Quantitative modeling predicts competitive advantages of a next generation anti‐NKG2A monoclonal antibody over monalizumab for the treatment of cancer

Abstract

A semimechanistic pharmacokinetic (PK)/receptor occupancy (RO) model was constructed to differentiate a next generation anti‐NKG2A monoclonal antibody (KSQ mAb) from monalizumab, an immune checkpoint inhibitor in multiple clinical trials for the treatment of solid tumors. A three‐compartment model incorporating drug PK, biodistribution, and NKG2A receptor interactions was parameterized using monalizumab PK, in vitro affinity measurements for both monalizumab and KSQ mAb, and receptor burden estimates from the literature. Following calibration against monalizumab PK data in patients with rheumatoid arthritis, the model successfully predicted the published PK and RO observed in gynecological tumors and in patients with squamous cell carcinoma of the head and neck. Simulations predicted that the KSQ mAb requires a 10‐fold lower dose than monalizumab to achieve a similar RO over a 3‐week period following q3w intravenous (i.v.) infusion dosing. A global sensitivity analysis of the model indicated that the drug‐target binding affinity greatly affects the tumor RO and that an optimal affinity is needed to balance RO with enhanced drug clearance due to target mediated drug disposition. The model predicted that the KSQ mAb can be dosed over a less frequent regimen or at lower dose levels than the current monalizumab clinical dosing regimen of 10 mg/kg q2w. Either dosing strategy represents a competitive advantage over the current therapy. The results of this study demonstrate a key role for mechanistic modeling in identifying optimal drug parameters to inform and accelerate progression of mAb to clinical trials.

NKG2A Immune Checkpoint in Vδ2 T Cells: Emerging Application in Cancer Immunotherapy

“…Despite Monolizumab, other anti-NKG2A mAbs are tested (KSQ). In particular, the use of novel screening techniques such as a semi-mechanistic pharmacokinetic/receptor occupancy (SM-PK/RO) model was used to identify anti-NKG2A mAbs with a high specific monovalent affinity for NKG2A and anti-tumor cytotoxicity [164]. This analysis suggests that the increased affinity of highly selective anti-NKG2A KSQ mAbs may translate into substantial clinical benefits by lowering the dose, and/or reducing the dosing frequency, while retaining the saturation of receptor occupancy in tumor tissue needed to achieve optimal therapeutic anti-tumor efficacy.…”

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

“…Monalizumab, a humanized anti-NKG2A mAb, is currently undergoing clinical trials in a variety of solid tumors ( 64 ). Frazao A showed that NK cells from tumor-draining lymph nodes expressed high NKG2A and checkpoint programmed cell death protein 1 (PD-1), which supported their potential as targets for immunotherapy using anti-NKG2A and/or anti-PD-1 in breast cancer ( 65 ).…”