Unlocking the Potential of RG6234: A Superior 2:1 GPRC5D-TCB for Multiple Myeloma Therapy

The abstract discusses the development and testing of a new T-cell bispecific antibody (TCB) named RG6234 for treating multiple myeloma (MM), a disease that is challenging to cure due to frequent relapses. The RG6234 TCB is designed to target the GPRC5D protein and has been compared with other TCBs in various clinical models.

The potency of RG6234 was evaluated against MM cell lines with varying levels of GPRC5D expression, showing superior T cell activation and cytokine production. It was particularly effective on cells with low GPRC5D expression.

In an ex vivo model using bone marrow aspirates from newly diagnosed MM patients, RG6234 demonstrated a lower effective dose for plasma cell depletion compared to other TCBs. In a xenograft tumor model in humanized mice, RG6234 was the only TCB that eradicated tumors at all tested doses.

Further studies in an in vivo model showed RG6234's quick action in eliminating MM cells from the bone marrow, with evidence of T cell expansion and activation. The timing of these effects correlated with shifts in T cell populations and cytokine release.

The therapeutic potential of RG6234 was also tested in combination with other drugs. It induced MM plasma cell lysis in all patients tested and showed enhanced effects when combined with daratumumab or pomalidomide. The combination with pomalidomide specifically increased T cell activation and cytokine release.

Finally, the combination of RG6234 with other treatments was tested in mice with established tumors. The combination with daratumumab induced tumor stasis, while the combination with lenalidomide led to tumor regressions, which were associated with an increase in intratumoral T cells.

Overall, the study presents RG6234 as a promising TCB for MM treatment, with potential for synergistic effects when combined with other therapies.