Low-dose Subcutaneous Anti-CD20 Therapy Effectively Depletes B Cells and Ameliorates Central Nervous System Autoimmunity (P2.359)

Objective: To characterize the impact of rodent anti-CD20 depleting antibody dose (low/high) and route of administration (subcutaneous [s.c.]/intravenous [i.v.]) on tissue B-cell depletion and determine the impact on functional immune surveillance. Background: Anti-CD20 therapies (rituximab, ocrelizumab, and ofatumumab) have shown clinical efficacy in multiple sclerosis (MS) studies. During RRMS, lymph node-resident B cells act as antigen-presenting cells, thereby facilitating autoimmune T-cell activation. Low-dose s.c. therapy (ofatumumab) may provide a more targeted lymph node B-cell depletion compared to oncology-like high-dose i.v. infusions (rituximab and ocrelizumab). Design/Methods: Mice were administered an anti-CD20 monoclonal antibody using two regimens: low-dose (20 μg/mouse) s.c. or high-dose (150 μg/mouse) i.v.. Three rodent models were used: B cell-dependent neuroinflammation; B cell-dependent trinitrophenylated lipopolysaccharide (TNP-LPS) induced antibody production; and T cell-dependent dinitrophenyl-keyhole limpet hemocyanin immunization. Lymph nodes, spleens and blood were analyzed using flow cytometry. Antibody titers were quantified using enzyme-linked immunosorbent assay. Results: Circulating blood B-cell depletion was similar irrespective of the anti-CD20 dose and route of administration. Low-dose s.c. treatment relatively spared mature B-cells within the spleen compared to high-dose i.v. therapy. Low-dose anti-CD20 treatment was equally effective in suppressing experimental neuroinflammation. High-dose anti-CD20 therapy profoundly suppressed splenic follicular B-cells resulting in an altered immune surveillance response to antigenic challenge. Conclusions: Low dose s.c. ofatumumab treatment provides effective B-cell depletion within the lymphoid tissues and has comparable efficacy to the high dose treatment in a neuroinflammation model. The s.c. adminstration of anti-CD20 may facilitate its entry into lymphatic drainage and in lymph node targeting. High-dose i.v. anti-CD20 therapy severely depletes mature splenic B-cells whilst they are spared by low-dose s.c. anti-CD20 treatment. Splenic B-cells are not critical for driving CNS autoimmunity but provide important immune surveillance against blood borne pathogens. Study Supported by: Novartis Pharma AG, Basel, Switzerland Disclosure: Dr. Smith has received personal compensation for activities with Novartis Institutes of BioMedical Research as an employee. Dr. Huck has received personal compensation for activities with BioMedical Research, Novartis Pharma AG as an employee. Dr. Wegert has received personal compensation for activities with Novartis Institutes of BioMedical Research and Novartis Pharma AG, Basel. Dr. Schmid has received personal compensation for activities with Novartis Institutes as an employee. Dr. Dunn has received personal compensation for activities with Novartis Research Foundation as an employee. Dr. Leppert has received personal compensation for activities with Novartis Pharma AG, Switzerland as an employee. Dr. Leppert holds stock and/or stock options in Novartis Pharma AG, Switzerland, which sponsored research in wich Dr. Leppert was involved as an investigator. Dr. Wallstroem has received personal compensation for activities with Novartis Pharma AG as an employee.