BACKGROUND: Human immunoglobulin (Ig)-like transcript 2 (ILT2) and 4 (ILT4) are immune inhibitory receptors on suppressive myeloid cells that are upregulated in many cancers, potentially enabling immune evasion. NGM707 is a humanized monoclonal antibody that binds and blocks ILT2 and ILT4 interactions with their human leucocyte antigen (HLA) ligands. Population analyses were conducted to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of NGM707 in patients with advanced or metastatic solid tumors.
METHODS: PK data from 28 subjects and receptor occupancy (RO) data from 19 subjects in a Phase 1/2, dose escalation/expansion study of NGM707 as a monotherapy or in combination with pembrolizumab were modeled using a population approach. The predictive performances of PK and PD models were assessed by goodness-of-fit diagnostics and visual predictive check (VPC).
RESULTS: Upon intravenous administration, the PK of NGM707 were adequately described by a two-compartment model with parallel first-order and receptor-mediated nonlinear elimination pathways. The observed RO data of NGM707 was adequately described by a sigmoidal Emax model. From population PK modeling, the estimated systemic clearance of the first-order elimination pathway (CL), central (Vc) and peripheral volume of distribution (Vp) were 0.291 L/d, 3.39 L and 1.59 L, respectively. Consistent with other therapeutic monoclonal antibodies, the CL and Vc of NGM707 increased with body weight. The estimated maximum RO of NGM707 was not significantly different from the theoretical 100% limit. The anti-ILT2 and anti-ILT4 EC50 estimates for NGM707 are 0.350 μg/mL and 0.276 μg/mL, respectively.
CONCLUSION: PK of NGM707 were typical for therapeutic monoclonal antibodies. Only body weight was identified as a relevant PK covariate. Age, sex, race, baseline albumin level and baseline peripheral blood mononuclear cell counts had no impact on NGM707 PK. Evaluation of model-predicted RO profiles under various dosing scenarios supported the rational design of subsequent clinical studies.