An Engineered Analog of Insulin-Like Growth Factor 1 With Reduced Immunogenicity and Retained Mitogenicity Publisher



Poorebrahim M¹ ; Asghari M² ; Derakhshandeh S³ ; Abazari MF⁴ ; Askari H⁵ ; Hassannia H^{6, 7} ; Heydari S⁸ ; Ghoraeian P⁴ ; Aboutalebi F² ; Nouri Aleagha M⁴ ; Nasresfahani MH² ; Dormiani K²
Source: Biochemical Engineering Journal Published:2019

Abstract

Insulin-like growth factor 1 (IGF1) is widely used for the long-term treatment of growth failure in children with severe primary IGF1 deficiency. However, the activity of this peptide is limited due to several adverse properties such a high antigenic potential. In this study, we have generated a modified IGF1 type with reduced immunogenicity, without sacrificing biological activity, utilizing bioinformatics and experimental approaches. The linear and conformational epitopes of IGF1 were predicted using IEDB and CBTOPE web tools, respectively. Several logical amino acid substitutions were created at non-functional residues of IGF1 epitopes. Molecular docking and molecular dynamics (MD) simulations were performed using Haddock and Gromacs v5 tools, respectively. Proliferation activity of the wild-type and mutant-type IGF1 was assessed by MTT assay. Furthermore, a number of New Zealand white rabbits were used for evaluating the immunogenicity potential of the peptides in vivo. It was demonstrated that the final selected IGF1 mutant, called IGF1-Ado, showed less immunogenicity when compared with the wild-type ligand in vivo. This study presents an engineered IGF1 analog that, relative to the wild-type peptide, exhibits reduced production of neutralizing antibodies in vivo with no loss in mitogenic activity in vitro. © 2019 Elsevier B.V.