Background/Purpose: CD6, a co-stimulatory receptor predominantly expressed on T cells, promotes CD4+ T cell proliferation and differentiation into Th1/Th17 cells. The CD6 ligand, activated leukocyte cell adhesion molecule (ALCAM), is expressed on antigen presenting cells, as well as epithelial and endothelial cells. Itolizumab (ITO) is a humanized IgG1 monoclonal antibody that binds CD6 and blocks ALCAM interaction to inhibit T cell activation and trafficking. ITO is being evaluated as a treatment for systemic lupus erythematosus (SLE) and lupus nephritis (LN).

Methods: EQUALISE is an open-label Phase 1b 2-part study that is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of subcutaneous doses (SC) of ITO (0.4 to 3.2 mg/kg). Part A enrolled adult patients with active or inactive SLE who had received ≥1 SLE treatment. Treated subjects received ITO SC Q2 weeks x 2. Part B of the study, which is evaluating ITO treatment of subjects with active proliferative Class III/IV LN for 24 weeks, is currently enrolling (NCT04128579).

Results: Part A enrolled 34 subjects in 5 cohorts: 0.4 mg/kg (n=6), 0.8 mg/kg (n=7), 1.6 mg/kg (n=7), 2.4 mg/kg (n=6), and 3.2 mg/kg (n=8). Similar baseline characteristics were noted across cohorts. The mean age was 51, with 94% female, 74% white (47% Hispanic) and ~11 years since SLE diagnosis (Table 1). The mean baseline SLEDAI-2K was 6.6.

SC dosing of cohorts 1-4 (0.4 mg/kg through 2.4 mg/kg (N=26)) was well tolerated (Table 2), with 3 subjects not receiving both doses, 1 due to a protocol eligibility deviation and 2 due to adverse events (AEs) (lymphopenia and urticaria). The most frequent AEs reported in these cohorts were mild to moderate injection site reactions. No serious adverse events (SAEs) were reported. For Cohort 5 (3.2 mg/kg), 8 subjects received at least 1 SC dose of ITO in at least 2 separate injection sites. In this cohort >85% of subjects reported an AE, the most common being injection site reactions, mainly moderate grade 2 reactions with erythema or pruritis. One subject (3.2 mg/kg) experienced 1 SAE (hypotension and syncope) that occurred in the follow-up period > 40 days after ITO. 4 subjects (50%) in Cohort 5 (3.2mg/kg) discontinued treatment after 1 dose. Across all cohorts, there were no notable changes in vital signs, ECGs, or safety lab parameters, with the exception of transient declines in absolute lymphocyte counts without clinical sequelae.

Preliminary PK results indicate dose-proportional increases in ITO exposure and rapid and dose-dependent decreases in CD4 cell surface expression of CD6, a PD marker of target engagement.

Conclusion: 2 SC doses of ITO up to 2.4 mg/kg in SLE subjects were well tolerated. There was reduced tolerability to the 3.2 mg/kg dose with 50% of patients discontinuing after the first dose. The PK, PD and safety data to date support continued evaluation of ITO in SLE/LN and other chronic autoimmune diseases. The ongoing EQUALISE Part B will assess ITO safety and efficacy in Class III/IV LN patients.

Table 1: Baseline demographics of study participants

Table 2: Summary of types of adverse events by cohort

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/itolizumab-a-novel-anti-cd6-therapy-in-systemic-lupus-erythematosus-patients-interim-safety-results-from-the-phase-1b-equalise-dose-escalation-study/