ABSTRACT
BACKGROUND: Natalizumab is a humanized monoclonal IgG4 antibody to human alpha4 integrin that blocks the interaction of alpha4beta1 and alpha4beta7 integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands are widely involved in mammalian development, lymphopoeisis, and hematopoiesis, natalizumab may interfere with these processes. METHODS: The effects of prenatal exposure to natalizumab on postnatal development were assessed in cynomolgus monkeys at doses of 0 and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70 or GD 20 to term. Infants were delivered by natural birth and evaluated for general health, survival, development, and immunological structure and function at 12 or 18 months. RESULTS: An increase in abortions was seen in the first cohort of natalizumab-treated dams (39.3 vs. 7.1% in the controls) but not in the second cohort (33.3, 37.5%). Infants in the term treatment group had elevated lymphocyte ( approximately 150%) and nucleated red blood cell counts ( approximately 400%), consistent with the pharmacological effect of natalizumab, and reductions in platelet counts ( approximately 28%), which were reversible following clearance of natalizumab. No anemia was observed. Infants in the term treatment group had significantly increased spleen weights at 12 months but not at 18 months. All other experimental observations in infants from natalizumab-treated dams were comparable with those of controls. CONCLUSION: Natalizumab had no adverse effects on the general health, survival, development, or immunological structure and function of infants born to dams treated with natalizumab during pregnancy.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Antibodies, Monoclonal/toxicity , Hematopoiesis/drug effects , Integrin alpha4/immunology , Macaca fascicularis/growth & development , Prenatal Exposure Delayed Effects , Splenomegaly/chemically induced , Abortion, Veterinary/chemically induced , Animals , Anti-Inflammatory Agents, Non-Steroidal/blood , Anti-Inflammatory Agents, Non-Steroidal/immunology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antibody Formation , Body Weight/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Embryonic Development/drug effects , Female , Fetus/drug effects , Leukocytosis/chemically induced , Lymphocyte Activation/drug effects , Lymphocyte Subsets/drug effects , Male , Milk/chemistry , Natalizumab , Pregnancy , Pregnancy Complications, Hematologic/chemically induced , Pregnancy Outcome , Random AllocationABSTRACT
Nonhuman primates are being used increasingly as a non-rodent animal model during preclinical toxicology and safety assessment on the basis of proven similarity and comparability between nonhuman primates and humans. The validity of the nonhuman primate models applies to many aspects of toxicological testing and holds particularly true for the evaluation of reproductive toxicology and developmental toxicology. More recently, the advent of humanized antibodies and vaccines imposed further demand on nonhuman primate models since many immunotherapeutics do not interact with rodent receptors but frequently only cross-react with primate tissue. In this paper we discuss the suitability of primate models for reproductive, developmental and immunotoxicology testing, and present our initial data on the development of lymphatic organs and immune system in a nonhuman primate model.