We are developing a second generation bifunctional drug called DRhQ that can simultaneously bind to and inhibit both the TCR and CD74 through distinct regions of the construct [6]. DRhQ is comprised of the HLA-DRα1 domain with an L50Q amino acid substitution (to enhance binding affinity for CD74) linked to an autoantigen peptide (myelin oligodendroglial cell glycoprotein, i.e. MOG-35-55 peptide) (Fig. 1 ). DRhQ was derived from soluble MHC Class II α1-β1-antigenic peptide constructs originally designed to ligate specific T cell receptors as the distal components of the trimolecular complex (called Recombinant TCR ligands – RTLs). As partial TCR agonists these constructs, containing various disease-associated MHC and antigenic peptide components, could indeed inhibit MHC-restricted antigen specific T cells, but translation of RTL1000 for human use in a Phase 1 clinical trial (showing safety and tolerability) required MHC-matched recipients [7]. Thus, the simpler DRhQ construct was designed, retaining just the conserved-in-human DRα1 domain (without the polymorphic HLA-DRβ1 domain) linked to the MOG-35-55 peptide extension, with the added benefit that it can be administered to all recipients without need for tissue type matching. This has enabled use of the DRα1-MOG-35-55 construct to reverse ongoing neuroinflammation and disease signs in animal models of multiple sclerosis, stroke, methamphetamine disorders and traumatic brain injury [8]. These and other studies ([9], [10], [11] & unpublished data) revealed down-regulation of multiple proinflammatory components driven by both innate and adaptive immune responses that also contribute to the SARS-CoV-2 cytokine storm, including complement receptor C5aR1, platelet activation, IL-1β, IL-2, IL-6, TNF-α, CCR2 (receptor for CCL2) and CXCR2. Of further importance, a partial HLA-DP RTL construct could inhibit activated pleural T cell infiltrates from patients with beryllium-induced lung fibroma [12], suggesting more-directly-relevant activity that could be potentially beneficial as a treatment of COVID-19 patients with ARDS.
Fig. 1 Dual activities of DRhQ that could block the “Cytokine Storm” induced by SARS-CoV-2. DRhQ is a bifunctional drug comprised of the HLA-DRα1 domain covalently linked to human myelin oligodendroglial cell glycoprotein (MOG)-35-55 peptide. Due to its unique design, DRhQ can bind to and inhibit both T cell receptors and the MHC “invariant” chain, CD74, that serves as the receptor for the proinflammatory homologs, MIF and MIF2, resulting in blockade of multiple contributors to the Cytokine Storm. DRhQ image: Green = DRα1L50Q domain; Dark green line = linker; Black = MOG-35-55 peptide extension.