Abstract
Background. Inclusion body myositis (IBM), a relentlessly progressive auto¬immune skeletal muscle disease, has no effective available pharmacological therapy. A prominent feature of IBM on microscopy is CD8+ highly cytotoxic T (Tc) cells invading non-necrotic myofibers (1, 2). These cells include T effector memory (TEM) and terminally differentiated T effector cells (TEMRA), known to be relatively resistant to apoptosis, and express markers including killer cell lectin-like receptor G1 (KLRG1) (3). ABC008, a first-in-class humanized, afucosylated monoclonal antibody (mAb) specific for KLRG1, was developed to selectively deplete these CD8+ Tc cells while sparing other cell populations, e.g., naïve, central memory, and regulatory T cells and B cells. ABC008 has been designed to treat diseases mediated by Tc cells such as IBM and T-cell large granular lymphocytic leukemia (T-LGLL). IBM overlaps clinically with T-LGLL (2) and shares similar expansions of large granular lymphocytes, which also express KLRG1. We report here preliminary data from our ongoing first-in-human trial of ABC008 in IBM (NCT04659031).
Methods. In this open label, single ascending dose trial with 3+3 design evaluating ABC008 administered subcutaneously (SC), eligible participants must have clinicopathologically defined, clinically defined, or probable IBM according to the European Neuromuscular Centre 2011 research diagnostic criteria (3) and an IBM Functional Rating Scale (IBMFRS) score <38. Four dose cohorts are planned: ABC008 0.1, 0.5, 2.0, and 5.0 mg/kg. Pharmacodynamics (PD), pharmacokinetics (PK), safety, and disease severity assessments are performed pre-dose (Day 0) and during the 6 month follow-up period.
Results. As of 12 February 2022, Cohorts 1 (C1) and 2 (C2) have received 0.1 and 0.5 mg/kg of ABC008 SC and completed 168 and 56 days of follow-up, respectively. Cohort 3 evaluating ABC008 2.0 mg/kg is enrolling. Across C1 and C2, mean baseline age is 65.7 years, IBM disease duration 6.8 years, and IBMFRS score 27.5. Maximum depletion of CD8+KLRG1+ cells in C1 and C2 ranged from 46-96% and 98-99%, respectively, with depletion evident within 24 hours (first time point assessed) (Figure). Recovery in C1 began at Day 84 with Day 168 depletion at 29-71%. Deep depletion was also present in other relevant pathogenic populations including CD4+KLRG1+, CD8+CD57+ (LGLs), CD8+ TEM, and CD8+ TEMRA cells. Protective populations of immune cells were preserved, including B cells, regulatory T cells that protect against autoimmunity, and central memory T cells that protect against infection (Figure). ABC008 SC displays a long absorption phase and slow clearance properties typical of mAb therapies. No severe adverse events (AEs) or discontinuations due to AEs have been reported. One unrelated serious AE of fall with muscle tear occurred in a participant with a prior history of falls.
Conclusions. In study participants with IBM, single SC doses of 0.1 and 0.5 mg/kg of ABC008 resulted in dose dependent depletion of CD8+KLRG1+ cells, CD8+CD57+ LGLs, and other highly cytotoxic populations, while sparing protective populations of immune cells, without apparent safety signals. Additional cohort dosing is ongoing, and a multi-ascending dose phase of the study is planned.