Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics
Dhiraj Kumar1, Akhilesh Mishra1,2, Ala Lisok1
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Abstract:
Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1). For PD-L1 quantification, we first developed a small peptide-based fluorine-18-labeled PET imaging agent, [18F]DK222, which provided high-contrast images in preclinical models. We then quantified accessible PD-L1 levels in the tumor bed during treatment with anti-PD-1 and anti-PD-L1 mAbs. Applying mixed-effects models to these data, we found subtle differences in the pharmacodynamic effects of two anti-PD-1 mAbs (nivolumab and pembrolizumab). In contrast, we observed starkly divergent target engagement with anti-PD-L1 mAbs (atezolizumab, avelumab, and durvalumab) that were administered at equivalent doses, correlating with differential effects on tumor growth. Thus, we show that measuring PD-L1 pharmacodynamics informs mechanistic understanding of therapeutic mAbs targeting PD-L1 and PD-1. These findings demonstrate the value of quantifying target pharmacodynamics to elucidate the pharmacologic activity of mAbs, independent of mAb biophysical properties and inclusive of all physiological variables, which are highly heterogeneous within and across tumors and patients.
Insights
Measuring accessible programmed death ligand 1 (PD-L1) levels using PET imaging reveals differences in monoclonal antibody (mAb) pharmacodynamics, aiding the understanding of cancer immunotherapy effectiveness.
Area of Science:
- Oncology
- Pharmacology
- Radiochemistry
Background:
- Large monoclonal antibodies (mAbs) often show poor tumor penetration, limiting drug exposure and treatment response.
- Quantitative tools to assess mAb activity within tumors are lacking, hindering drug development and comparison.
- Understanding mAb pharmacodynamics is crucial for optimizing cancer immunotherapies targeting immune checkpoints.
Purpose of the Study:
- To develop quantitative tools for assessing mAb pharmacologic activity within tumors.
- To evaluate the pharmacodynamics of monoclonal antibodies targeting programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1).
- To compare the activity of different anti-PD-1 and anti-PD-L1 mAbs using target engagement measurements.
Main Methods:
- Development of a novel fluorine-18-labeled PET imaging agent ([18F]DK222) for PD-L1 quantification.
- Utilizing positron emission tomography (PET) to measure accessible PD-L1 levels in preclinical tumor models during mAb treatment.
- Application of mixed-effects models to analyze pharmacodynamic data and assess target engagement.
Main Results:
- The PET imaging agent [18F]DK222 provided high-contrast images for PD-L1 quantification.
- Subtle differences in pharmacodynamic effects were observed between two anti-PD-1 mAbs (nivolumab, pembrolizumab).
- Starkly divergent PD-L1 target engagement was observed with different anti-PD-L1 mAbs (atezolizumab, avelumab, durvalumab) at equivalent doses, correlating with tumor growth effects.
Conclusions:
- Measuring PD-L1 pharmacodynamics using PET imaging provides mechanistic insights into the activity of therapeutic mAbs targeting PD-1/PD-L1.
- This quantitative approach elucidates mAb pharmacologic activity irrespective of biophysical properties and accounts for physiological heterogeneity.
- The findings highlight the value of target pharmacodynamics assessment for optimizing cancer immunotherapies.
