Journal
PEPTIDE SCIENCE
Volume 110, Issue 1, Pages -Publisher
WILEY
DOI: 10.1002/bip.23095
Keywords
copper-free click chemistry; peptibody; peptide-Fc fusion protein; sortase-mediated protein ligation; streamlined-expressed protein ligation
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Funding
- Portuguese Funding Agency, Fundacao para a Ciencia e a Tecnologia, FCT IP [PD/BD/128281/2017, SFRH/BPD/94466/2013, PTDC/BBB-NAN/1578/2014]
- Marie Sklodowska-Curie Research and Innovation Staff Exchange (MSCA-RISE) [H20 644167-INPACT]
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Chimeric proteins composed of a biologically active peptide and a fragment crystallizable (Fc) domain of immunoglobulin G (IgG) are known as peptibodies. They present an extended half-life due to neonatal Fc receptor (FcRn) salvage pathway, a decreased renal clearance rate owing to its increased size (approximate to 70 kDa) and, depending on the peptide used in the design of the peptibody, an active-targeting moiety. Also, the peptides therapeutic activity is boosted by the number of peptides in the fusion protein (at least two peptides) and to some peptides' alterations. Peptibodies are mainly obtained through recombinant DNA technology. However, to improve peptide properties, unnatural changes have been introduced to the original peptides' sequence, for instance, the incorporation of D- or non-natural amino acid residues or even cyclization thus, limiting the application of genetic engineering in the production of peptibodies, since these peptides must be obtained via chemical synthesis. This constrains prompted the development of new methods for conjugation of peptides to Fc domains. Another challenge, subject of intense research, relates to the large-scale production of such peptibodies using these new techniques, which can be minimized by their proved value. To date, two peptibodies, romiplostim and dulaglutide, have been approved and stay as the standard of care in their areas of action. Furthermore, a considerable number of peptibodies are currently in preclinical and clinical development.
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