PL2-SN-27 - ADAMTS13-Chimeric Auto-Antigen Receptor (CAAR) T cells To Target Autoreactive B cells As A Treatment For Immune-mediated Thrombotic Thrombocytopenic Purpura

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy characterized by thrombosis due to dysregulated platelet activation. iTTP results from autoantibodies directed against ADAMTS13, a plasma protease that regulates platelet activation via cleavage of von Willebrand Factor (vWF) multimers. Autoantibodies bind to and reduce ADAMTS13 activity resulting in ultralarge-vWF multimers that induce inappropriate platelet activation and microvascular thrombi leading to the clinical features of TTP. Current therapeutic approaches offer transient benefit and comprise daily plasma exchange therapy with or without the addition of anti-CD20 (rituximab) or anti-vWF monoclonal antibodies (caplacizumab). However, relapses are frequent and often accompanied with significant patient morbidity.


Study

Design/Methods: To develop a curative therapy via selective depletion of anti-ADAMTS13 B cells, we generated Chimeric AutoAntibody Receptors (CAARs) employing different combinations of ADAMTS13 domains as extracellular targeting domains.


Results/Findings:

ADAMTS13-CAAR T cells demonstrated efficacy, specificity, and long-term fitness in short- and long-term in vitro assays against Nalm6 target cells expressing a panel of iTTP patient-derived B cell receptors. ADAMTS13-CAAR T cells maintained their cytotoxic activity in the presence of soluble ADAMTS13 autoantibodies and ADAMTS13 autoantigen. In an in vivo murine xenograft model, ADAMTS13-CAAR T cells controlled target Nalm6 cells with potency comparable to the non-selective pan-B cell ablative “gold standard” CD19-directed CAR-T. Lastly, the ability of ADAMTS13-CAARs to target polyclonal patient B cell was indirectly assessed using a patient-plasma adsorption assay. ADAMTS13-CAAR T cells significantly depleted autoantibodies compared to adsorption with control T cells (p < 0.05, t-test).


Conclusions:

In summary, we have successfully generated ADAMTS13-based CAAR T cells that effectively and specifically target B cells expressing anti-ADAMTS13 autoantibodies. This approach has the potential to target autoimmune B cells in iTTP patients with the promise of curative therapy.