DR?1-MOG: A Novel Immunomodulatory Therapeutic for Stroke

Period of Performance: 08/01/2017 - 07/31/2018

$299K

Phase 1 STTR

Recipient Firm

Virogenomics, Inc.
Portland, OR 97223
Principal Investigator

Abstract

This is a Phase I STTR to investigate the preclinical efficacy of a novel immunomodulator, DR?1-MOG, in a clinically relevant thromboembolic stroke model in mice. We have previously shown that T cells are activated after stroke, infiltrate brain, and exacerbate ischemic brain damage. Strategies that reduce T cell activation and brain tissue infiltration have been investigated as potential therapeutic strategies for stroke; however, non- specific inhibition of T cell function is immunosuppressive. We therefore developed Recombinant T cell receptor (TCR) Ligands (RTLs), which are partial MHC II molecules comprised of covalently linked ?1 and ?1 chains tethered to antigenic peptides. Early RTL constructs were successful in protecting against ischemia-induced brain injury but only if the RTL contains a neuroantigen peptide and the matched Class II MHC moiety of the recipient. A significant limitation for using these early RTL constructs to treat human stroke is the need to rapidly match recipient MHC class II with the ?1 domain of the pMHC construct. We, therefore, designed a novel recombinant protein comprised of the HLA-DR?1 domain linked to MOG-35-55 peptide (DR?1-MOG) but lacking the ?1 domain found in pMHC. Because the DR?1 domain is present in all humans and would not be recognized as foreign, treatment using DR?1 constructs would not require HLA screening of potential recipients. In a proof of principle study, we demonstrated that four daily treatments with DR?1-MOG significantly reduced infarct size after stroke in mice. That study, however, was conducted using the intraluminal middle cerebral artery occlusion (MCAO) model, which causes mechanical, rather than thromboembolic occlusion, the most common cause of human stroke. To more faithfully mimic clinical stroke, we have developed a novel thromboembolic model of stroke in mouse, which will form the basis of the current proposal. Furthermore, aging and biological sex are well documented key determinants of stroke outcome, in part by exerting differential influences on stroke-induced inflammatory response. The proposed STTR will further characterize the protective effect of DR?1-MOG using the clinically relevant thromboembolic model of stroke, and the clinically important variables of time of initial treatment, sex and age to estimate how broadly DR?1-MOG could be used to treat stroke patients.