Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo.
Kuc, Rhoda E
Holt, Lucy J
Basic & clinical pharmacology & toxicology
126 Suppl 6
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Read, C., Yang, P., Kuc, R. E., Nyimanu, D., Williams, T., Glen, R., Holt, L. J., et al. (2020). Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo.. Basic & clinical pharmacology & toxicology, 126 Suppl 6 96-103. https://doi.org/10.1111/bcpt.13227
Abstract The apelin receptor is a potential target in the treatment of heart failure and pulmonary arterial hypertension where levels of endogenous apelin peptides are reduced but significant receptor levels remain. Our aim was to characterise the pharmacology of a modified peptide agonist, MM202, designed to have high affinity for the apelin receptor and resistance to peptidase degradation and linked to an anti-serum albumin domain antibody (AlbudAb) to extend half-life in the blood. In competition binding experiments in human heart MM202-AlbudAb (pKi=9.39±0.09) bound with similar high affinity as the endogenous peptides [Pyr1]apelin-13 (pKi=8.83±0.06) and apelin-17 (pKi=9.57±0.08). [Pyr1]apelin-13 was 10-fold more potent in the cAMP (pD2=9.52±0.05) compared to the β-arrestin (pD2=8.53±0.03) assay, whereas apelin-17 (pD2=10.31±0.28; pD2=10.15±0.13, respectively) and MM202-AlbudAb (pD2=9.150.12; pD2=9.26±0.03, respectively) were equipotent in both assays, with MM202-AlbudAb 10-fold less potent than apelin-17. MM202-AlbudAb bound to immobilised human serum albumin with high affinity (pKD=9.02). In anaesthetised, male Sprague-Dawley rats, MM202-AlbudAb (5nmol, n=15) significantly reduced left ventricular systolic pressure by 6.61±1.46mmHg and systolic arterial pressure by 14.12±3.35mmHg and significantly increased cardiac contractility by 533±170mmHg/s, cardiac output by 1277±190RVU/min, stroke volume by 3.09±0.47RVU and heart rate by 4.64±2.24BPM. This study demonstrates that conjugating an apelin mimetic peptide to the AlbudAb structure retains receptor and in vivo activity and may be a new strategy for development of apelin peptides as therapeutic agents.
Medical Research Council MC_PC_14116 Wellcome Trust [107715/Z/15/Z, Programme in Metabolic and Cardiovascular Disease [096822/Z/11/Z, 203814/Z/16/A PY, DN, TLW], British Heart Foundation [TAF 03, APD, JJM, RCG; FS/14/59/31282, CR,], CRUK [C33616/A27229 to RCG, APD, JJM], and in part by the National Institute for Health Research Cambridge Biomedical Research Centre, Cardiovascular Theme, RG64226.
WELLCOME TRUST (107715/Z/15/Z)
MRC (MC_PC_14116 v2)
British Heart Foundation (FS/14/59/31282)
External DOI: https://doi.org/10.1111/bcpt.13227
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290748