Oleg Demin Jr: No financial relationships to disclose
Objectives: The minimal anticipated biological effect level (MABEL) approach remains a preferred strategy for establishing the safe clinical starting dose of T-cell engagers (TCE). However, it can occasionally yield conservative minimal recommended starting doses (MRSD), resulting in multiple dose escalations and sub-therapeutic doses for patients [1]. Our aim was to evaluate the MRSD predictions for HPN536, a trispecific TCE which binds to mesothelin (MSLN), CD3 and albumin, employing mechanistic translational pharmacokinetic (PK), receptor occupancy (RO), pharmacological activity (PA) modeling, and the MABEL PK-driven approach.
Methods: In vitro model was developed to describe published data on T-cell dependent cytotoxicity (TDCC), cytokine secretion (IFNg, TNFa), and T-cell activation (% of CD25+ cells) in presence of various HPN536 concentrations [2]. PK/RO/PA model was developed to fit PK in cynomolgus monkey and translate it to human using standard allometric scaling exponents without fitting. The model for cancer patients includes distribution of TCE into the tumor (ovarian cancer was considered) and PA (cytotoxicity, T-cells activation, and cytokine secretion) based on EC50 values identified in the in vitro model. PA depends on a number of timers of HPN536 bound with CD3 and MSLN in immunological synapse between T-cell and cancer cell. MABEL PK-driven approach was also used to estimate MRSD.
Results: PK data in cancer patients were successfully predicted via translation from cynomolgus monkey data. EC50 values of cytotoxicity, T-cells activation and cytokine secretion were in the range of 500-900 trimers. MRSD was identified using 20%-50% PA as a target level of activity for both approaches. MRSD calculated by MABEL PK-driven approach (1 – 23 ng/kg) and starting dose used in phase 1 clinical trial of HPN536 (6 ng/kg) were lower than MRSD predicted by the model (35 – 228 ng/kg). If binding of soluble MSLN with HPN536 was turned off in the model, predicted MRSD range was lower than in presence of soluble MSLN (18 – 114 ng/kg). Model prediction was validated by the fact that lowest dose resulted in CRS grade 3 without premedication with dexamethasone was 54 ng/kg [3].
Conclusions: The conventional allometric scaling method efficiently aids in translating PK from cynomolgus monkeys to humans for therapeutic antibody targeting albumin, thereby extending PK profile. The model demonstrated the influence of soluble MSLN concentration within the tumor on the predicted MRSD. Application of mechanistic modeling to predict MRSD in addition to the MABEL PK-driven approach might help to reduce the number of dose escalation steps exposing patients to sub-therapeutic doses in first-in-human trials.
Citations: [1] Saber et al. An Regul Toxicol Pharmacol. 2017 Nov;90:144–152. [2] Molloy et al. Clin Cancer Res. 2021 Mar 1;27(5):1452–1462. [3] Harpoon Therapeutics Investor Presentation February 2022.
