TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have shown good safety profile and efficacy in preclinical cancer models. However, clinical success has been limited due to poor PK and/or development of resistance to death receptor-induced apoptosis. To address these issues we have conceived and produced a fusion protein of arginine deiminase (ADI) and TRAIL. ADI is an enzyme that converts arginine into citrulline. Arginine deprivation can inhibit growth of arginine auxotrophic cancers that lack key enzymes enabling normal cells to produce arginine from citrulline. ADI is currently being evaluated in clinical trials and is well-tolerated. We (and others) observed synergy between ADI and TRAIL in inducing apoptosis in a number of cancer cell lines including those that are otherwise resistant to rhTRAIL. We have explored potential mechanisms of synergy and will present our findings. Using in silico modeling we predicted structural complementarity between ADI and TRAIL with each modality stabilized when part of the fusion protein. We were able to produce multiple ADI-TRAIL fusion protein variants and have tested their activity in enzymatic and cell-based assays. Our experimental data confirmed in silico predictions of the structural advantages for ADI and TRAIL in the fusion protein. ADI enzymatic activity improved when part of the fusion protein and the fusion protein appeared to have higher potency than the combination of the two separate proteins in inducing cancer cell death. In mice ADI-TRAIL fusion protein exhibited extended half-life and was efficacious in HCT116 xenograft model, superior to rhTRAIL administered at the same molar amounts. Serum concentrations of the fusion protein had an inverse correlation with the tumor volume. ADI-TRAIL is a novel biologic that benefits from structural and functional synergies between its components and is showing promise as a cancer therapeutic in preclinical studies.
Citation Format: Elena Brin, Katherine Wu, Yudou He, Wei-Jong Shia, Mario M. Kuo, Li-Chang Chen, Eleanor Dagostino, Richard Hickey, Bob Almassy, Richard Showalter, Jim Thomson. A novel biologic ADI-TRAIL fusion protein benefits from structural and functional complementarity of its components arginine deiminase and TRAIL, induces cancer cell apoptosis in vitro, and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3902.