Allosteric modulation of immune checkpoint complexes as a new mode of therapeutic intervention in immunotherapy

Introduction

The fastidious balance of our immune system to fight infections or cancer while avoiding autoimmune reactions is regulated by coinhibitory and co-stimulatory immune checkpoint complexes (ICCs), which have become major drug targets.

Current Landscape

We witness the skyrocketing progression in cancer immunotherapy with antibodies that block inhibitory ICCs, whereas Abs that block stimulatory ICCs are in clinical trials for treating autoimmune diseases.

Research Gap

Surprisingly, but likely fueled by the most obvious focus on IC inhibitors, the field largely ignored that ICCs are genuine transmembrane receptors that transmit signals upon binding of an extracellular protein ligand. This leaves unexplored modes of therapeutic intervention that I will uncover by validating Nanobodies (Nbs) as first-in-class modulators of signaling pathways associated with immune receptors in a unique, previously unexplored fashion.

Methodology

By applying innovative immunization and bio-selection techniques and building on POC data, I will deliver Nbs for representative ICCs to demonstrate the efficacy and selectivity of these Nbs in preclinical models of various inflammatory conditions, focusing on cancer and autoimmune diseases.

Expected Outcomes

We will deliver novel therapeutic agents which may outperform current inhibitor-based immunotherapies that trigger a magnitude of side effects. In this regard, the Nbs will exert their therapeutic effect through a distinctive mode of action that will ensure patient safety, even in the event of an overdose.