Assessment of placental transfer and the effect on embryo-fetal development of a humanized monoclonal antibody targeting lymphotoxin-alpha in non-human primates

Reprod Toxicol. 2016 Aug:63:82-95. doi: 10.1016/j.reprotox.2016.05.014. Epub 2016 May 20.

Abstract

An enhanced embryo-fetal development study was conducted in cynomolgus monkeys using pateclizumab, a humanized IgG1 monoclonal antibody (mAb) targeting lymphotoxin-alpha. Pateclizumab administration between gestation days (GD) 20 and 132 did not induce maternal or developmental toxicities. The ratio of fetal-to-maternal serum concentration of pateclizumab was 0.73% on GD 50 and 61% by GD 139. Decreased fetal inguinal lymph node-to-body weight ratio was present in the high-dose group without microscopic abnormalities, a change attributable to inhibition of lymphocyte recruitment, which is a pharmacologic effect of pateclizumab during late lymph node development. The effect was observed in inguinal but not submandibular or mesenteric lymph nodes; this was attributed to differential susceptibility related to sequential lymph node development. Placental transfer of therapeutic IgG1 antibodies; thus, begins during the first trimester in non-human primates. Depending on the potency and dose levels administered, antibody levels in the fetus may be pharmacologically or toxicologically relevant.

Keywords: Embryo-fetal development; Lymphotoxin alpha; Non-human primate; Placental transfer; Sequential lymph node development; Therapeutic monoclonal antibody.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / blood
  • Antibodies, Monoclonal, Humanized / pharmacokinetics*
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Dendritic Cells, Follicular / drug effects
  • Embryo, Mammalian / drug effects*
  • Embryonic Development / drug effects*
  • Female
  • Fetal Development / drug effects*
  • Immunoglobulin G / blood
  • Immunoglobulin G / pharmacology
  • Lymph Nodes / drug effects
  • Lymph Nodes / growth & development
  • Lymph Nodes / immunology
  • Lymphocytosis / chemically induced
  • Lymphotoxin-alpha / immunology*
  • Macaca fascicularis
  • Male
  • Maternal-Fetal Exchange*
  • Pregnancy

Substances

  • Antibodies, Monoclonal, Humanized
  • Immunoglobulin G
  • Lymphotoxin-alpha
  • pateclizumab