Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide.
To prolong the circulation half-life of human prolactin (hPRL), human GH (hGH), and their competitive antagonists, hPRL-G129R and hGH-G120R, we examined the effects of fusing a serum albumin-binding peptide (SA20) to their amino- or carboxyl-terminus. Fusion of the SA20 peptide to the amino-terminus of the ligands was less detrimental upon their ability to induce or inhibit signal transduction and cell proliferation in vitro than fusion to the carboxyl-terminus. Pharmacokinetic (PK) studies in mice revealed that the half-life of SA20-hPRL and SA20-hGH was prolonged and their clearance was reduced in comparison with hPRL and hGH. Pharmacodynamic (PD) studies in 8-week-old female mice revealed that lobuloalveolar development in mammary glands was greater in all three groups (daily, every 2 days, or every third day over a 12-day period) of mice treated with SA20-hPRL (4 mg/kg) compared with hPRL (3.59 mg/kg). Similarly, daily administration (i.p.) of SA20-hGH (8 mg/kg) or hGH (7.15 mg/kg) to 23-day-old female mice over a 40-day period revealed the superiority of SA20-hGH over hGH as measured by weight gain, body length, and lobuloalveolar development in the mammary glands. These findings indicate that SA20 modification of hPRL, hGH, and their respective antagonists improves their PK/PD properties.
Langenheim
John F
JF
Oncology Research Institute, Greenville Hospital System, 900 West Faris Road, Greenville, South Carolina 29605-4255, USA.
Chen
Wen Y
WY
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D013006:Growth Hormone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008321:Mammary Glands, Animal / Q000187:drug effects; D051379:Mice; D011388:Prolactin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000493:pharmacokinetics*; D050799:STAT5 Transcription Factor / Q000378:metabolism
D002352:Carrier Proteins; C093172:G120R protein, human; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C545653:SA20 peptide; D050799:STAT5 Transcription Factor; C402398:prolactin, Arg(129)-; D019382:Human Growth Hormone; D011388:Prolactin; D013006:Growth Hormone; D053614:Janus Kinase 2