Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab, an alpha4 integrin inhibitor.
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.


CONCLUSIONS
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.
Wehner
Nancy G
NG
Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. nancy.wehner@elan.com
Shopp
George
G
Osterburg
Ingrid
I
Fuchs
Antje
A
Buse
Eberhard
E
Clarke
Janet
J
D000034:Abortion, Veterinary / Q000139:chemically induced; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000917:Antibody Formation; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D039441:Integrin alpha4 / Q000276:immunology*; D007964:Leukocytosis / Q000139:chemically induced; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects; D008252:Macaca fascicularis / Q000254:growth & development*; D008297:Male; D008892:Milk / Q000737:chemistry; D000069442:Natalizumab; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000139:chemically induced; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D013163:Splenomegaly / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D039441:Integrin alpha4