MULTIPLE DOSES OF TRX1 (ANTI-CD4 MAB) WHEN ADMINISTERED BY INTRAVENOUS INFUSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. INTRODUCTION Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that affects primarily the skin, but may also involve the hair and mucous membranes. Part of the pathogenesis involves autoimmunity characterized by the appearance of autoreactive T cells that exhibit the loss of self-tolerance. TRX1 is a humanized IgG1? monoclonal antibody that reacts with the human lymphocyte antigen CD4. CD4 is a monomeric glycoprotein expressed on a subpopulation of T effector lymphocytes known as T-helper cells. These cells play a central role in the orchestration of adaptive immunity, being required for both robust B-cell mediated humoral responses as well as the generation of potent CD8+ cytotoxic lymphocytes. While the mechanism(s) of action of TRX1 is now known, TRX1 may cause hyporesponsiveness to antigen stimulation. PRIMARY OBJECTIVES: 1. Characterize the tolerability, safety, and pharmacokinetics of multiple doses of TRX1 when given by intravenous (IV) infusion to subjects with CLE. SECONDARY OBJECTIVES: 1. Characterize the Pharmacodynamics (PD) of TRX1 via effects on: cytokine release, CD4 saturation/expression, lymphocyte subset analysis, and other markers of immune function (e.g. responses to recall antigens and neoantigens). 1) Evaluate whether TRX1 has an effect on viral reactivation. 2. Characterize whether TRX1 is immunogenic by measurement of anti-TRX1 antibodies. EXPLORATORY OBJECTIVES: 1. Determine whether TRX1 can tolerize subjects to a concurrently administered antigen, bacteriophage ?X174 (PhiX). 2. Determine whether TRX1 decreases the CLASI score. 3. Determine whether TRX1 decreases the use of corticosteroids and/or hydroxychloroquine. 4. Measure serological gene expression for the sub-types of CLE. 5. Measure various immunohistology parameters in the primary lesion(s) pre- and post-dose for Cohort 3. 6. Measure gene and proteomic expression profiles in the primary lesion(s) pre- and post dose for Cohort 3. STUDY DESIGN This is a Phase 1b, open-label, dose-escalation, consecutive cohort study of the tolerability, safety, and pharmacokinetics of four IV infusions of TRX1 in subjects with CLE. TRX1 will be administered via IV infusion over a period of two hrs. Three cohorts of subjects will receive doses of 0.5, 1.5 mg/kg, and 3.0 mg/kg on Days 1, 5, 9, and 13. First doses of Cohort 2 and 3 will not begin until 21 days after the last dose of the previous cohort and all safety data from the prior cohort has been received and reviewed.