Friday, May 9, 2025
5/9/2025
Silencing autoantibody secretion for SLE therapy - Silencing autoantibody secretion for SLE therapy Abstract Systemic Lupus Erythematosus (SLE) is a chronic and often life-threatening multisystem autoimmune disorder characterized by autoantibody production and immune-complex–mediated tissue damage. Unfortunately, although efficacious in some patients, current immunotherapies, e.g., rituximab, belimumab, leave the plasma cell factories of offending autoantibodies untouched. Furthermore, these therapies are predicated on B-cell depletion, which is problematic from a safety standpoint. B cells are critical for generation of protective immunity against newly emergent infections such as COVID-19 and Monkey Pox, and, for those unvaccinated, Polio. We live is a world where pandemics caused by newly emerged pathogens is increasingly becoming the norm. It is incumbent upon us to develop therapeutic strategies that do not render patient immunity permanently compromised. We have developed an alternative, non-cell-depleting and reversible approach to B cell silencing involving the targeting of CD79a, the transducer subunit of the B cell antigen receptor (BCR). The effects of CD79a- targeted mAbs do not require Fc region effector functions; rather, the mAbs act as inverse agonists by stimulating inhibitory signaling circuitry that suppresses BCR responses to antigen. Importantly, treatment with anti-79a antibodies that lack Fc effector function also silences antibody production by plasmablasts and plasma cells suggesting a novel, well-differentiated and lower risk approach for therapy of SLE and other auto-inflammatory conditions. Furthermore CD79a is expressed only in B cells, eliminating risk of off-target effects. In the murine MRL/lpr model of SLE, anti-CD79 antibodies effectively decreased inflammation and improved animal survival, and in a collagen-induced arthritis model of rheumatoid arthritis a single injection of antibody prevented the onset of arthritis and decreased arthritis scores until antibody levels had waned. We have generated, humanized and affinity matured a monoclonal anti-human CD79a antibody, and demonstrated that in an ADCC and C’ fixation incompetent formulation it is able to prevent development of autoimmunity by induction of a transient and reversible state of polyclonal B cell anergy. Aided by transgenic knock-in mice in which murine extracellular domains of CD79a or b, or both, have been replaced with human counterparts, we now seek in AIM 1 to further define the spectrum of B cells whose activity is targeted by the antibody, and to prolong antibody T1/2 in order to allow less frequent treatment. In AIM 2 we will determine the ability of antibody to cure disease in the pristane-induced SLE model using our human CD79 knock-in mice. In AIM 3 will extend these results to a huSCID model of SLE. We expect our anti-CD79a antibody to provide a best-in-class immunomodulatory therapeutic with a significantly greater safety and efficacy profile than existing B cell-depleting therapies. Overall, these studies should yield a next generation therapy for SLE and other autoimmune diseases.
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