Reddy, Venkata Ranga; (2018) Understanding the variability in clinical and biological response to B-cell depletion therapy in rheumatoid arthritis and systemic lupus erythematosus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Factors including pharmacokinetics, B-cell internalisation of anti-CD20 monoclonal antibodies (mAbs) and disease-associated defects in complement system, NK cells and macrophages may influence the efficiency of rituximab, a Type I anti-CD20 mAb disposed to internalisation by B cells, and contribute to variable clinical and biological response in patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The work presented in this thesis investigated the potential of Obinutuzumab, a commercially available, mechanistically different Type II anti-CD20 mAb with an afucosylated Fc portion not disposed to internalisation, as an alternative B-cell depleting agent in RA and SLE. In patients with SLE, the duration of B-cell depletion was shorter and serum rituximab levels were significantly lower compared to RA. Hypogammaglobulinemia in the SLE cohort was mostly limited to the IgM isotype and was associated with lower baseline IgM levels, sequential therapy with mycophenolate mofetil and lower frequency of IgD+CD27+ unswitched memory B cells. Anti-dsDNA antibodies in those with high pretreatment levels remained elevated in the long-term, a potential mechanism of poor response to rituximab. Obinutuzumab was at least two-fold more efficient than rituximab at inducing cytotoxicity in B cells from patients with RA and SLE in whole blood assays. B cells from patients with RA and SLE internalised obinutuzumab to a significantly lower extent than rituximab, which was significantly more efficient than obinutuzumab at evoking complement-dependent cellular cytotoxicity of isolated B cells. In contrast, obinutuzumab was significantly more efficient at inducing NK cell activation, an indirect measure of antibody-dependent cell cytotoxicity, in RA and SLE; and also activated neutrophils, an indirect measure of antibody-dependent cell phagocytosis, more efficiently than rituximab in SLE. Obinutuzumab was also more efficient at inducing direct cell death in CD19+ B-cells and switched (IgD-CD27+) memory B cells specifically, a higher frequency of which is associated with poor clinical response to rituximab. Thus, increased clearance and/or internalisation of rituximab may impair its efficiency in RA and SLE. Regardless, obinutuzumab was more efficient than rituximab at inducing B-cell cytotoxicity in vitro in both RA and SLE samples mediated by superior FcγR-dependent and -independent effector mechanisms with greater ability to remain at the cell surface following CD20 engagement despite inferior ability to evoke complement-dependent cellular cytotoxicity. These data provide compelling mechanistic reasons for expecting better outcomes with obinutuzumab as an alternative B-cell depleting agent in RA and SLE.

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