1. Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.
- Author
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Kumar, Dhiraj, Mishra, Akhilesh, Lisok, Ala, Kureshi, Rakeeb, Shelake, Sagar, Plyku, Donika, Sen, Rupashree, Doucet, Michele, De Silva, Ravindra A., Mease, Ronnie C., Forde, Patrick M., Jaffee, Elizabeth M., Desai, Prashant, Ganguly, Sudipto, Gabrielson, Edward, Vaidya, Dhananjay, Spangler, Jamie B., and Nimmagadda, Sridhar
- Subjects
IMMUNE checkpoint proteins ,CELL receptors ,POSITRON emission tomography ,THERAPEUTICS ,MONOCLONAL antibodies - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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