Z-domain protein nano-bio interfaced MRI visible anti-program death ligand-1 nanoconjugates for enhanced local immune checkpoint inhibitor immunotherapy

Monoclonal antibody (mAb) based immune checkpoint inhibitors (ICIs) have emerged as an effective and promising therapeutic agent for cancer immunotherapy. In the setting of tumor immune-suppression, an effective delivery of mAbs ICI might be essential to overcome tumor resistance, immune tolerance, and immune-related adverse effects (irAEs). Herein we report engineered MRI visible anti-programmed cell death ligand-1 mAb (aPD-L1) nanoconjugates using nano-bio interface Z-domain (Z) protein adaptors for the local ICI immunotherapy. Z protein adaptors, which are binding with Fc region of IgG mAb, were modified to be attached on the surface of MRI visible ferumoxytol (Fer). Z-protein adaptors on the surface of Fer allowed an oriented conjugation of aPD-L1 exposing active Fab binding sites outward for effective blockage of immune checkpoints. Enhanced affinity and avidity of engineered Z mediated aPD-L1 nanoconjugates (aPD-L1-Z-Fer) to block the PD-1/PD-L1 axis were demonstrated in vitro and in vivo. Transcatheter-directed hepatic intra-arterial (IA) infusion of aPD-L1-Z-Fer showed superior in vivo hepatocellular carcinoma (HCC) tumor suppression, immune conversion, and minimized irAEs compared to the experimental groups treated with systemic aPD-L1, local aPD-L1, or chemically conjugated aPD-L1@Fer. Nano-bio interface Z protein adaptors mediated conjugation of functional nanoparticles and mAbs ICI will provide a new avenue to expand local ICI immunotherapy.