https://orcid.org/0000-0001-8470-1952
Watch the video of this contribution at Over the last 25 years, the success of rituximab, the first B cell–depleting monoclonal antibody (mAb), has lent support to the notion that B cells are involved in most if not all autoimmune diseases. The efficacy of this treatment, however, is not uniform across diseases and patients, which may be due to a variable role of B cells or to insufficient B-cell targeting. This has fuelled the search for alternative therapies with a B cell–depleting or B cell–modulating effect. Here we discuss the main aspects of B-cell involvement in autoimmune kidney diseases and present the new B cell–targeting therapies used in the management of these conditions.
THE B-CELL LINEAGE AND ITS INVOLVEMENT IN AUTOIMMUNITY
B cells originate in the bone marrow (BM) and express a unique B-cell antigen receptor (BCR). They mature through several developmental stages primarily to oversee humoral immunity (Fig. 1, upper panel). B cells reactive to self-antigens are normally deleted or made unable to activate, but this negative selection may fail in states of excess B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, which may result in autoimmune responses. Naïve B cells that recognize the antigen proliferate and undergo somatic mutations and class switch recombination, which allows the generation of distinct immunoglobulin classes, e.g. IgA or IgG. Such events usually take place within follicles of secondary lymphoid organs and are dependent on T-helper lymphocytes. Mature B cells become memory B cells, plasmablasts, i.e. short-lived antibody-producing cells, or long-lived plasma cells (PC), which mainly reside in the BM and maintain the long-term production of immunoglobulins (Fig. 1, upper panel).
The B-cell lineage and the new B cell–targeting therapies. The upper panel depicts the ontogenesis of B cells and plasma cells and highlights their main antigens, most of which are targets of therapies. The lower panel shows the main B cell–directed therapies (distinguishing them into B cell–depleting and B cell–modulating) and their molecular targets.
B cells appear involved in autoimmune diseases as precursors of cells producing pathogenic autoantibodies, but experimental and clinical observations have also pointed to an autoantibody-independent role [1]. B cells are known to present antigens to T lymphocytes, which is critical to the initiation of the autoimmune response. Furthermore, they can release pro-inflammatory cytokines and guide the formation of ectopic lymphoid structures in tissue infiltrates, thereby perpetrating inflammation and local autoantibody production. Numbers of activated B cells and plasmablasts are increased in the blood of patients with active autoimmune diseases, such as antineutrophilic cytoplasmic antibody–associated vasculitis (AAV) [2], systemic lupus erythematosus (SLE) [3] and IgG4-related disease (IgG4-RD) [4], further suggesting their participation in disease flare.
B CELL–DEPLETING THERAPIES
B cell–depleting therapies, initially introduced for the treatment of B-cell malignancies, target transmembrane proteins, known as cluster of differentiation (CD), and cause cell removal through antibody-dependent cytotoxicity (ADCC), phagocytosis, complement-dependent cytotoxicity (CDC) or direct cell death (DCD).
Anti-CD20 mAb deplete cells from pre-B to memory B stages, but do not affect plasmablasts and PC, which are mainly CD20-negative, nor progenitors that are able to reconstitute the B cell pool (Fig. 1, upper panel). Rituximab, the first chimeric anti-CD20 mAb, is widely used in autoimmune kidney diseases, including AAV, membranous nephropathy (MN), primary podocytopathies and lupus nephritis (LN). Since rituximab failure has been associated with incomplete B-cell depletion and its murine portions can cause infusion reactions, new humanized mAb with greater B cell–depleting properties have been generated. They are classified based on CD20 binding as type I (rituximab-like), which elicit stronger CDC, and type II (tositumomab-like) mAb, that predominantly induce DCD. Ocrelizumab is a type I humanized mAb with increased affinity to fragment crystallizable (Fc) gamma receptor III (FcγRIII) allowing enhanced ADCC. Results of the only randomized controlled trial (RCT) in active LN, which was terminated early because of excessive risk of serious infections, however, did not show a significant treatment difference between ocrelizumab and placebo [5]. Ofatumumab, a fully human type I mAb binding a distinct CD20 portion with slower dissociation time than rituximab, did not prove superior to rituximab in childhood-onset nephrotic syndrome (usually due to primary podocytopathy), but was tolerated by rituximab-intolerant patients [6]. Obinutuzumab is the only type II anti-CD20 agent under study. In a phase II RCT, obinutuzumab as add-on therapy for proliferative LN met the primary endpoint [7], which has prompted evaluation in a phase III trial (NCT04221477). Trials in MN (NCT04629248) and AAV (www.cctu.org.uk) are in progress.
CD19 is expressed by most B cells and by CD20-negative plasmablasts. Inebilizumab, an anti-CD19 mAb approved for neuromyelitis optica disorder spectrum, is under evaluation in IgG4-RD (NCT04540497). CD19-positive cells have also been targeted through chimeric antigen receptor T (CAR-T) cells. These are autologous T lymphocytes genetically modified to express a chimeric receptor comprising an extra-cellular immunoglobulin-like domain, which enables them to recognize unprocessed antigens on cell membrane, e.g. CD19, and activate, causing cell death. Such an approach is able to induce a profound depletion of B cells and plasmablasts, including tissue-resident and tissue-infiltrating ones, which are usually less accessible to mAb. The use of anti-CD19 CAR-T cells has led to complete clinical and serological remission in cases of refractory SLE and other autoimmune diseases, with a good safety profile [8]. Further studies on LN are underway (NCT05938725).
Anti-CD38 mAb are used in the treatment of monoclonal gammopathies to target PC and may allow suppression of autoreactive clones. Daratumumab has been beneficial in some cases with refractory AAV, MN, idiopathic nephrotic syndrome (iNS) and SLE [9–11] and is being tested in trials on LN (NCT04868838), while felzartamab is being studied in MN (NCT04733040) and IgAN (NCT05065970).
B CELL–MODULATING THERAPIES
Several therapies target molecules involved in B-cell homeostasis and functions, such as BAFF (Fig. 1, lower panel). Through binding to three different receptors, BAFF promotes survival of B cells (BAFF-R), maturation of PC (B-cell maturation antigen, BCMA) and antibody production (transmembrane activator and calcium modulator and cyclophilin ligand interactor, TACI). High levels of BAFF were noted in SLE and led to the development of belimumab, a recombinant mAb targeting soluble BAFF. RCTs of belimumab as an add-on therapy showed a significant benefit in SLE and LN, leading to its approval. Belimumab has also been used in combination with rituximab but results of trials have been disappointing. Further studies on this combined therapy are ongoing in SLE (NCT03747159), but also AAV (NCT03967925) and MN (NCT03949855). Other anti-BAFF, i.e. tabalumab and blisibimod, did not achieve primary endpoints in SLE trials and no additional studies are currently planned.
A proliferation-inducing ligand (APRIL) is another member of the TNF family that binds TACI and BCMA and promotes particularly IgA production. Atacicept, a recombinant fusion protein comprising the extra-cellular domain of TACI, can neutralize both BAFF and APRIL. In a phase II trial on SLE, atacicept improved the risk of flare [12] and a phase III trial is ongoing (NCT05609812). Furthermore, a phase II trial on immunoglobulin A nephropathy (IgAN) showed reduction in proteinuria and galactose-deficient IgA1 following atacicept [13] and is being followed by a phase III trial (NCT04716231). Telitacicept, another recombinant TACI-like protein, has been approved in China for SLE and is under evaluation in a global phase III trial (NCT05306574). In IgAN, telitacicept significantly improved proteinuria [14] and is being tested in a phase III trial (NCT05799287). Significant amelioration of proteinuria in IgAN has also been achieved by sibeprenlimab, a humanized anti-APRIL mAb currently studied in a phase III trial (NCT05248646) [15].
Unlike FcγRIII, FcγRIIb exerts inhibitory effects. Obexelimab is a bispecific mAb that binds CD19 and co-engages FcγRIIb, thus inhibiting B cells and plasmablasts. A pilot study on IgG4-RD showed improvement in clinical features and a phase III trial is recruiting (NCT05662241) [16]. Furthermore, obexelimab has been evaluated in a phase II trial on SLE but it did not achieve the primary endpoint [17]. CD22 is a co-receptor of BCR targeted by epratuzumab, which results in the internalization of CD22-BCR, thus preventing activation. Epratuzumab showed promising results in phase II trials on SLE but failed to show superiority in phase III studies and no further trials are planned in kidney diseases [18]. BCR signals are transduced by Bruton's Tyrosine Kinase (BTK), an intracellular tyrosine kinase involved in cell survival, proliferation and activation. BTK inhibitors are orally active and were first introduced in B-cell malignancies. Despite benefits in murine SLE models, both evobrutinib and fenebrutinib met neither their primary nor their secondary endpoints in phase II studies on SLE [19]. Zanubrutinib is under evaluation in SLE (NCT04645470), IgG4-RD (NCT04602598) and MN (NCT05707377).
CONCLUSIONS
A deeper appreciation of the role of B cells in autoimmune diseases has fostered the development of new B cell–targeting agents, including better-designed anti-CD20 mAb, anti-BAFF/APRIL and therapies using innovative strategies, such as bispecific antibodies and cell-based approaches. However, despite similarities in immunopathogenesis of these conditions, there seems to be no single therapy that works for all diseases and all patients, but the experience with the new agents, although limited, suggests scenarios in which some treatments may be preferable. A broader and complete depletion of the B-cell lineage, such as that achieved by anti-CD19 CAR-T cells, may be key to revert the course of SLE and other autoimmune disorders, while targeting the BAFF/APRIL axis holds promise for IgAN, which has not benefited from standard B-cell depletion. The place of the new B cell–targeting therapies in the management of autoimmune kidney diseases is yet to be defined, but their introduction raises hopes for new treatment options and a refined understanding of these ‘B cell–mediated’ diseases.
CONFLICT OF INTEREST STATEMENT
None declared.
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