Background/Purpose: Inclusion body myositis (IBM), a relentlessly progressive autoimmune skeletal muscle disease, has no effective available pharmacological therapy. A prominent feature of IBM on microscopy is highly differentiated effector CD8+ cytotoxic T (Tc) cells invading non-necrotic myofibers¹. These Tc cells are known to be relatively resistant to apoptosis and express markers including killer cell lectin‑like receptor G1 (KLRG1)². ABC008, a first-in-class humanized, afucosylated monoclonal antibody (mAb) specific for KLRG1, selectively depletes these highly differentiated Tc cells while sparing other blood cell populations, e.g., naïve, central memory, and regulatory T cells. ABC008 has been designed to treat diseases mediated by these Tc cells, including IBM and T-large granular lymphocytic leukemia (T-LGLL). IBM as well as rheumatoid arthritis overlap clinically with T-LGLL and share similar expansions of blood large granular lymphocytes (LGLs), which also express KLRG1⁺. We report here our preliminary data from our ongoing trial of ABC008 in IBM (NCT04659031).

Methods: In this ongoing first-in-human, 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 criteria² and an IBM Functional Rating Scale score of ≤38. Four dose cohorts are planned: ABC008 0.1, 0.5, 2.0, and 5.0 mg/kg. Pharmacodynamic, pharmacokinetic (PK), safety, and disease severity assessments are performed pre‑dose (Day 0) and during the 6‑month follow-up period.

Results: Three Caucasian male participants, mean age ± standard deviation (SD) = 64 ± 11.4 years, mean IBM disease duration ± SD = 9.7 ± 5.91 years, and mean baseline IBMFRS ± SD = 30 ± 5, were each dosed with ABC008 at 0.1 mg/kg SC x 1 and completed ≥28 days of follow-up. Maximum depletion of CD8⁺KLRG1⁺ cells (Figure 1) through Day 28 ranged from 46‑96% of baseline, with depletion evident from Day 2 onward and largely maintained through at least Day 28 (mean depletion 68%). Other hematologic parameters generally remained stable including T regulatory cells. CD8⁺ LGLs, because they are mostly KLRG1⁺, were also depleted (Figure 2). Preliminary PK show that ABC008 displays a long absorption phase following SC administration and slow clearance properties typical of mAb therapies. No moderate, severe, or serious adverse events were reported.

Conclusion: In study participants with IBM, a single SC dose of 0.1 mg/kg of ABC008 resulted in the depletion of CD8⁺KLRG1⁺ cells with no apparent safety concerns.  Higher dose cohorts are planned. Based on these results, a study evaluating ABC008 for the treatment of T-LGLL is also intended.

1. Engel AG, et al. Ann Neurol. 1984;16:209-15.
2. Greenberg SA, et al. Brain. 2016;139:1348-60.
3. Rose MR, et al. Neuromuscul Disord. 2013;23:1044–55.

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/depletion-of-klrg1-t-cells-in-a-first-in-human-clinical-trial-of-abc008-in-inclusion-body-myositis-ibm/