Effects of CNTO 530, an erythropoietin mimetic-IgG4 fusion protein, on embryofetal development in rats and rabbits.
BACKGROUND
CNTO 530is a biopharmaceutical consisting of a novel peptide that mimics the actions of erythropoietin, fused to the Fc fragment of human IgG4. Pharmacokinetic and pharmacodynamic studies showed that CNTO 530 produced sustained increases in red blood cell parameters in rats and rabbits and that the serum half life of CNTO 530 was 2 days in rabbits and 3 days in rats.


METHODS
For the evaluation of embryofetal development, CNTO 530 was injected at loading doses of 0, 0.9/1, 6, or 60 mg/kg subcutaneously (SC) on gestation day (GD)7 followed by maintenance doses of 0, 0.3, 2, or 20 mg/kg SC every 3 days through GD16 in rats and every 2 days through GD19 in rabbits (GD0 was the day of mating). Rats were Caesarean sectioned on GD21, rabbits on GD29.


RESULTS
Administration of CNTO 530 was associated with an increase in hematocrit at all dose levels and a decrease in maternal body weight gains. Fetuses exhibited reduced body weight and delayed ossification. Soft tissue changes were limited to cardiovascular alterations in the high-dose rabbits only. Rat and rabbit fetuses were exposed to CNTO 530 in all dose groups.


CONCLUSIONS
These studies show that the embryo/fetal development effects observed following CNTO 530 treatment during organogenesis are qualitatively similar to those seen with other erythropoietin agonists and are likely a secondary consequence of increased hematocrit in the dams. Unlike other erythropoietin receptor agonists, CNTO 530 was able to cross the placental barrier, which was considered likely the result of FcRn-mediated transcytosis.
Martin
Pauline L
PL
Centocor Research and Development, Inc., Radnor, Pennsylvania, USA. pmarti27@its.jnj.com <pmarti27@its.jnj.com>
Sachs
Clifford
C
Hoberman
Alan
A
Jiao
Qun
Q
Bugelski
Peter J
PJ
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000196:embryology; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D020567:Fetal Weight / Q000187:drug effects; D007279:Injections, Subcutaneous; D010012:Osteogenesis / Q000187:drug effects; D011086:Polycythemia / Q000139:chemically induced; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017467:Receptors, Erythropoietin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000145:classification / Q000633:toxicity*; D013723:Teratogens / Q000145:classification / Q000633:toxicity*
C541126:CNTO 530; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D013723:Teratogens