Abstract Details

Title Effects of Cladribine on Immune Cell Subsets and Autoantibody Responses in Generalized Myasthenia Gravis Peripheral Blood Mononuclear Cells in Vitro

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P9 - Poster Session 9 (5:00 PM-6:00 PM)

Poster/Presentation
Number 9-013

Objective To investigate the functional effects of cladribine on immune cells from generalized myasthenia gravis (gMG) peripheral blood mononuclear cells (PBMCs).

Background gMG is a B cell-driven, T cell-dependent, autoimmune disease characterized by autoantibody production. Cladribine incorporates into B and T lymphocytes, leading to their selective and temporal depletion. Cladribine tablets are approved for relapsing forms of multiple sclerosis, while cladribine capsules are under evaluation for gMG in a Phase 3 clinical trial (MyClad; NCT06463587).

Design/Methods Whole blood was collected from people with gMG. Isolated PBMCs were treated with cladribine in vitro and stimulated to activate B and T cell proliferation or induce plasma cell differentiation. Flow cytometry was used to assess cladribine half-maximal inhibitory concentrations (IC₅₀) on cell depletion, cell proliferation, and plasma cell differentiation. Total IgG and anti-AChR IgG levels were analyzed using enzyme-linked immunosorbent assays.

Results Cladribine demonstrated concentration-dependent depletion of naïve and proliferating B and T cell subsets, memory-B cells and plasmablasts in gMG PBMCs (n=10). IC₅₀ for total B cells = 0.03–0.06µM; T cells = 0.07–0.12µM; CD20⁺T cells = 0.9µM [n=10]). In a plasma cell differentiation assay, cladribine reduced gMG plasma cells/plasmablasts (IC₅₀=0.06µM; n=2), reduced production of IgG (IC₅₀=0.3µM; n=12), and inhibited anti-AChR IgG production at 0.06 and 0.6µM; n=2.

Conclusions Cladribine, at concentrations intended to mimic the plasma exposure of people with gMG treated with oral cladribine, depletes B and T cell subsets, inhibits plasma cell differentiation, and reduces IgG and anti-AChR IgG production in gMG PBMCs in vitro. These data suggest that cladribine targets drivers of autoimmunity in gMG, supporting the upstream mechanism of cladribine in reducing autoantibody production in gMG.

Authors/Disclosures
Dominic Jack (Merck Serono Ltd) PRESENTER	Dominic Jack has received personal compensation for serving as an employee of Merck KGaA, Darmstadt, Germany.
Kunling Wu	Ms. Wu has nothing to disclose.
Elina Jarvinen	Elina Jarvinen has received personal compensation for serving as an employee of Merck Oy, Espoo, Finland, an affiliate of Merck KGaA.
Tobias Derfuss	An immediate family member of Tobias Derfuss has received personal compensation for serving as an employee of Roche. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. The institution of Tobias Derfuss has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GeNeuro. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuraxpharm. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson&Johnson. The institution of Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Sharp Dome. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MedDay. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion. The institution of Tobias Derfuss has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Merck. Tobias Derfuss has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Roche. An immediate family member of Tobias Derfuss has stock in Novartis. An immediate family member of Tobias Derfuss has stock in Roche. The institution of Tobias Derfuss has received research support from Roche. The institution of Tobias Derfuss has received research support from Biogen. The institution of Tobias Derfuss has received research support from Alexion.
Kevin C. O'Connor, PhD (Yale University School of Medicine)	Kevin C. O'Connor, PhD has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Immunovant. Kevin C. O'Connor, PhD has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Argenx. Kevin C. O'Connor, PhD has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurocrine. Kevin C. O'Connor, PhD has stock in Cabaletta. The institution of Kevin C. O'Connor, PhD has received research support from Seismic. The institution of Kevin C. O'Connor, PhD has received research support from Argenx. Kevin C. O'Connor, PhD has received intellectual property interests from a discovery or technology relating to health care.
Yiyi Sun	Mr. Sun has nothing to disclose.

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