Contributions
Abstract: P401
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Background: Anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) have consistently shown significant clinical efficacy in relapsing-remitting multiple sclerosis (RRMS) patients. Rituximab and ocrelizumab are administered as high-dose intravenous infusions, whereas ofatumumab is a relatively low-dose subcutaneous formulation. During RRMS, lymph node-resident B cells act as antigen-presenting cells, thereby facilitating autoimmune T-cell activation.
Objective: Using a rodent anti-CD20-depleting antibody, we characterised the impact of dose (high/low) and administration route (subcutaneous / intravenous) on B-cell subset frequencies in blood and lymphoid tissues. The treatment regimens were subsequently evaluated in a B cell-dependent neuroinflammation model for efficacy. Lastly, we investigated the kinetics of B-cell repletion upon treatment cessation.
Methods: Mice were treated with a depleting anti-CD20 monoclonal antibody or isotype control using two different regimens: low-dose subcutaneous or high-dose intravenous administration. B cell-dependent, experimental autoimmune encephalomyelitis (EAE) was induced via immunisation with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in an adjuvant. Lymph nodes, spleens and blood were analysed for B-cell subsets and T-cell populations by flow cytometry.
Results: Maximum depletion of circulating blood B cells was similar irrespective of anti-CD20 dose and administration route; however, the time to nadir occurred slightly later with the subcutaneous treatment. Lymph node B-cell depletion was slightly enhanced following the subcutaneous treatment, whereas splenic B-cell numbers were consistent between the treatment regimens. Follicular (FO) and Marginal Zone (MZ) B-cell subsets rapidly depleted, whereas Germinal Centre (GC) populations were relatively unchanged. Low-dose subcutaneous anti-CD20 therapy delayed EAE disease onset and significantly inhibited neurological deficits; no additional efficacy was observed in the high-dose intravenous treated group.
Conclusions: Low-dose, subcutaneous anti-CD20 therapy is highly effective in depleting B cells within lymph nodes and blood, resulting in amelioration of CNS autoimmune inflammation. No superiority was observed with the high-dose intravenous anti-CD20 therapy.
Disclosure: This abstract is supported by Novartis Pharma AG, Basel, Switzerland.
All the authors are employees of Novartis.
Abstract: P401
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Background: Anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) have consistently shown significant clinical efficacy in relapsing-remitting multiple sclerosis (RRMS) patients. Rituximab and ocrelizumab are administered as high-dose intravenous infusions, whereas ofatumumab is a relatively low-dose subcutaneous formulation. During RRMS, lymph node-resident B cells act as antigen-presenting cells, thereby facilitating autoimmune T-cell activation.
Objective: Using a rodent anti-CD20-depleting antibody, we characterised the impact of dose (high/low) and administration route (subcutaneous / intravenous) on B-cell subset frequencies in blood and lymphoid tissues. The treatment regimens were subsequently evaluated in a B cell-dependent neuroinflammation model for efficacy. Lastly, we investigated the kinetics of B-cell repletion upon treatment cessation.
Methods: Mice were treated with a depleting anti-CD20 monoclonal antibody or isotype control using two different regimens: low-dose subcutaneous or high-dose intravenous administration. B cell-dependent, experimental autoimmune encephalomyelitis (EAE) was induced via immunisation with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in an adjuvant. Lymph nodes, spleens and blood were analysed for B-cell subsets and T-cell populations by flow cytometry.
Results: Maximum depletion of circulating blood B cells was similar irrespective of anti-CD20 dose and administration route; however, the time to nadir occurred slightly later with the subcutaneous treatment. Lymph node B-cell depletion was slightly enhanced following the subcutaneous treatment, whereas splenic B-cell numbers were consistent between the treatment regimens. Follicular (FO) and Marginal Zone (MZ) B-cell subsets rapidly depleted, whereas Germinal Centre (GC) populations were relatively unchanged. Low-dose subcutaneous anti-CD20 therapy delayed EAE disease onset and significantly inhibited neurological deficits; no additional efficacy was observed in the high-dose intravenous treated group.
Conclusions: Low-dose, subcutaneous anti-CD20 therapy is highly effective in depleting B cells within lymph nodes and blood, resulting in amelioration of CNS autoimmune inflammation. No superiority was observed with the high-dose intravenous anti-CD20 therapy.
Disclosure: This abstract is supported by Novartis Pharma AG, Basel, Switzerland.
All the authors are employees of Novartis.