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: 10436041
• 负责人: Petr B. Makhov
• 金额: $ 21.97万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436041
• 关键词: Affinity; Antibodies; Binding; Bypass; 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; Pharmacology; 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; Variant; Vascular Endothelial Growth Factors; Work; Xenograft Model; base; 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; 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.

项目概要 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。先进治疗方法的前景 近年来，随着农村信用社发展取得重大进展，农村信用社规模迅速扩大。 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。另一个限制晚期 VEGFR 靶向治疗成功的因素 ccRCC，是均匀发展的阻力。多项研究揭示了成纤维细胞的关键作用 生长因子-2 (FGF2) 在晚期 ccRCC 耐药性发展中的作用，无论是 TKI 还是 使用抗VEGF/VEGFR2抗体作为抗VEGFR剂。因此，我们第一次设计了， 一类新型双陷阱肽（F/V 陷阱），可阻断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 进展至关重要。通过将我们的 F/V 陷阱与抗的 Fab 片段融合 CD70抗体，我们开发了一种新型三特异性抗CD70-FGF/VEGF Trap融合抗体（F/V-trap FA）。 该抗体同时结合 CD70（一种在 ccRCC 中特异性表达的配体），并中和两者， VEGF-A 和 FGF2 细胞因子。预计通过中和 FGF2（一种关键的促血管生成细胞因子替代品）， F/V-trap FA 将预防或至少显着延迟抗 VEGF/VEGFR 耐药性的发展 晚期 ccRCC 的治疗。重要的是，肿瘤内 VEGF 和 FGF 细胞因子家族的耗竭 F/V-trap FA 有望克服因 VEGF/VEGFR 脱靶抑制而引起的副作用 全身性抗血管生成方法。拟议的研究将检验新型双特异性 F/V- 的假设 trap FA 与现有 VEGF 中和剂相比有两大优势。通过靶向 FGF/VEGF 陷阱 肿瘤，它将：（i）实现更高的 FGF/VEGF Trap 肿瘤内浓度； (ii) 克服FGF2- 介导晚期 ccRCC 对常规抗血管生成治疗产生耐药性； (iii) 限制 系统性抗 VEGF 方法中观察到的脱靶 VEGFR 抑制引起的副作用。来测试我们的 假设并验证 F/V-trap FA 的治疗价值，我们提出以下具体目标：(1) 具有卓越 FGF/VEGF 的领先 F/V-trap FA 衍生物的开发、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 耐药 PDX 小鼠模型。