An Evaluation of the Impact of PD‐1 Pathway Blockade on Reproductive Safety of Therapeutic PD‐1 Inhibitors
- 7 April 2016
- journal article
- review article
- Published by Wiley in Birth Defects Research Part B: Developmental and Reproductive Toxicology
- Vol. 107 (2), 108-119
- https://doi.org/10.1002/bdrb.21176
Abstract
This report discusses the principles of reproductive toxicity risk assessment for biopharmaceuticals blocking the PD‐1/programmed cell death ligand 1 (PD‐L1) pathway, which have been developed for the treatment of patients with advanced malignancies. The PD‐1/PD‐L1 pathway is a T‐cell co‐inhibitory pathway that normally maintains immune tolerance to self. Its role in pregnancy is to maintain immune tolerance to the fetal allograft. In cancer patients, this signaling pathway is hijacked by some neoplasms to avoid immune destruction. PD‐1/PD‐L1‐blocking agents enhance functional activity of the target lymphocytes to eventually cause immune rejection of the tumor. A therapeutic blockade of PD‐1/PD‐L1 pathway that occurs at full target engagement provides a unique challenge to address the risk to pregnancy because disruption of the same pathway may also reduce or abrogate maternal immune tolerance to the fetal alloantigens inherited through the father. Typically, nonclinical reproductive and developmental toxicity (DART) studies in animals (rats and rabbits) with clinical drug candidates are conducted to identify potential risk in humans and to determine exposure margin for the effects on reproduction as part of the risk assessment. However, for biopharmaceuticals for which the desired mechanism of action cannot be separated from potential deleterious effects to the fetus and when the only relevant toxicology species is nonhuman primate (NHP), the risk to reproduction can be predicted by a mechanism‐based assessment using data generated from murine surrogate models as supportive information without conducting DART in NHPs. Such an approach has been used in the evaluation of pregnancy risk of anti‐PD‐1 agent, pembrolizumab, and has been demonstrated as an important alternative to performing DART studies in NHPsKeywords
This publication has 77 references indexed in Scilit:
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerNew England Journal of Medicine, 2012
- Review: Fetal antigens – Identity, origins, and influences on the maternal immune systemPlacenta, 2011
- Immune Regulation of CancerJournal of Clinical Oncology, 2010
- The PD‐1 pathway in tolerance and autoimmunityImmunological Reviews, 2010
- PD‐1 signaling in primary T cellsImmunological Reviews, 2009
- Maternal PD-1 regulates accumulation of fetal antigen-specific CD8+ T cells in pregnancyJournal of Reproductive Immunology, 2009
- Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1New England Journal of Medicine, 2008
- PD-1 and Its Ligands in Tolerance and ImmunityAnnual Review of Immunology, 2008
- Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetusJCI Insight, 2007
- Tissue expression of PD-L1 mediates peripheral T cell toleranceThe Journal of Experimental Medicine, 2006