开发的抗 CD70-VEGF trap 融合抗体，以及（2）评估抗肿瘤药物的抗肿瘤功效 CD70-VEGF 使用 RCC 直接人鼠异种移植模型捕获 FA。