A Novel CTLA-4 affinity peptide for cancer immunotherapy by increasing the integrin αvβ3 targeting

Abstract

Immune checkpoint inhibitors (ICIs) are changing all aspects of malignant tumour therapy as an immunotherapy subverter in oncology. However, the current ICIs might induce systemic immune activation in other tissues and organs since they are not tumour-specific, causing the immune system to attack some normal tissues and organs of the human body. The toxicity can also amplify greatly although combined immunotherapy for cancer has increased the curative efficacy. The LC4 peptide was modified to improve its tumour-targeting ability and reduce peripheral immune system activation, which was obtained through phage display peptide library screening and could block the CTLA-4/CD80 interaction. The LC4 peptide as a result, like other ICIs, exerts anti-tumour effects by refreshing T cell function, and also activates the peripheral immune system. We used the PLGLAG peptide as a linker at the C-terminal of LC4 to connect with a tumour-targeting peptide RGD to increase the tumour tissue targeting ability, and obtain LC4-PLG-RGD. Further experiments demonstrated that the anti-tumour LC4-PLG-RGD activity was better than LC4 in vivo, and the ability to activate the peripheral immune system was weakened. In conclusion, LC4-PLG-RGD can increase the ICIs tumour-targeting and reduce excessive peripheral tissue immune activation, thereby reducing the side effects of ICIs, while increasing their anti-tumour efficacy. This study confirmed that enhanced ICI tumour targeting can effectively reduce immune-related adverse reaction occurrence.