John C. Timmer

Abstract 613: Development of FPA154, a novel tetravalent anti-GITR antibody, for the treatment of solid tumors

Glucocorticoid-induced TNFR-related (GITR, TNFRSF18) is a member of the TNFR superfamily with pleiotropic T cell modulatory activity. We are developing a novel anti-GITR antibody with enhanced agonist activity for the treatment of solid tumors. Our candidate molecule, FPA154, is constructed with single-domain antibodies (sdAbs) in a tetravalent format, with an effector-competent IgG1 Fc domain. Both FPA154 and the mouse-reactive surrogate molecule (cmFPA154, mIgG2a isotype) bind to cell-surface GITR with high affinity. GITR is most highly expressed in vivo on activated and intratumoral T reg , and our data indicates that FPA154 and cmFPA154 potently mediate ADCC activity against T reg expressing high levels of GITR. In contrast, activated effector T cells express modest levels of cell-surface GITR, and FPA154 and cmFPA154 drive GITR-induced NF-κB activation. This activity is independent of Fc-mediated crosslinking, which is normally required for bivalent GITR antibodies to induce GITR signaling. cmFPA154 has potent antitumor activity in several syngeneic mouse tumors, both as a monotherapy treatment and in combination with anti-PD-1. In summary, FPA154 is a promising candidate with multiple mechanisms of action that contribute to generation of an antitumor immune response mediated by different T cell subsets. Citation Format: Susannah D. Barbee, Amanda Chen, Susan Johnson, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges. Development of FPA154, a novel tetravalent anti-GITR antibody, for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2017-613