STR3/19

The lead candidate STR3/19 is a B cell targeting in vivo CAR-T and a frontrunner to validate the technology platform within the field. The candidate is intended for treatment of B cell dependent autoimmune disease.

Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have relatively low clinical efficacy in autoimmune disease, probably due to the persistence of autoreactive B cells in inflamed organs. Autologous ex vivo CAR-T therapy directed against CD19 on B cells has been shown to induce rapid and sustained depletion of circulating B cells, as well as complete clinical remission of refractory SLE (Muller et al 2024). LNP-based in vivo CAR-T therapy is an off-the-shelf alternative to current CAR-T options, with the potential to be equally effective without the need for lengthy and costly personalized production and without the need for chemotherapy-induced immunodepletion. While several lentiviral platforms for generation of in vivo CAR-Ts are currently under development, an mRNA-based non-viral approach, enabled by targeted LNP delivery to T cells, have many potential advantages in that it does not involve permanent gene modification, is less immunogenic and holds the potential for repeated administration over extended periods of time. While this differentiation may be important even for the treatment of patients with advanced cancer with short expected survival, it is believed to be critical for general uptake of CAR-T therapy within the field of chronic autoimmune disease.

STR3/19 is based on T-cell directed LNPs carrying mRNA for CD19-binding chimeric antigen receptors (CARs). The LNP is affinity-conjugated to a bsAb that binds both to the pTag of the LNP and to CD3 on T cells. The CD19 CAR mRNA is thus delivered to T cells that are subsequently reprogrammed to B-cell targeting in vivo CAR-Ts. STR3/19 is currently in preclinical development.

Figure: STR3/19 is based on two building blocks, an LNP carrying mRNA for a anti-CD19 CAR on the one hand, and a bispecific antibody that binds to the LNP-tag and to CD3. The antibody will deliver the LNP-cargo to T-cells inside the body, which will take up the mRNA and start expressing anti-CD19 CARs. The T cells are thus reprogrammed to seek out and kill CD19-expressing B cells.