To address these challenges, our research team is developing next?generation precision immunotherapies that selectively target pathogenic cytokine autoantibodies or their antibody?producing cells. By integrating innovative protein and cellular engineering strategies, our goal is to preserve normal humoral immune function while achieving durable, safe, and effective therapeutic outcomes.
I. Development of a Cytokine Chimeric Autoantibody Receptor (CAAR) Screening Platform
To overcome the limitations of current therapies, we designed T cell–based Chimeric Autoantibody Receptor (CAAR) T cells that can specifically recognize and eliminate autoreactive B cells expressing anti?IFN?γ autoantibody (AIGA) B?cell receptors. By integrating patient?derived autoantibodies, structural information of interferon?gamma (IFN?γ) and its receptor, and a Jurkat NFAT reporter system, we established a comprehensive CAAR screening platform targeting anti?cytokine autoantibodies.
Using this platform, we successfully identified modified IFN?γ variants that lack biological activity but retain autoantibody recognition capacity, leading to the development of IFN?γ CAAR T cells. In vitro and in vivo studies demonstrated that IFN?γ CAAR T cells exhibit high specificity and safety, with no detectable receptor cross?reactivity or Fc?mediated off?target toxicity. Importantly, these cells maintained functionality even under conditions mimicking high circulating AIGA levels.
We further demonstrated that IFN?γ CAAR T cells can be successfully generated from patient?derived autologous T cells and effectively eliminate autoreactive B cells within peripheral blood mononuclear cells. Collectively, these results establish IFN?γ CAAR T cells as a promising therapeutic strategy for AIGA?associated diseases (Peng et al., Science Immunology, 2025).
Notably, this CAAR platform is highly adaptable and can be extended to other anti?cytokine autoantibody–associated diseases, such as those involving anti?GM?CSF or anti–type I interferon autoantibodies, which play critical roles in multiple life?threatening infections and autoimmune conditions. This work provides a strong proof of concept and opens new avenues for immunotherapy targeting cytokine autoantibody–mediated diseases.
II. Enhancing the Clinical Translational Potential of Cytokine CAAR Therapy
While Cytokine CAAR T cells can selectively eliminate autoantibody?producing B cells, high circulating levels of anti?cytokine autoantibodies in patients may bind to CAARs, potentially suppressing function or triggering immune?mediated rejection. Therefore, a major focus of this research direction is to elucidate rejection mechanisms induced by autoantibody binding, including NK cell–mediated antibody?dependent cellular cytotoxicity (ADCC), phagocyte?mediated antibody?dependent cellular phagocytosis (ADCP), and complement?dependent cytotoxicity (CDC).
Based on mechanistic insights, we are developing strategies to mitigate these immune rejection pathways, such as mimicking viral immune?evasion mechanisms, incorporating “don’t?eat?me” signals to prevent phagocytosis, or introducing complement?inhibitory proteins. These approaches are being integrated into Cytokine CAAR T cells to enhance their in vivo persistence and durability.
In parallel, we are developing in vivo Cytokine CAAR T?cell generation platforms, including lipid nanoparticle (LNP) systems encapsulating CAAR?encoding mRNA with T?cell–targeting antibodies on the particle surface, as well as T?cell?tropic lentiviral vectors for direct in vivo T?cell engineering. These approaches aim to significantly reduce manufacturing costs and accelerate the clinical translation of Cytokine CAAR therapies.
Beyond T cells, we are extending the CAAR strategy to other immune effector cells. For example, macrophages, which possess strong phagocytic and immune complex–clearing capabilities, may be particularly suitable for treating anti?GM?CSF autoantibody–mediated pulmonary alveolar proteinosis (PAP). By matching optimal effector cells to specific disease characteristics, we aim to establish a flexible and versatile CAAR effector cell platform.
III. Development of Anti?Cytokine Autoantibody Degraders
To selectively eliminate pathogenic cytokine autoantibodies, we are developing anti?cytokine autoantibody degraders. These molecules use engineered cytokine fragments as decoys to capture disease?causing autoantibodies and redirect them to lysosomal degradation pathways via specific receptors such as IGF2R or ASGPR.
Unlike FcRn inhibitors that broadly suppress IgG recycling, this strategy enables selective removal of target autoantibodies, minimizing global immunosuppression and infection risk. Anti?cytokine autoantibody degraders therefore represent a precise and safer therapeutic modality for autoantibody?mediated diseases.
IV. Identification of Novel Therapeutic Targets in Anti?Cytokine Autoantibody Diseases
Beyond autoreactive B cells, other pathogenic immune populations—including autoreactive T follicular helper (Tfh) cells and long?lived plasma cells—remain difficult to identify and target. Their roles in disease initiation, tissue localization, and interactions with other immune cells remain poorly understood.
Our goal is to develop strategies to label, track, and functionally characterize these cells, enabling deeper insights into disease networks. Through systematic analysis, we aim to uncover novel, druggable molecular targets and open new therapeutic avenues for diseases driven by anti?cytokine autoantibodies.