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Updated: Jul 18, 2026
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Murine Model of CD40-activation of B cells
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Dose Selection for DuoBody®-CD40x4-1BB (GEN1042/BNT312) Using a mPBPK/RO Model Leveraging Preclinical and Clinical
Gaurav Bajaj1, Dmitry Shchelokov2, Oleg Demin2
1Genmab, Plainsboro, New Jersey, USA.
Clinical Pharmacology and Therapeutics
|May 10, 2025
Summary
Optimizing bispecific antibodies (bsAbs) requires understanding trimolecular complex (trimer) formation. A novel model predicts bsAb trimer levels in vivo, aiding dose selection for GEN1042, a CD40x4-1BB bispecific antibody, to enhance anti-tumor immunity.
Area of Science:
- Immunology
- Pharmacology
- Biotechnology
Background:
- Bispecific antibodies (bsAbs) offer targeted therapy but optimizing their dose is complex due to trimolecular complex (trimer) formation and bell-shaped dose-response curves.
- Quantifying bsAb trimer levels in vivo is crucial for efficacy and safety but currently not feasible.
- GEN1042 is a novel agonistic bispecific antibody targeting CD40 and 4-1BB to enhance anti-tumor immunity.
Purpose of the Study:
- To develop and apply a minimal physiologically based pharmacokinetic and receptor occupancy (mPBPK/RO) model to predict GEN1042 trimer levels in tumors and lymph nodes.
- To support the dose selection for the expansion phase of the GEN1042 clinical trial.
Main Methods:
- Utilized pharmacokinetic (PK) data, physiological parameters, and in vitro data to parameterize the mPBPK/RO model for GEN1042 kinetics, distribution, and target receptor interactions.
- Modeled GEN1042 trimers crosslinked to CD40 and 4-1BB in tumors and lymph nodes.
- Integrated model predictions with clinical safety, tolerability, efficacy, and PK/pharmacodynamics data for dose selection.
Main Results:
- The mPBPK/RO model successfully predicted GEN1042 trimer levels in relevant tissues.
- An initial expansion dose of GEN1042 100 mg every 3 weeks was selected based on comprehensive data analysis, including model predictions and clinical findings.
- This dose is under evaluation in combination therapies within the GEN1042 Phase 1/2 trial.
Conclusions:
- A predictive mPBPK/RO model can quantify bispecific antibody trimer formation in vivo, aiding dose selection.
- The established dose of 100 mg of GEN1042 every 3 weeks is supported by modeling and early clinical data.
- Further exploration of alternative doses is ongoing to optimize treatment strategies.
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