Tumor-specific anti-angiogenic anti-CD70-FGF/VEGF-trap fusion antibodies for renal cancer therapy

用于肾癌治疗的肿瘤特异性抗血管生成抗 CD70-FGF/VEGF-trap 融合抗体

• 批准号: 10608152
• 负责人: Petr B. Makhov
• 金额: $ 25.84万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608152
• 关键词: Affinity; Angiogenesis Inhibitors; Antibodies; Binding; Bypass; Categories; Clear Cell; Clear cell renal cell carcinoma; Clinical; Data; Development; Disease; Dose; Endothelial Growth Factors Receptor; FGF2 gene; Fab Immunoglobulins; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future; Human; Immunotherapeutic agent; Immunotherapy; Incidence; Interruption; KDR gene; Kidney Neoplasms; Lead; Ligands; Malignant Neoplasms; Mediating; Metastatic Renal Cell Cancer; Molecular Target; Mus; Outcome; Pathway interactions; Patients; Peptides; Persons; Pharmaceutical Preparations; Positioning Attribute; Production; Progression-Free Survivals; Property; Receptor Inhibition; Renal Cell Carcinoma; Renal carcinoma; Resistance; Resistance development; Signal Pathway; Surface; TRAP Peptide; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Tyrosine Kinase Inhibitor; VEGF Trap; VEGFA gene; Variant; Vascular Endothelial Growth Factors; Work; Xenograft Model; bevacizumab; cancer therapy; cancer type; combinatorial; cytokine; design; experimental study; improved; in vivo; mouse model; neoplastic cell; next generation; novel; novel strategies; patient derived xenograft model; pharmacologic; prevent; resistance mechanism; response; side effect; success; targeted agent; targeted treatment; tumor

PROJECT SUMMARY 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 have 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. Another factor, limiting the success of VEGFR-targeting therapy of advanced ccRCC, is the resistance which uniformly develops. Multiple studies have revealed the key role of fibroblast growth factor-2 (FGF2) in the development of resistance in advanced ccRCC, irrespective of whether TKIs or anti-VEGF/VEGFR2 antibodies were used as anti-VEGFR agents. Therefore, we have designed for the first time, a novel class of dual-trap peptides (F/V traps), to block two biologically distinct pro-angiogenic pathways, VEGFR- and FGFR-dependent, critical for ccRCC progression. By fusion of our F/V trap to Fab fragment of anti- CD70 antibody, we have developed a new tri-specific anti-CD70-FGF/VEGF Trap fusion antibody (F/V-trap FA). This antibody does simultaneously bind CD70, a ligand, specifically expressed in ccRCC, and neutralize both, VEGF-A and FGF2 cytokines. It is expected that by neutralizing FGF2, a key alternative pro-angiogenic cytokine, F/V-trap FA will prevent or at least significantly delay the development of resistance to anti-VEGF/VEGFR therapy in advanced ccRCC. Importantly, the intra-tumoral depletion of VEGF- and FGF- cytokine families by F/V-trap FA is anticipated to overcome side-effects arising from off-target VEGF/VEGFR inhibition seen with systemic anti-angiogenic approaches. The proposed studies will test the hypothesis that novel bi-specific F/V- trap FA have two major advantages over existing VEGF-neutralizing agents. By targeting the FGF/VEGF trap to tumors, it will: (i) achieve higher intra-tumoral concentrations of the FGF/VEGF Trap; (ii) overcome FGF2- mediated development of resistance to conventional anti-angiogenic therapy in advanced ccRCC; and (iii) limit side-effects arising from off-target VEGFR inhibition seen with systemic anti-VEGF approaches. To test our hypothesis and to validate the therapeutic value of F/V-trap FA, we propose the following Specific Aims: (1) Development, identification and characterization of the leading F/V-trap FA derivative with superior FGF/VEGF neutralizing activity; (2) To examine the anti-angiogenic efficacy of F/V-trap FA in vivo using anti-VEGFR TKI- resistant PDX mouse models of RCC.

项目摘要 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。高级治疗方法的景观 近年来，由于发展的发展，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。另一个因素，限制了先进的VEGFR靶向疗法的成功 CCRC是均匀发展的抗性。多项研究揭示了成纤维细胞的关键作用 生长因子2（FGF2）在高级CCRCC中的抗性发展中，无论TKIS还是TKIS 抗VEGF/VEGFR2抗体用作抗VEGFR剂。因此，我们首次设计了 一类新型的双陷阱肽（F/V陷阱），以阻止两种生物学上不同的促血管生成途径 VEGFR和FGFR依赖性，对于CCRCC的进展至关重要。通过将我们的f/v陷阱融合到抗 - CD70抗体，我们已经开发了一种新的TRI特异性抗CD70-FGF/VEGF陷阱融合抗体（F/V-TRAP FA）。 该抗体同时结合CD70，一种特异性在CCRCC中表达的配体，并中和两者 VEGF-A和FGF2细胞因子。可以预期，通过中和FGF2，这是一种关键的替代性促血管生成细胞因子， f/v-trap FA将预防或至少显着延迟抗VEGF/VEGFR的抗性的发展 晚期CCRC的治疗。重要的是，通过 预计F/V-trap FA将克服因脱离目标VEGF/VEGFR抑制而引起的副作用 全身性抗血管生成方法。拟议的研究将检验以下假设：新型的双特异性f/v- 与现有VEGF中和代理相比，陷阱FA具有两个主要优势。通过将FGF/VEGF陷阱定位到 肿瘤将：（i）达到较高的FGF/VEGF陷阱的肿瘤内浓度； （ii）克服FGF2- 在晚期CCRC中介导对常规抗血管生成疗法的抗性发展； （iii）限制 通过全身性抗VEGF方法观察到的脱靶VEGFR抑制产生的副作用。测试我们的 假设并验证f/v-trap fa的治疗价值，我们提出以下特定目的：（1） 具有上FGF/VEGF的领先F/V-TRAP FA导数的开发，鉴定和表征 中和活性； （2）使用抗VEGFR tki检查F/V-TRAP FA在体内的抗血管生成功效 RCC的抗性PDX小鼠模型。