Model-Informed First-In-Human Dose Selection for AZD2796, a High-Affinity Anti-LILRB2 Antibody

AZD2796 is a humanized anti-LILRB2 monoclonal antibody designed to promote immune activation by inhibiting LILRB2 on myeloid cells. Because AZD2796 does not bind cynomolgus monkey or rodent LILRB2, conventional approaches to first-in-human dose selection were limited. An affinity-based minimum anticipated biological effect level (MABEL) approach would predict a very low starting dose despite the potential for substantial target-mediated drug disposition (TMDD). To support dose selection, pharmacokinetic and receptor occupancy (PK-RO) models were developed using AZD2796 pharmacokinetics in cynomolgus monkeys and TMDD data estimated from a cynomolgus-reactive surrogate anti-LILRB2 antibody. An alternative approach using neonatal Fc receptor- and LILRB2-transgenic mouse models was also explored. The cynomolgus surrogate model predicted substantial TMDD at low doses and supported an intravenous starting dose of 30 mg every 3 weeks (Q3W) that was predicted to maintain peripheral LILRB2 occupancy. The model further predicted that approximately 300 mg Q3W would maintain > 95% tumor LILRB2 occupancy under conservative assumptions regarding target burden and tumor exposure. Model performance was supported by the model's ability to reproduce the clinically observed PK and RO characteristics of other anti-LILRB2 antibodies. The transgenic mouse approach was less robust and generally predicted higher dose requirements. These findings demonstrate that surrogate antibody PK-RO modeling can support the selection of a pharmacologically active first-in-human starting dose for therapeutic antibodies that lack cross-reactivity with standard preclinical species.