Targeting B-Cells with Various Monoclonal Antibodies

Ron Milo, MD
Department of Neurology, Barzilai Medical Center, Ashkelon; Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel

Increasing evidence suggests that B cells contribute to both regulation of normal autoimmunity and to the pathogenesis of immune mediated diseases including MS. B cells in MS are skewed towards a pro-inflammatory profile, exhibiting excess of pathogenic memory B-cells, decrease in B regulatory cells and increase in pro-inflammatory cytokines. B cells contribute to the pathogenesis of MS by antibody production, antigen presentation, stimulation and activation of T cells, including memory-B cell driven autoproliferation of brain-homing autoreactive CD4+ T cells, production of pro-inflammatory cytokines and formation of ectopic germinal centers under the meninges that drive cortical pathology and contribute to neurological disability. 

The recent interest in the key role of B cells in MS has primarily been raised by the beneficial and profound anti-inflammatory effects of rituximab, a chimeric monoclonal antibody (mAb) targeting the B cell surface marker CD20, observed in patients with relapsing-remitting (RR) MS. This has been reaffirmed by clinical trials with less immunogenic and more potent humanized and fully human B cell-depleting mAbs targeting CD20, namely ocrelizumab and ofatumumab. Ocrelizumab is also the first disease-modifying drug (DMD) that has shown efficacy in primary-progressive (PP) MS, and is currently approved for both indications. Ublituximab, a movel third-generation anti-CD20 chimeric glycoengineered IgG1 mAb with increased affinity for FcγRIIIa and enhanced antibody-dependent cellular cytotoxicity (ADCC) has also shown high efficacy and favorable safety profile in a recently-completed phase-2 clinical trial in RRMS. Collectively, B cell depletion with anti-CD20 mAbs is safe and highly effective in MS, without significant compromise of the normal immune reactivity.

While anti-CD20 mAbs do not target stem cells, pro-B cells, plasmablasts and plasma cells that do not express CD20, thus sparing B cell reconstitution and antibody formation, the anti-CD19 glycoengineered mAb inebilizumab (MEDI-551) targets wider range of cells of the B cell lineage from pro-B cells to antibody-secreting plasmablasts and some plasma cells. Phase-1 dose-escalation clinical trial with inebilizumab in RRMS showed complete B cell depletion across all doses and fewer new gadolinium-enhancing and new or newly enlarging T2 MRI lesions in Inebilizumab-treated compared to placebo-treated patients. It is still unclear whether the broader range of depleted B cells entails greater clinical benefits (e.g. by a longer lasting depletion or elimination of later differentiation stages of B cells) or more potentially serious side effects (e.g. by delaying and/or negatively affecting B cell reconstitution after treatment cessation due to the elimination of earlier stages in the bone marrow or reducing humoral immunity by elimination of antibody-producing cells).

Another mAb that depletes both B cells and T cells is alemtuzumab which targets CD52, a cell-surface molecule of unknown function expressed on most lymphocytes and monocytes and on some natural killer cells and other leukocytes. Two annual courses of alemtuzumab lead to prolonged lymphocyte depletion with marked and durable suppression of clinical and radiological disease activity in patients with RRMS. Earlier B cell than T cell reconstitution may contribute to the high frequency of secondary autoimmunity observed after alemtuzumab treatment that may be also associates with increased rate of infections and probably of malignancy.

Other mAbs that target B cells but have not yet been explored in MS include epratuzumab (anti-CD22), which negatively regulates B cell receptor-derived activation signals; daratumumab (anti-CD38), which depleted plasmablasts and some plasma cells; LTbR-IgG (anti-lymphotoxin-b receptor), which blocks the formation of ectopic germinal centers; NNC114-0005 (anti-IL-21, a key contributor to the development of autoantibodies); otilimab which targets GM-CSF, a key driver of pro-inflammatory myeloid cell responses; and several other mAbs that block co-stimulatory pathways important for B cell activation.