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

Cancer Research, 2017

Abstract

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 Treg, and our data indicates that FPA154 and cmFPA154 potently mediate ADCC activity against Treg 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 ...

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