Induction Of Avidity-Driven Hyperclustering Of Dr5 By A New Fap-Dr5 Bispecific Antibody (Rg7386) Leads To Strong Anti-Tumor Efficacy

Background: Activation of the extrinsic apoptotic pathway by TRAIL is dependent on clustering of death receptors (DR) on the surface of cells. However, current TRAIL-based strategies have proven ineffective in clustering death receptors and failed to demonstrate robust therapeutic activity in clinical trials. More potent DR agonist therapies could help to overcome insufficient pathway activation and resistance to TRAIL activation. RG7386 is a novel bispecific FAP-DR5 antibody, binding with high affinity to fibroblast activation protein (FAP) and with low affinity to DR5. FAP is expressed at high prevalence on cancer associated fibroblasts (CAFs) in various tumor types as well as on tumors of mesenchymal origin, such as sarcomas. Avidity-driven binding of the bispecific antibody induces hyperclustering of DR5, which leads to potent induction of extrinsic apoptosis pathway signaling and tumor cell death. Biomarkers will be crucial in predicting sensitivity to DR5 activation and apoptosis induction and for selection of patients most likely to benefit from treatment with RG7386. Aim: The aim of the study was to explore the efficacy of RG7386 in vitro and in vivo. CRC and PDAC xenograft models expressing FAP on tumor stroma as well as sarcoma models were used to explore in vivo efficacy. Molecular profiling of sensitive and resistant tumors was also performed to identify response prediction markers. Results: RG7386 demonstrated additive efficacy in vitro with clinically relevant combinations (e.g. irinotecan, paclitaxel) in a variety of CRC and PDAC cell lines. In a xenograft model, where CRC cells (DLD-1) were co-injected with fibroblasts, RG7386 showed strong anti-tumor efficacy in combination with irinotecan. Remarkably, in a patient-derived CRC xenograft model (Co5896), the efficacy of RG7386 in combination with irinotecan induced complete tumor remission in all mice (n = 10/10). Furthermore, the combination of RG7386 with doxorubicin generated complete remissions in FAP+ sarcoma patient and desmoplastic melanoma cell line derived xenograft models such as Sarc4605 and LOX-IMVI. Finally, extensive molecular profiling of sensitive and resistance models in vitro revealed a distinct response prediction signature of DR5 sensitivity. Conclusion: RG7386 is a novel bispecific antibody inducing avidity-driven DR5 crosslinking by binding to FAP. This induces potent apoptosis of tumor cells, making it an attractive therapeutic approach for treatment of FAP+ solid tumors. Encouraging data indicate the high potential of RG7386 to treat FAP positive sarcomas. A comprehensive biomarker program will be employed in the early clinical development of RG7386 to enable selection of patients likely to benefit and to corroborate the mode of action, anti-tumor activity and potential response prediction markers. Citation Format: Thomas Friess, Stefanie Lechner, Esther Abraham, Ann-Marie Broeske, Sabine Bader, Andreas Roller, Meher Majety, Katharina Wartha, Suzana Vega-Harring, Hadassah Sade, Oliver Krieter, Peter Bruenker. Induction of avidity-driven hyperclustering of DR5 by a new FAP-DR5 bispecific antibody (RG7386) leads to strong anti-tumor efficacy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 952. doi:10.1158/1538-7445.AM2015-952