Preclinical development of ABCL575, a half-life extended anti-OX40L monoclonal antibody for the treatment of autoimmune conditions

Summary: Abstract Body: The OX40/OX40L pathway is a key regulator of inflammation underlying T cell-mediated autoimmune conditions of high unmet need, such as atopic dermatitis. Antibody-mediated blockade of the OX40/OX40L axis has shown promise in the clinic as a targeted, non-depleting mechanism to modulate inflammation. Here, we present preclinical data on ABCL575, a novel anti-OX40L antibody that potently inhibits OX40/OX40L binding. ABCL575 is a fully human IgG1 monoclonal antibody with high affinity to human and cynomolgus monkey(cyno) OX40L and a modified Fc domain(LALA-YTE) to support Fc-silencing and half-life extension. Variable region sequences were generated by deep screening of ~1.3 million B cells obtained from human immunoglobulin mice immunized with OX40L protein. Antibodies were screened in high-throughput functional and developability assays to identify potent molecules with favorable properties. Function was measured in reporter and primary cell assays. In vivo pharmacokinetics(PK), tolerability, and safety were assessed in Tg32 (FcRn transgenic) mice and cyno. ABCL575 shows potent in vitro activity comparable to the most advanced clinical benchmark, with inhibition of OX40L-induced signaling (IC50 2.7 nM), T-cell activation (IC50 10.9-14.1 nM), and Th2 cytokine release (single-digit to sub-nM IC50). In vivo PK and safety studies support potential best-in-class dosing frequency and show that ABCL575 is well-tolerated. Non-clinical safety studies, including tissue cross-reactivity and non-GLP toxicology, indicate early signals of safety. Further, in vitro antibody-dependent cellular cytotoxicity assessment shows abrogation of Fc-mediated effector function. ABCL575 is formatted as a high-concentration formulation to support subcutaneous administration and exhibits low viscosity and favorable stability/product quality attributes. Together, these data show that ABCL575 is a potential best-in-class antibody for the treatment of T cell-mediated autoimmune conditions and support further clinical evaluation. Emilie Lameignere¹, Eoin Cosgrave¹, Adelaide Frimpong¹, Peter Bergqvist¹, Stephanie K. Masterman¹, Christopher Williamson¹ 1. AbCellera Biologics Inc, Vancouver, BC, Canada. Translational Studies: Preclinical