Cutting-edge approaches to B-cell depletion in autoimmune diseases

Abstract

B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases.

Keywords: B-cell depletion therapy; T-cell engager; autoimmune disease; effector function-enhanced monoclonal antibodies; imvotamab.

Figure 1

Receptor expression on B-cell subsets throughout B-cell development. BCMA, B-cell maturation antigen.

Figure 2

Key events in the BCDT timeline. ALL, acute lymphoblastic leukemia; BCDT, B-cell depletion therapy; CAR-T, chimeric antigen receptor T cell; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FDA, US Food and Drug Administration; FL, follicular lymphoma; Ig, immunoglobulin; mAb, monoclonal antibody; LG/F NHL, relapsed/refractory low-grade or follicular non-Hodgkin’s lymphoma; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TCE, T-cell engager.

Figure 3

Overview of the MOA for anti-CD20 monoclonal antibodies in autoimmune disease. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CDC, complement-dependent cytotoxicity; FcγR, Fc gamma receptor; MAC, membrane attack complex; MOA, mechanism of action; NK, natural killer; PFN, perforin.

Figure 4

Overview of the MOA for CAR-T therapy in in autoimmune disease. CAR-T, chimeric antigen receptor T cell; GzmB, granzyme B; IFNγ, interferon gamma; MOA, mechanism of action; PFN, perforin; TNFα, tumor necrosis factor alpha.

Figure 5

Overview of the MOA for IgG TCEs in autoimmune disease. GzmB, granzyme B; Ig, immunoglobulin; IFNγ, interferon gamma; MOA, mechanism of action; PFN, perforin; TDCC, T-cell dependent cellular cytotoxicity; TNFα, tumor necrosis factor alpha.

Figure 6

Overview of the MOA for IgM TCEs in autoimmune disease. CAR-T, chimeric antigen receptor T cell; CDC, complement-dependent cytotoxicity; GzmB, granzyme B; IFNγ, interferon gamma; MAC, membrane attack complex; MOA, mechanism of action; PFN, perforin; TDCC, T-cell dependent cellular cytotoxicity; TNFα, tumor necrosis factor alpha.