Preclinical neonatal rat studies of heparin-binding EGF-like growth factor in protection of the intestines from necrotizing enterocolitis.
We have previously demonstrated that enterally administered heparin-binding EGF-like growth factor (HB-EGF) produced in Escherichia coli decreases the incidence and severity of intestinal injury in a neonatal rat model of necrotizing enterocolitis (NEC). In preparation for upcoming human clinical trials, large-scale production of HB-EGF according to Good Manufacturing Practice (GMP) has been successfully accomplished using a Pichia pastoris yeast system. The current studies used a neonatal rat model of NEC to elucidate several important preclinical characteristics of HB-EGF therapy. We found that enteral administration of HB-EGF (800 microg/kg/dose) four times a day effectively reduced the incidence and severity of NEC, that Pichia-derived HB-EGF was not significantly different from E. coli-derived HB-EGF in preventing NEC, that EGF was not superior to HB-EGF in preventing NEC, and that prophylactic administration of HB-EGF added to formula starting with the first feed or 12 h later significantly reduced the incidence of NEC, with no change in the incidence of NEC noted if HB-EGF was added to the formula starting 24, 48, or 72 h after birth. Thus, large-scale production of GMP-grade HB-EGF in Pichia pastoris yeast produces a biologically active molecule suitable for human clinical trials.
Radulescu
Andrei
A
Center for Perinatal Research, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
Zorko
Nicholas A
NA
Yu
Xiaoyi
X
Besner
Gail E
GE
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004750:Enteral Nutrition; D020345:Enterocolitis, Necrotizing / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D000860:Hypoxia / Q000150:complications; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008070:Lipopolysaccharides; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index; D013997:Time Factors
D005765:Gastrointestinal Agents; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor