In Situ Self-Assembly of Bispecific Peptide for Cancer Immunotherapy

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 alpha(V)beta(3) receptor for proof-of-concept study. In the presence of alpha(V)beta(3) protein, the critical assembly concentration of free G7-RGD decreases from 525 to 33 mu M 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.

Automated summary

This study reports a programmable peptide molecule that enables specific and efficient assembly by binding to targeting receptor proteins. By designing different peptide sequences and receptor bindings, it is possible to promote oligomerization and functional regulation of protein complexes.