Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide

Abstract

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 halflife 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.

Periplasmic production via the pET expression system of soluble, bioactive human growth hormone

“…Both pelB- and ompA-hGH bind the hGH-R with similar affinity (Figure 4a and Table 2) indicating the choice of secretion sequence for periplasmic targeting does not influence receptor binding. The affinity of pelB- and ompA-hGH by SPR and ELISA is slightly lower than that of TEV-TROPIN likely due to the C-terminal poly-histidine tag given alternative peptide fusions to the carboxy-terminus of hGH also have reduced potency [33]. Analysis of the SPR sensograms indicates the slight reduction in affinity at pH 7.4 is mainly attributed to a reduction in the rate of association (Figure 5).…”

Conjugation to Albumin‐Binding Molecule Tags as a Strategy to Improve Both Efficacy and Pharmacokinetic Properties of the Complement Inhibitor Compstatin

“…Albumin constitutes ∼60 % of the total plasma protein pool and has a long circulation residence ( t 1/2 ∼20 d); binding to serum albumin has therefore been recognized as an attractive route to extend the plasma residence of biopharmaceuticals 12. 13 Alongside direct coupling approaches,13, 14 several affinity tags based on albumin‐binding peptides or molecules (ABP and ABM, respectively) have been developed that allow noncovalent interaction with circulating albumin 15–19. Chimeras of a compstatin derivative with an ABP have been successfully constructed,20 yet their synthesis is demanding, given the involvement of two cyclic peptides.…”

Non-covalent albumin-binding ligands for extending the circulating half-life of small biotherapeutics

“…68 The SA21 peptide was later applied to other small proteins and exhibited promising preclinical results. 69,70 Recently, Neri and co-workers identified specific macrocyclic binders against human serum albumin by exploiting a novel DNA-encoded chemical library displaying multiple diversity elements into one side of a structurally defined β-sheet scaffold (Fig. 3d).…”