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

• 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
• 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

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.

项目摘要/摘要 肾细胞癌（RCC）是一种致命的疾病，其发病率正在上升。它被分类为各种 亚型，具有透明细胞RCC（CCRCC），约占所有RCC肿瘤的85％。电流靶向分子 包括酪氨酸激酶抑制剂（TKIS）在内的策略导致无进展生存率增加了一倍 CCRCC患者的总体生存率显着增长。尽管取得了治疗进展，但 仅在少数情况下注意到了持久的响应。治疗方法的景观 近年来，由于发展的发展，Advanced RCC的发展迅速 免疫治疗药物。 VEGFR靶向和免疫疗法的结合已显示出显着的 临床承诺，并为这种致命疾病提供了治愈的可能性。但是，这种疗法也有 赋予了从中度到不良的其他毒性，需要剂量中断或减少， 从而限制了功效。我们已经开发了新型的双特异性抗CD70-VEGF陷阱融合抗体（FA） 对于CD27/CD70和VEGFR途径的双重靶向，对于CCRCC的发展和进展至关重要。这 抗体同时结合了在CCRCC中专门表达并中和VEGF的配体CD70。这是 预计抗CD70-VEGF陷阱对VEGF的肿瘤内耗竭将克服产生的副作用 从全身性抗VEGF方法可以看出的脱离靶向VEGF抑制作用。拟议的研究将测试 假设新型双特异性抗CD70-VEGF陷阱FA比现有VEGF具有两个主要优势 中和剂。通过将VEGF陷阱靶向肿瘤，它将（i）达到较高的肿瘤内浓度 VEGF陷阱； （ii）限制了由靶向抗靶向的VEGF抑制作用引起的副作用 VEGF的方法。为了检验我们的假设并验证抗CD70-VEGF陷阱FA的治疗价值， 我们提出以下特定目的：（1）生化，生物学和药理学特征 新开发的抗CD70-VEGF陷阱融合抗体，（2）评估抗肿瘤的抗肿瘤功效 CD70-VEGF TRAP FA使用RCC的直接人类到小鼠异种移植模型。