Brendan P. Eckelman

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

Abstract 4694: The humanized anti-CD47 monclonal antibody, CC-90002, has antitumor activity in vitro and in vivo

Cluster of differentiation 47 (CD47) is a transmembrane protein ubiquitously expressed on human cells but overexpressed on many different tumor cells. The interaction of CD47 with signal-regulatory protein alpha (SIRPα) expressed on macrophages results in the inhibition of phagocytosis. Thus, tumor cell overexpression of CD47 enables escape from immune surveillance via the blockade of phagocytic mechanisms. We report here the characterization of CC-90002, a humanized anti-CD47 monoclonal antibody (mAb) that is being developed as a potential therapeutic for hematologic malignancies and solid tumors. CC-90002 has a high affinity for binding to CD47 with a subnanomolar dissociation constant (Kd) value. The IC50 required for the blockade of the CD47-SIRPα interaction was also in the subnanomolar range. CC-90002 is unique among previously reported anti-CD47 antibodies for its inability to promote hemagglutination while maintaining high affinity binding to CD47 and inhibition of the CD47-SIRPα interaction. CC-90002 enabled antibody-mediated phagocytosis of a panel of hematological cancer cell lines in vitro, including ALL, multiple myeloma (MM) and acute myeloid leukemia (AML) cells, and primary AML patient samples. The phagocytosis index for this panel (at 1 μg/mL) ranged from approximately 20% to 60% for all the cell lines tested. Antibody concentration-response studies indicated that the CC-90002 effect was concentration-dependent in the ALL and AML cell lines. CC-90002 treatment significantly enabled the phagocytosis of two lenalidomide-resistant MM cell lines and primary AML cells from three patients. Additionally, CC-90002 treatment elicited the phagocytosis of solid tumor lines, including those from ovarian, breast, head and neck, lung, and pancreatic cancers. The in vivo efficacy of CC-90002 was evaluated across cell line-derived and patient-derived xenograft models. Significant dose-dependent antitumor activity was observed with CC-90002 treatment in the MM cell line-derived xenograft models, RPMI 8226 and the parental NCI-H929 and lenalidomide-resistant NCI-H929 (H929/R1). Treatment with CC-90002 demonstrated significant tumor regression in solid tumor xenografts including a cell line-derived model of triple negative breast cancer (TNBC), MDA-MB-231, and a patient-derived TNBC model, AA1126 and significantly prolonged survival in the HL-60-disseminated AML tumor model. Mechanistic studies in the RPMI 8226 xenograft model confirmed binding of CC-90002 to tumor cells and recruitment of F4-80-positive macrophages into the tumor. RPMI 8226 tumor lysates from CC-90002-treated animals demonstrated an increase in select chemokines and cytokines of murine origin. Taken together, the in vitro and in vivo data demonstrate the potential for activity of CC-90002 across both hematological malignancies and solid tumors. CC-90002 is currently in early clinical development. Citation Format: Rama Krishna Narla, Hardik Modi, Lilly Wong, Mahan Abassian, Daniel Bauer, Pragnya Desai, Bonny Gaffney, Pilgrim Jackson, Jim Leisten, Jing Liu, Antonia Lopez-Girona, Maria Romero, WenQing Yang, Brendan P. Eckelman, Quinn Deveraux, Laurie Phillips, Heather K. Raymon, Laure Escoubet, John Boylan, Kandasamy Hariharan. The humanized anti-CD47 monclonal antibody, CC-90002, has antitumor activity in vitro and in vivo [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 4694. doi:10.1158/1538-7445.AM2017-4694