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

项目总结/摘要 肾细胞癌（Renal cell carcinoma，RCC）是一种致死性疾病，其发病率呈上升趋势.它被分为各种 RCC是透明细胞RCC（ccRCC）亚型，占所有RCC肿瘤的约85%。电流靶向分子 包括酪氨酸激酶抑制剂（TKI）在内的治疗策略， ccRCC患者的总体生存率显著提高。尽管治疗取得了进展， 只有少数几个案件得到了持久的答复。治疗方法的前景 近年来，先进的RCC迅速扩大，这是由于在发展方面取得了重大进展， 免疫药物。靶向VEGF和免疫疗法的组合已经显示出显著的 临床前景，并打开了治愈这种致命疾病的可能性。然而，这种疗法也 产生额外的毒性，范围从中度到不良，需要中断或减少剂量， 从而限制了功效。我们开发了新型的双特异性抗CD 70-VEGF陷阱融合抗体（FA）， 用于双重靶向CD 27/CD 70和VEGFR通路，这对ccRCC的发展和进展至关重要。这 抗体同时结合在ccRCC中特异性表达的配体CD 70并中和VEGF。是 预期抗CD 70-VEGF陷阱FA对VEGF的肿瘤内消耗将克服肿瘤内产生的副作用。 来自全身性抗VEGF方法观察到的脱靶VEGF抑制。拟议的研究将测试 假设新型双特异性抗-CD 70-VEGF捕获FA相对于现有VEGF具有两个主要优点 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， 和（ii）限制由全身性抗VEGF捕获剂观察到的脱靶VEGF抑制引起的副作用。 VEGF方法。为了检验我们的假设并验证抗CD 70-VEGF Trap FA的治疗价值， 我们提出了以下具体目标：（1）生物化学，生物学和药理学表征 新开发的抗CD 70-VEGF陷阱融合抗体，和（2）评估抗CD 70-VEGF陷阱融合抗体的抗肿瘤功效。 使用RCC的直接人-小鼠异种移植模型的CD 70-VEGF陷阱FA。

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.