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Maximilian Ferdinand Konig, MD

Assistant Professor

Johns Hopkins University School of Medicine



Targeting autoreactive B cells to prevent thrombosis and fetal loss in SLE

Antiphospholipid syndrome (APS), which causes dangerous blood clots, is responsible for up to one-third of deaths in lupus patients. Current treatments for APS include the long-term use of blood thinners to reduce the risk of heart attack, stroke, lung embolism, or severe pregnancy complications; however, blood thinners can either fail to prevent blood clots or cause severe bleeding. The clotting issues and organ damage in APS are due to hyperactive B cells producing antibodies that attack tissues in the body, and these antibodies cause blood clots to form in arteries and veins. Dr. Konig will use this Lupus Innovation Award to develop a new protein-based precision treatment approach for APS. This therapeutic agent redirects a patient’s own immune system to kill the harmful APS-causing B cells while leaving healthy B cells, which produce protective antibodies that neutralize infection-causing microbes, untouched.

What this study means for people with lupus

This research could lay the groundwork for a highly optimized APS treatment in patients with lupus that would eliminate rogue B cells producing disease-causing antibodies without harming the normal B cells.

The antiphospholipid syndrome (APS) affects up to one-third of patients with systemic lupus erythematosus (SLE). Thrombosis from APS is a leading cause of mortality and irreversible organ damage in SLE, accounting for 27% of deaths in lupus patients. Additionally, APS is a major cause of recurrent fetal loss and pregnancy morbidity. Antiphospholipid antibodies are the immunological hallmark of APS. These antibodies target phospholipid-binding proteins (PLBPs) and promote immune activation, thrombosis, and end-organ damage. Specifically, antibodies against domain I of beta-2-glycoprotein I (ß2GPI) are directly pathogenic in vivo and inhibiting this antibody subset prevents thrombosis. Despite this detailed understanding of molecular disease mechanism, the treatment of APS has not significantly changed over the past three decades, relies primarily on anticoagulation, and is often insufficient. T cell immunotherapies targeting B cells hold immense promise for refractory SLE. However, such pan-B-cell depleting therapies result in excess mortality from infection and B-cell aplasia, which precludes their broad use as a treatment and prevention strategy. Therefore, there is a critical need for the development of precision immunotherapies that can selectively eliminate autoreactive B cells that are sources of disease-causing antibodies in APS, while preserving normal B cells to maintain protective immunity. Autoreactive B cells in APS uniquely express B cell receptors (BCRs) that bind PLBPs (e.g., ß2GPI domain I) on the surface, making them ideal therapeutic targets for precision therapies. In this proposal, we hypothesize that this shared BCR specificity creates a vulnerability that can be therapeutically exploited to selectively eliminate pathogenic B cells in APS while preserving other B cells. We aim to achieve this by developing a new class of protein-based precision immunotherapies that are designed to selectively kill target B cells expressing cognate BCRs. Specifically, we propose to 1) comprehensively define the heterogeneity of antiphospholipid antibody fine specificities against different PLBP-phospholipid complexes (i.e., ß2GPI/ cardiolipin; endothelial protein C receptor [EPCR]/ lysobisphosphatidic acid [LBPA]; prothrombin [PT]/ phosphatidylserine [PS]) using a multiplexed bead-based assay in individual lupus patients—building a basis for personalized precision therapies, 2) design, express, and functionally characterize our protein-based precision therapeutics targeting anti-ß2GPI B cells, anti-EPCR/LBPA B cells, and anti-PT/PS B cells in vitro, and 3) test the efficacy and safety of leading therapeutics in a humanized mouse model to accelerate early translation of these tailored immunotherapies.

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