Inflammation Causes Resistance to Anti-CD20–Mediated B Cell Depletion

Abstract

B cells play a central role in antibody-mediated rejection and certain auto-immune diseases. However, B-cell-targeted therapy such as anti-CD20 B cell-depleting antibody(aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B-cell reconstitution leading to aCD20 depletion-resistance could account for these discrepancies. Using a transplantation model, we found that antigen-independent inflammation, likely through TLR signals, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics(PK) and pharmacodynamics(PD) of aCD20 therapy by shortening drug half-life and accelerating the reconstitution of the peripheral B-cell pool by bone marrow-derived B cell precursors. IVIG co-administration also shortened aCD20 drug half-life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell-dependent, antibody-independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PD of monoclonal antibody treatment in inflammatory conditions and highlight the disconnect between B cell depletion on peripheral blood and on secondary lymphoid organs, the deleterious effect of IVIG when given with aCD20, and the relevance of re-dosing of aCD20 for effective B cell depletion in alloimmunity.

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

“…Because CD20 depletion is short-lived in transplant contexts, 24 dosing was repeated on days 2, 7, 14, and 21. Peripheral blood B cells rose after LT in mice in the Iso group, but B cells were almost completely depleted by aCD20 in the blood and allograft ( Figure 7A,B).…”

“…For B cell depletion, 250 μg of anti-mouse CD20 antibody (clone SA271G2 Rat IgG2bκ, BioLegend, San Diego, CA) (aCD20) or isotype control rat IgG2bκ (clone RTk4530, BioLegend) (Iso) were administered intraperitoneally 2 days before and 2, 7, 14, and 21 days after LT. At this dose, SA271G2 depletes >90% of peripheral blood and secondary lymphoid organ B cells for >20 days in steady state settings, but repeat dosing is required in inflammatory contexts. 24…”

Outstanding questions in transplantation: B cells, alloantibodies, and humoral rejection

“…However, no published controlled trial exists comparing the efficacy of these approaches. Moreover, combination therapies may yield unexpected results, as suggested by Riella's work in mice showing that coadministration of IVIg with rituximab led to shortening of the half‐life of anti‐CD20 monoclonal antibody and quicker recovery of B cells . More recently, Jordan et al reported on the successful use of the IgG endopeptidase, IdES, which cleaves IgG at the Fc portion, thereby eliminating antibody‐mediated complement activation and antibody‐dependent cellular cytotoxicity.…”

Current status of alloimmunity

“…Using an allogeneic, syngeneic cardiac transplant model and TLR agonists, Laws et al demonstrated that inflammation mitigates B cell depletion by altering the pharmacokinetics and pharmacodynamics (PK/PD) of anti-CD20 mAb therapy leading to accelerated reconstitution of the B cell pool (23). A single dose of anti-CD20 mAb at the time of transplant fails to maintain B cell depletion.…”