Assessment of immunization against recombinant human bone morphogenetic protein-2 (dibotermin alpha) on reproduction and development in rabbits

Birth Defects Res B Dev Reprod Toxicol. 2011 Dec;92(6):543-52. doi: 10.1002/bdrb.20324. Epub 2011 Sep 15.

Abstract

Background: To determine if the fetus was affected by maternal antibodies to BMP-2, the antibody response and developmental effects in fetuses from does immunized against recombinant human BMP-2 were evaluated.

Methods: Female New Zealand White rabbits received four intramuscular injections (on premating days 1, 8, 22, and 43 [3 days before mating]) of saline and adjuvant (TiterMax(®) Gold [control]) or recombinant human BMP-2 (2 mg/dose) and adjuvant (treated). On GD 29, fetuses were examined, and maternal and fetal anti-BMP-2 titer levels and neutralizing activity were assessed.

Results: Anti-BMP-2 antibodies were detected in 17 of 18 treated does (127 of 151 fetuses), and low levels were detected in 2 of 16 control does (no fetal exposure observed). In general, levels of fetal anti-BMP-2 antibodies were similar to those in the does, and pregnancy did not boost the immune response to BMP-2. There were no effects of immunization or anti-BMP-2 antibody titer levels on embryo-fetal viability, fetal weight, or fetal external, visceral, or skeletal development. Only a small number of fetuses (n = 4) displayed detectable neutralizing anti-BMP-2 antibodies, but there were no treatment-related effects in those fetuses.

Conclusions: The lack of embryo-fetal effects may be due to dosage effects of neutralizing anti-BMP-2 antibodies, timing of exposure (stage and duration) to neutralizing anti-BMP-2 antibodies, and/or redundancy of effects of the various BMPs.

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / blood
  • Antibodies, Neutralizing / immunology
  • Bone Morphogenetic Protein 2 / administration & dosage
  • Bone Morphogenetic Protein 2 / immunology
  • Bone Morphogenetic Protein 2 / metabolism*
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism*
  • Embryonic Development*
  • Female
  • Fetal Development*
  • Humans
  • Immunization
  • Pregnancy
  • Rabbits
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Reproduction*
  • Transforming Growth Factor beta / administration & dosage
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Neutralizing
  • Bone Morphogenetic Protein 2
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • recombinant human bone morphogenetic protein-2