Trispecific Killer Cell Engager for the Treatment of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE), the predominant form of the disease, represents a chronic autoimmune disorder characterized by the production of autoantibodies from hyperactive immune cells, along with pervasive inflammation. This immune dysregulation culminates in severe tissue damage to vital organs such as the kidneys, heart, joints, and skin. Despite significant advancements in SLE treatment over the past five decades, encompassing the use of immunosuppressive agents, numerous complications endure, including inflammation, osteoporosis, cardiovascular issues, acute renal failure, and lupus nephritis, perpetuating the burden of disease. To confront these enduring challenges, monoclonal antibodies (mAbs) targeting CD20 or CD19 antigens on B cells, such as rituximab, ocrelizumab, obexelimab, and obinutuzumab have been developed. These mAbs make a “low affinity” immunologic synapse with natural killer (NK) cells and a high affinity connection with B cells, instigating B cell depletion through antibody-dependent cell-mediated cytotoxicity (ADCC). However, the low affinity interaction of mAbs with NK cells poses a critical obstacle, leading to inefficient clearance of B cells, including memory B cells, in peripheral blood and tissues, contributing to rapid disease relapse. To bridge this gap in treatment efficacy, our proof-of-concept investigation endeavors to pioneer a new approach for SLE therapy. The objective of this study is to engineer a Trispecific Killer Cell Engager (TriKE), designed to engage and activate NK cells with high affinity, thereby facilitating efficient clearance of pathogenic immune cells in SLE. To our knowledge, the utilization of "high affinity" NK cell engagers for SLE therapy represents uncharted territory in medical research, signifying a technically innovative strategy. Leveraging our expertise, our laboratory has successfully isolated a unique single-domain antibody with “high affinity” and specificity for the CD16a receptor on NK cells. Capitalizing on this breakthrough, we intend to construct a TriKE that can bind to three target antigens, empowering NK cells to effectively identify and clear pathogenic immune cells. Through rigorous evaluation using peripheral blood from lupus patients, the efficacy of TriKE in eliminating pathogenic immune cells will be meticulously examined. Rituximab and obexelimab will serve as benchmark controls in our comparative analyses. Validation of NK cell activation and subsequent target immune cell death will be achieved through the quantification of NK cell degranulation, along with the release of granzyme B and perforin. In summary, our focus lies in the eradication of autoreactive immune cells. By eliminating these aberrant cells, we aim to offer not just transient symptomatic relief, but the potential for enduring alleviation for a majority of patients and even the possibility of a cure for select individuals. This transformative approach holds promise for revolutionizing the landscape of SLE treatment, offering hope for improved outcomes and enhanced quality of life for those affected by this debilitating condition. Project Number: 1R21AI189372-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Arash Hatefi | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $235,500 | Activity Code: R21 | Study Section: Mechanisms of Autoimmunity Study Section[MAI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18937201