The Use of Surrogate Antibodies to Evaluate the Developmental and Reproductive Toxicity Potential of an Anti-TNFα PEGylated Fab′ Monoclonal Antibody

Abstract

Certolizumab pegol (CZP) is a PEGylated Fab' fragment of a humanized monoclonal immunoglobulin G (IgG)1 antibody that binds to human tumor necrosis factor alpha (TNFα) with high affinity. As for many monoclonal antibodies (mAbs), nonclinical safety assessment of CZP has been constrained because of its limited species cross-reactivity and recognition of only nonhuman primate and human TNFα, which presents particular challenges for assessing reproductive and developmental safety. To comprehensively assess the potential liability of TNFα suppression on reproductive and developmental processes, a PEGylated Fab' anti-rat TNFα antibody surrogate (cTN3 PF) has been developed and evaluated for reproductive toxicity. Conventional rat fertility and early embryonic development, embryo-fetal toxicity and pre- and postnatal development studies have been shown to be free of maternal, reproductive, or development toxicity effects, following sustained TNFα inhibition with cTN3 PF. Importantly, these studies have also shown that in marked contrast to a whole IgG anti-TNFα antibody, the PEGylated Fab' antibody cTN3 PF homologous to certolizumab pegol demonstrated negligible fetal exposure following maternal administration during the period of organogenesis. In addition to minimal placental transmission, transfer to milk was lower and fetal absorption negligible compared with the whole IgG antibody cTN3 γ1, resulting in little or no detectable antibody in the plasma of lactating pups.