Abstract 4077: ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells

ATOR-1144 is a human CTLA-4 x GITR bispecific IgG1 antibody generated by fusing a high affinity CTLA-4 binder, derived by FIND® optimization of the CTLA-4 binding domain of CD86, to an agonistic GITR antibody isolated from the human antibody library ALLIGATOR-GOLD®. CTLA-4 and GITR are highly expressed on Tregs in the tumor microenvironment, and GITR is also expressed on NK cells and certain tumor cells. ATOR-1144 was designed to induce a tumor-directed immune activation for treatment of solid tumors and hematological malignancies. The in vitro activity of ATOR-1144 in terms of Treg depletion and activation of T cells and NK cells was investigated using purified cells from healthy human donors. ATOR-1144 induced depletion of primary Tregs in an ADCC assay with NK cells. T-cell activation in terms of IL-2 and IFN-γ release was demonstrated in the presence of CTLA-4 and Fcγ receptor crosslinking. NK cells treated with ATOR-1144 released IFN-γ, perforin and granzyme B, and displayed enhanced cytolytic killing of tumor cells. Moreover, NK cell-mediated depletion of CTLA-4-expressing cells was significantly improved upon stimulation with ATOR-1144 compared to monospecific anti-CTLA-4, indicating that NK cells activated via GITR acquire an enhanced capacity to induce ADCC. In conclusion, ATOR-1144 is a first-in-class bispecific tumor directed antibody targeting CTLA-4 and GITR. ATOR-1144 acts through several mechanisms, including depletion of Tregs, activation of effector T cells and activation of NK cells for enhanced Treg depletion and tumor cell killing. Citation Format: Sara Fritzell, Mattias Levin, Ida Aberg, Maria Johansson, Magnus Winnerstam, Karin Enell Smith, Peter Ellmark, Christina Furebring, Per Norlen, Anne Kvarnhammar. ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4077.