Positive allosteric modulators of the PD-1•PD-L1 interaction as a new mode of therapeutic intervention for autoimmune diseases: preclinical proof of concept in humanized mice

The immune system's balance in fighting infections or cancer while avoiding autoimmune reactions is regulated by co-inhibitory and co-stimulatory immune checkpoints (ICs). ICs are major drug targets in immunotherapy, with antibodies (Abs) blocking inhibitory ICs to fight cancer, and Abs blocking stimulatory ICs in clinical trials for autoimmune diseases.Surprisingly, but likely fuelled by the worldwide focus on IC inhibitors, the field largely ignored that ICs are genuine transmembrane receptors that transmit signals upon binding of an extracellular ligand. This leaves unexplored modes of therapeutic intervention that we uncover in my granted ERC-2023-ADG by validating allosteric Nanobodies (Nbs) that bind and stabilize ICs, to agonize their activity as first-in-class allosteric modulators, thus tipping the immune homeostasis balance opposite to IC inhibitors for treating autoimmunity.Recently, we discovered the first-ever positive allosteric modulators (PAMs) of an IC and characterized several PAMs of the human PD-1•PD-L1 complex that agonize PD-L1 binding to PD-1 (affinity) and stimulate IC signalling (efficacy) in a spatio-temporal-selective and pathway-selective manner. Building on these exceptional proof of concept data, I’m founding our next integrated drug discovery company focussing on allosteric immunotherapies as a new mode of therapeutic intervention.With PAMinMICE, I will perform pioneering experiments in animal models and test positive allosteric modulation of the PD-1•PD-L1 interaction in double-humanized PD-1•PD-L1 knock-in mice as a new mode of therapeutic intervention for diverse autoimmune diseases: psoriasis, colitis, atopic dermatitis, lupus, rheumatoid arthritis. This study may provide the first preclinical evidence supporting the use of allosteric modulators targeting inhibitory ICs for treating such disorders, with the goals of (i) benefiting patients, (ii) strengthening our IP portfolio, and (iii) positioning us for successful fundraising toward the spin-off.