The construction of a bispecific T-cell engager (BiTE)-like molecule is proposed. The peptide consists of dual CD3 and integrin αvβ3 targeting sequence, conjugated by a self-assembling peptide. The molecule is designed to target the CD3 receptor on T cells and induce T cell-mediated cytolysis against tumor cells overexpressing integrin αvβ3.
Abstract
Precise and effective manipulation of protein functions still faces tremendous challenges. Herein we report a programmable peptide molecule, consisted of targeting and self-assembly modules, that enables specific and highly efficient assembly governed by targeting receptor proteins. Upon binding to the cell membrane receptor, peptide conformation is somewhat stabilized along with decreased self-assembly activation energy, promoting peptide-protein complex oligomerization. We first design a GNNQQNY-RGD peptide (G7-RGD) to recognize integrin αVβ3 receptor for proof-of-concept study. In the presence of αVβ3 protein, the critical assembly concentration of free G7-RGD decreases from 525 to 33 μM and the resultant G7-RGD cluster drives integrin receptor oligomerization. Finally, a bispecific assembling peptide antiCD3-G7-RGD is rationally designed for cancer immunotherapy, which validates CD3 oligomerization and concomitant T cell activation, leading to T cell-mediated cancer cell cytolysis.
Open Access