Abstract 1540: FS222 mAb2, a bispecific conditional agonist antibody targeting CD137 and PD-L1, induces potent lymphocyte activation and has a favorable safety profile
Authors: Lakins Matthew A. , Koers Alexander , Olaya Jose Munoz , Giambalvo Raffaella , Jones Daniel , Pechouckova Sarka , Goodman Emma , Marshall Sylwia , Wydro Mateusz , Gradinaru Cristian , Wollerton Francisca , Batey Sarah , Gliddon Daniel , Davies Michael , Morrow Michelle , Tuna Mihriban , Brewis Neil 
Published: August 2019

Abstract
PD-1/L1 immune checkpoint blockade shows durable responses and extends overall survival in a subset of cancer patients. Tumour Necrosis Factor Receptor (TNFR) activation is being tested clinically to improve patient responses. However, low affinity FcΓR-mediated crosslinking often limits monoclonal antibody (mAb) clinical efficacy, which is further restricted by adverse safety effects. The generation of a bispecific agonist of CD137, where potent agonist activity is conditional upon PD-L1 crosslinking, allows a greater therapeutic window. FS222, an anti-CD137/PD-L1 mAb2, was generated by introducing a CD137-binding specificity into the Fc-region of a human IgG1 mAb targeting PD-L1. A LALA mutation significantly reduces FcΓR binding. Binding characterisation was assessed by surface plasmon resonance (SPR) and cell binding, and in vitro activity measured in human primary T cell assays. A dose-range finding study in cynomolgus monkey was performed to investigate toxicity, pharmacokinetics (PK) and pharmacodynamics (PD). A murine surrogate molecule was generated and its anti-tumor activity and PK/PD was tested in multiple syngeneic mouse tumor models. FS222 binds to human PD-L1 with subnanomolar affinity. This PD-L1 binding is a prerequisite to subsequently enable highly potent CD137 agonism (low nM EC50 values in primary cell in vitro assays). We term this mechanism conditional agonism. In cynomolgus monkey FS222 has a half-life of ~150h and single and repeat dosing resulted in observable PD changes in lymphocytes and soluble receptor levels at low doses. Furthermore, no hepatotoxicity as defined by changes in clinical chemistry and histopathology was detected. A surrogate anti-mouse-mAb2 significantly reduced tumor growth in multiple syngeneic mouse tumor models. The observed dose-dependent tumor growth inhibition resulted in a significant survival benefit and was concomitant with increases in tumor and peripheral activated CD8+ T cells. FS222 is a conditional CD137/PD-L1 bispecific agonist antibody and has superior activity to control mAbs and relevant combinations in vitro assays. A favorable safety profile and immunopharmacology was observed in a cynomolgus dose-range finding study and with the surrogate molecule in multiple syngeneic mouse tumor models. Anti-CD137 agonistic mAbs in clinical development have so far shown limitations due to dose limiting toxicity or poor clinical activity. In preclinical tumor models anti-CD137/PD-L1 surrogate mAb2 treatment resulted in intra-tumoral and peripheral PD changes leading to an increase in CD8+ T cell proliferation. These changes were dose dependent and coincident with tumor growth inhibition. FS222 is a highly active bispecific molecule with a favorable safety profile with the potential to serve a significant unmet need in the immunotherapy of solid tumors.
Citation Format: Matthew A. Lakins, Alexander Koers, Jose Munoz Olaya, Raffaella Giambalvo, Daniel Jones, Sarka Pechouckova, Emma Goodman, Sylwia Marshall, Mateusz Wydro, Cristian Gradinaru, Francisca Wollerton, Sarah Batey, Daniel Gliddon, Michael Davies, Michelle Morrow, Mihriban Tuna, Neil Brewis. FS222 mAb2, a bispecific conditional agonist antibody targeting CD137 and PD-L1, induces potent lymphocyte activation and has a favorable safety profile [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 1540.