Descartes-08 transiently targets BCMA to precisely recalibrate autoimmune reactivity in Myasthenia Gravis in a randomized, controlled Phase 2b trial

Topic:

Translational Research

Poster Number: 215 M

Author(s):

Renee Fedak, PhD, Cartesian Therapeutics, Rachel Ruggerie, Cartesian Therapeutics, Andrew Stewart, PhD, Cartesian Therapeutics, Christopher Jewell, PhD, Cartesian Therapeutics, Miloš Miljković, MD, Cartesian Therapeutics, Eva Rybak, PharmD, Cartesian Therapeutics, Hafsa Kamboh, MD, Cartesian Therapeutics, Tuan Vu, MD, University of South Florida, James F. Howard Jr., MD, University of North Carolina, Hacer Durmuş, MD, Istanbul University, Tahseen Mozaffar, MD, University of California, Irvine, Aaron Bodansky, MD, University of California San Francisco, Joseph DeRisi, PhD, University of California San Francisco, Mark Anderson, MD, PhD, University of California San Francisco, Samantha Garcia, University of California San Francisco, David Yu, University of California San Francisco, Kelsey Zorn, University of California San Francisco

Chimeric antigen receptor (CAR) T cell therapies could revolutionize treatment for autoimmune disease by resetting the immune system. However, adoption is limited by challenges that include in-patient treatment, a need for lymphodepletion, and safety risks such as off-target toxicity, CRS, ICANS, and non-specific immunosuppression. mRNA-based cell therapy offers a promising strategy to overcome these limitations. Descartes-08 is a mRNA-engineered cell therapy in which cells transiently express a CAR targeting B cell maturation antigen (BCMA). This antigen is predominantly expressed on a rare group of cells, primarily plasma cells (PCs) and plasmacytoid dendritic cells (pDCs), that have a significant role in autoimmune disease pathogenicity. For example, PCs secrete pathogenic autoantibodies, while pDCs produce inflammatory type 1 interferons that exacerbate many autoimmune processes. In a successful randomized, placebo-controlled, Phase 2b trial in generalized myasthenia gravis (MG), most patients treated with Descartes-08 in an outpatient setting and without lymphodepletion achieved durable clinical efficacy. Pharmacological and mechanistic data from this trial support a precision retuning of autoimmunity via transient BCMA targeting that is not associated with non-specific immunosuppression. Comparison of data from active and placebo cohorts revealed Descartes-08, reduced maintenance and activation signals on PCs and pDCs, modified transcriptional profiles, drove unique changes in antibody self-reactivity, and restrained key MG-associated cytokines. These results were achieved without safety concerns or immune suppression, as indicated by maintenance of lymphocyte subsets, immunoglobulins, and vaccine-specific antibodies. Our findings reveal a distinct form of immune system reset, highlighting the ability of anti-BCMA mRNA cell therapy to precisely retune autoreactivity. The study suggests further clinical development could contribute to a safe and accessible strategy for the treatment of autoantibody-driven autoimmune diseases.