Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma
Schmidts A, Ormhøj M, Choi BD, Taylor AO, Bouffard AA, Scarfò I, Larson RC, Frigault MJ, Gallagher K, Castano AP, Riley LS, Cabral ML, Boroughs AC, Velasco Cárdenas RM, Schamel W, Zhou J, Mackay S, Tai YT, Anderson KC, Maus MV.
One aim of the Excellence Cluster is to use synthetic biology approaches to re-wire signaling processes. One prime example are chimeric antigen receptors (CARs) that when expressed in T cells recognise tumour cells and subsequently lead to the activation of the T cells, in order to kill the tumour cell. CAR T cells have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CAR therapy of MM to date, but not all remissions are sustained, due to the emergence of BCMA escape variants. Thus, there is a clinical need for the improvement of CAR therapies for MM. In this publication we teamed up with the group of Marcela Maus at Harvard Medical school, to show that a novel trimeric APRIL-based CAR efficiently targets MM even in the absence of BCMA expression. APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and TACI. However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to best trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CAR T cell activity against MM in vitro and in vivo in a mouse model. Thus, dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.
