Immunogenicity-related placental infarcts and abortions in nonhuman primate developmental and reproductive toxicity studies: Proposed mechanism and impact on study interpretation.

Previous analysis of 3 developmental toxicity studies (1 EFD, 2 ePPND) conducted in cynomolgus monkeys for biotherapeutics indicated an association between immunogenicity and abortions. This led to the hypothesis that immunogenic responses to biotherapeutics administered to pregnant nonhuman primates (NHPs) can cause altered placental hemodynamics and/or vascular pathology, resulting in placental infarcts and abortion secondary to compromised uteroplacental perfusion. Retrospective analysis of an additional 17 NHP developmental and reproductive toxicity (DART) studies was conducted for further support of this hypothesis. Of 366 placentas evaluated from the 20 total studies (2 EFD, 18 ePPND), 18 % (n = 66) had central placental infarctions/hematomas associated with maternal immunogenicity; these were significant enough to lead to abortion in 32/66 (48 %) of these pregnancies. Abortions in anti-drug antibody positive females with placental infarction were found in 40 % (n = 8) of the studies but accounted for only a 5 % fetal loss rate. Thus, although immunogenicity was commonly observed in these studies, its impact to study outcome/interpretation was manageable in most cases. In the event of immune-mediated responses such as formation of anti-drug antibodies and/or abnormal placental morphology (e.g., infarcts), it is imperative to take a carefully considered, weight-of-evidence approach to interpretation of direct (test article related) vs. indirect (secondary to immunogenicity) effects. In cases where the biotherapeutic being tested is expected to be highly immunogenic in an NHP DART study, with potential confounding impact to study interpretation, alternatives to NHPs should be given high priority in the strategic approach to developmental toxicity testing.