Shah, Kavina; (2025) Overcoming Rituximab Resistance with CD19-TCB to Improve B Cell Depletion Therapy in Rheumatoid Arthritis and Systemic Lupus Erythematosus. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) can be successfully managed with anti-CD20 monoclonal antibodies, however, refractory disease with incomplete depletion remains a significant problem and is associated with poor clinical response. Three important mechanistic explanations for resistance to rituximab-mediated B cell depletion include: 1) CD20-/lo cells that may evade rituximab’s effects; 2) internalisation of rituximab-CD20 complexes limits effector cell recognition of B cells; and 3) limited vascular access for effector cells such as macrophages results in disparate depletion of specific subpopulations residing in areas such as lymph nodes and inflammatory sites. Here, I examined B cell phenotypes in RA and SLE, followed by in-vitro investigation of a CD19-T cell bispecific antibody (CD19-TCB), which employs T cells as effector cells, in RA and SLE blood samples. My results identified: 1) CD19+CD20- B cells which evade rituximab treatment demonstrate greater proliferative capacity compared to CD19+CD20+ B cells, 2) autoimmune prone IgD-CD27-T-bet+ B cells that display increased levels of IFN-γ, TLR7 and TLR9, as shown previously, were noted to have high levels of CD19 whereas a subpopulation of these cells had low levels of CD40 and BAFF-R, collectively, providing support for CD19 as an optimal target for B cell depletion to overcome current B cell targeted therapies; and 3) CD19-TCB recruits both CD4+ and CD8+ T cells to delete B cells in whole blood assays and in PBMC cultures. Variability of CD19-TCB efficiency may partially relate to baseline activation of CD8+ T cells, 4) CD19-TCB evoked secretion of inflammatory cytokines including IL-6, TNF-α and IFN−γ in supernatants from whole blood assays and increased intracellular B cell expression of CXCL-10, which recruits effector T cells, noted in samples incubated with TCBs. Collectively, these results provide the rationale and potential biomarkers for consideration when evaluating the therapeutic potential of CD19-TCB, in vivo.

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