Validation of a Negative Regulator as a Novel Therapy for Autoimmune Disease

DESCRIPTION provided by applicant Systemic lupus erythematosus SLE is a devastating autoimmune disease that most commonly affects women in their child bearing years SLE attacks multiple organ systems but renal and neurologic involvement are the usual harbingers of poor outcome Despite effective albeit toxic immunosuppressive therapy only of patients with these serious manifestations will be alive years after diagnosis SLE remains a disease in critical need of better and safer interventions VISTA V region Immunoglobulin containing Suppressor of T cell Activation is a novel structurally distinct Ig superfamily negative checkpoint regulator whose closest phylogenetic relative is PD L Like PD L VISTA profoundly suppresses immunity and blocking VISTA enables the development of therapeutic immunity to cancer in mouse models We now demonstrate that a VISTA Immunoglobulin fusion protein VISTA Ig a VISTA pathway agonist renders T cells unresponsive in vitro and is effective when administered in vivo early and late in murine models of SLE NZBWF and NZM and multiple sclerosis EAE VISTA Ig is one of the first members of a new promising class of drugs negative checkpoint regulator pathway agonists that actively and potently suppress immunity and as such may play an unprecedented role in the safe and effective treatment of SLE Importantly the VISTA Ig effect is at the level of organ damage and onset of action is immediate with inhibition of T cell activation in andlt minutes of engagement of the putative receptor in vitro and an abrupt reversal of proteinuria in mice within days in vivo These properties predict a highly desirable rapid clinical response potential synergy with slower onset B cell targeted therapies and possibly a major early steroid sparing effect This STTR proposal defines our strategy for advancing the translation of VISTA Ig from a dramatically effective agent in murine SLE to a legitimate candidate for clinical trials in human SLE These Phase II studies will continue to optimize both murine and human VISTA Ig reagents in terms of the need for FcR binding potency half life and immunogenicity using a number of bioengineering techniques both in vivo in murine SLE models and in vitro in studies of PBMC from non human primates NHPs human controls and SLE patients While doing so we will further elucidate the mechanism of action of VISTA Ig Based on these studies a lead candidate hVISTA Ig will be produced in sufficient quantity and quality to move onto critical safety studies in non human primates ImmuNext has a successful track record of commercializing immunotherapies from SBIR projects and we have assembled in very deliberate fashion a top notch team of scientists and clinicians to bring this SLE translational project to fruition PUBLIC HEALTH RELEVANCE Systemic lupus erythematosus SLE is a devastating autoimmune disease that commonly affects women in their childbearing years but can strike anyone Current SLE treatments are often effective but can have serious side effects We have identified a molecule called andquot VISTAandquot that normally functions as a brake on our immune system thereby preventing overactive responses that could result in damage to our own organs as occurs in SLE Giving a form of VISTA to mice with SLE inhibits overactive immune cells and stops their otherwise fatal attack on the kidneys We are developing a human version of the VISTA molecule to test in non human primates as a final step before human clinical trials We are optimistic that this drug will be safe and effective for SLE greatly improving the lives of patients with this dreaded disease