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