Abstract 1797: Preclinical characterization of Sym024, a novel anti-CD73 antibody

Abstract

Abstract Tumor cells are surrounded by a complex microenvironment (the tumor microenvironment, or TME) that influences each step of tumorigenesis. In the TME, increased concentrations of immune modulating factors such as adenosine help tumor cells evade host anti-tumor immune responses. Adenosine binds to adenosine receptors (ARs) expressed on various immune cells such as CD4+ and CD8+ T cells, myeloid cells and natural killer (NK) cells. These receptors exhibit distinct properties and cell and tissue distribution. Binding of adenosine to a subset of ARs suppresses the anti-tumor responses of T cells and NK cells and augments the activity of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells, thus promoting tumor progression. The generation of adenosine in the TME is mediated by a group of ectonucleotidases, including CD39 and CD73, which work in a common pathway converting extracellular ATP to adenosine. CD73 is frequently overexpressed on human tumor cells and mediates the hydrolysis of AMP to adenosine, particularly under hypoxic conditions. Importantly, CD73 overexpression correlates with poorer prognosis in various cancers, including lung, gastric, head and neck, pancreatic, cholangiocarcinoma, colorectal, bladder, triple negative breast, ovarian, and kidney cancer, and melanoma. Inhibition of the enzymatic activity of CD73 therefore represents an attractive way of relieving the immune suppressive activity of adenosine in the TME.Sym024 is an Fc-attenuated human monoclonal antibody that binds to human and cynomolgus monkey CD73 with sub-nanomolar avidity. Sym024 binds to a distinct epitope on the enzyme on the opposite side relative to the catalytic center and potently inhibits the activity of soluble CD73 as well as CD73 expressed on numerous cancer cell lines and primary lymphocytes. Importantly, CD73 inhibition by Sym024 alleviates AMP-mediated inhibition of T cell proliferation and activation. In vitro one-way mixed lymphocyte reaction results demonstrate the utility of combining CD73 inhibition with PD-1 blockade, as Sym024 acts to reverse the immune suppressive effect of adenosine production, thereby allowing effective T cell activation by an anti-PD-1 antibody (Sym021). Mechanistically, Sym024 inhibits cellular CD73 by direct enzymatic inhibition with moderate shedding or degradation of CD73 in vitro. In preclinical in vivo tumor models, Sym024 effectively inhibits CD73 activity and tumor growth. Sym024 was well tolerated with no observed toxicity in repeat dose studies in monkeys at dose levels up to 100 mg/kg. Dose-proportional and linear pharmacokinetics (PK) was observed at high dose levels while nonlinear PK became evident at lower exposure levels. Sym024 is currently under clinical investigation. Citation Format: Janus S. Jakobsen, Matteo Riva, Maria C. Melander, Randi W. Hansen, Klaus Kofoed, Mikkel W. Pedersen, Jutta Deckert, Lene Hansen, Niels Jorgen Skartved, Johan Lantto, Camilla Frohlich, Michael Monrad Grandal. Preclinical characterization of Sym024, a novel anti-CD73 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1797.