Pharmacometrics and systems pharmacology of immune checkpoint inhibitor nivolumab in cancer translational medicine

摘要: Nivolumab, a fully human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that targets the programmed cell death-1 (PD-1) inhibitory receptor expressed on lymphocytes and dendritic cells, has been approved for metastatic melanoma, advanced squamous non-small lung cancer (NSCLC) renal carcinoma. In this review, pharmacology pharmacometrics systems of immunopharmaceutical are discussed. Mechanistic actions T-cell biology with respect to both “priming phase” (anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA-4) mAb; ipilimumab) “effector (anti-PD-1 nivolumab) was discussed, respectively. Key pharmacometric variables in anticancer efficacy nivolumab such as target engagement, metabolism, clearance elucidated an emphasis current knowledge from pre-clinical well phase 1, 2 3 clinical trials information, including data presented at American Society Clinical Oncology (ASCO) 2015 European Cancer Congress 2015. Nivolumab biomarkers, safety, synergistic combination immunotherapies delineated. administered via intravenous infusion, acceptable safety profile good efficacy. Indeed, way forward leverage maximum benefits patient may be synergize anti-PD-1 blockade complementary immune checkpoint pathways or other oncogenic signal transduction pathways. The encouraging results lend credence promise therapeutic strategy come-of-age oncology. Of necessity, burden “financial toxicity” patients families must factored considering therapy. problem ligand PD-L1 being weak biomarker practice Appropriate selection methods immunopharmacogenomics used identify those who most likely benefit Taken together, potential success strengthens case accelerated development immunopharmaceuticals basic drug discovery oncology, potentially non-oncology indications, by stakeholders oncologists, pharmacists scientists academia pharmaceutical industry concerted fashion.