786 Dose selection for DuoBody®-PD-L1×4-1BB (GEN1046) using a semimechanistic pharmacokinetics/pharmacodynamics model that leverages preclinical and clinical data

Abstract

BackgroundDuoBody-PD-L1×4-1BB (GEN1046) is a class-defining bispecific antibody, designed to elicit an anti-tumor immune response by simultaneous and complementary blockade of PD-L1 on tumor cells and conditional stimulation of 4-1BB on T-cells and NK cells. Optimizing target engagement for a bispecific antibody is challenging, as it involves binding with two targets, and predicting trimer levels in tumors based on affinity of individual arms and target expression. Here we describe a semimechanistic, physiologically based pharmacokinetic/pharmacodynamic (PK/PD) model that predicts a dosing regimen for DuoBody-PD-L1×4-1BB, which results in the formation of maximum levels of a therapeutically active 4-1BB-bispecific antibody-PD-L1 trimolecular complex (trimer), and optimal PD-L1 receptor occupancy (RO).MethodsAn integrated semimechanistic PK/PD model that describes the distribution of DuoBody-PD-L1×4-1BB into central and peripheral compartments and partitioning into tumor/lymph nodes was developed. The model used PK/PD data and physiological parameters from the literature for parameterizations of PD-L1 and 4-1BB expression levels and T-cell trafficking. The model incorporates dynamic binding of DuoBody-PD-L1×4-1BB to its targets to predict trimer formation and RO for PD-L1 in tumors. Model parameters were calibrated to match in vitro PD studies, such as analyses of T-cell proliferation and cytokine release, as well as clinical PK data. Sensitivity to model assumptions were assessed by varying PK/PD parameters, and assessing their impact on trimer formation and PD-L1 RO. The model was subsequently used to explore in vivo trimer levels and PD-L1 RO in tumors at various dosing regimens.ResultsThe model was able to adequately describe the PK of DuoBody-PD-L1×4-1BB in the central compartment. Simulations showed a bell-shaped response for average trimer levels in tumors that peaked at 100 mg every 3 weeks (Q3W), with doses >100 mg resulting in reduced trimer formation. Average PD-L1 receptor occupancy at the 100 mg dose was predicted to be approximately 70% over 21 days and increased at higher doses. Based on these model predictions, and available safety, anti-tumor activity, and PD data from the ongoing GCT1046-01 trial (NCT03917381), 100 mg Q3W was chosen as the expansion dose for further evaluation in Part 2 of the study.ConclusionsThis semimechanistic PK/PD model provides a novel approach for dose selection of bispecific antibodies such as DuoBody-PD-L1×4-1BB, by using preclinical and clinical PK/PD data to predict formation of optimal trimer levels and PD-L1 receptor occupancy.AcknowledgementsThe authors thank Friederike Gieseke and Zuzana Jirakova at BioNTech SE; Kalyanasundaram Subramanian at Applied Biomath LLC for their valuable contributions.Trial RegistrationWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors

“…To help identify the expansion dose, a semimechanistic, physiologically based pharmacokinetic/pharmacodynamic model that incorporated dynamic simultaneous binding of GEN1046 to PD-L1 and 4-1BB in tumors and lymph nodes was used to evaluate two key surrogates of efficacy: receptor occupancy of PD-L1 in tumors and trimer formation between GEN1046, tumor cells expressing PD-L1, and immune cells expressing 4-1BB ( 28 ). This integrated model predicted a bell-shaped curve for average trimer formation that peaked near 100 mg Q3W, with doses greater than 100 mg Q3W resulting in reduced mean trimer levels.…”

Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology

“…Based on recent clinical data, maintaining a persistently high level of target engagement in bispecific modalities may lead to ineffective signaling and lead to a suboptimal immune response. 34 If this is the case, this opens up the possibility of using Bicycles with superior tissue penetration and short-circulating exposure to target other co-stimulatory receptors (e.g., OX40) in this class that have failed in the clinic, possibly due to the physiochemical properties of the drug. In contrast to both the second generation of tumor-targeted and nontargeted CD137 agonists undergoing clinical development, this approach may achieve the perfect balance of potent tumor-localized activity and short peripheral exposure to drive efficacy while providing a wider safety margin and preventing overstimulation and activation-induced cell death of the immune cells.…”

“…We believe that transient but potent agonism of CD137 (and other tumor necrosis factor receptor (TNFR) family members) may be superior to prolonged receptor agonism. Based on recent clinical data, maintaining a persistently high level of target engagement in bispecific modalities may lead to ineffective signaling and lead to a suboptimal immune response . If this is the case, this opens up the possibility of using Bicycles with superior tissue penetration and short-circulating exposure to target other co-stimulatory receptors (e.g., OX40) in this class that have failed in the clinic, possibly due to the physiochemical properties of the drug.…”

ATG-101, a tetravalent PD-L1×4-1BB bispecific antibody, augments anti-tumor immunity through PD-L1 blockade and PD-L1-directed 4-1BB activation

“…In addition, GEN1046 appears to have a manageable safety pro le with at dosages up to 1200 mg 32 . However, a much lower 100 mg at dose of GEN1046, which was predicted to yield only 70% PD-L1 RO 33 , was chosen for the dose expansion phase and the combination with anti-PD-1 is being evaluated in a clinical trial 34 . This was owing to the fact that greater dosages resulted in decreased trimer formation or the "hook effect" 33 .…”

“…However, a much lower 100 mg at dose of GEN1046, which was predicted to yield only 70% PD-L1 RO 33 , was chosen for the dose expansion phase and the combination with anti-PD-1 is being evaluated in a clinical trial 34 . This was owing to the fact that greater dosages resulted in decreased trimer formation or the "hook effect" 33 . These ndings suggest that although being safely administered, GEN1046 could not reach a dose level at which it could deliver saturated biological activity.…”