Dual targeting of BCMA and GPRC5D with the trispecific antibody ramantamig addresses antigenic heterogeneity in myeloma

Abstract Despite advances in terms of bispecific antibodies (BsAbs) targeting single tumor‐associated antigens in multiple myeloma (MM), not all patients respond, and most eventually relapse. Using flow cytometry, we found that BCMA and GPRC5D expression is highly heterogeneous within and between patients. Dual targeting with ramantamig (JNJ‐79635322), a trispecific antibody targeting both BCMA and GPRC5D on the tumor cell surface, has been hypothesized to improve efficacy by overcoming heterogeneous target expression and preventing resistance due to antigen escape. Using T‐cells from healthy donors, ramantamig was significantly more effective than mono‐targeting antibodies against BCMA + GPRC5D + MM cell lines, and also efficiently eliminated single antigen‐positive MM cell lines. Additionally, ramantamig effectively induced MM cell lysis in 32 BM samples from MM patients (mean lysis with 0.4 nM: 60%), demonstrating superior cytotoxic activity compared to BCMA‐ and GPRC5D‐mono‐targeting BsAbs (13% and 5%, respectively). There was no difference in ramantamig‐mediated lysis of MM cells from newly diagnosed or heavily pretreated, BsAb‐naïve patients. Importantly, tumor cell target expression was an important determinant of ex vivo response, shown by superior MM cell lysis in samples with higher than median baseline proportion of GPRC5D/BCMA double‐antigen‐positive MM cells, when compared to lower GPRC5D/BCMA expression. Notably, ramantamig potency was less affected by the presence of soluble BCMA, compared to the BCMA‐mono‐targeting control antibody. Finally, ramantamig showed superior potency, compared to the combination of two single‐targeted BsAbs, probably due to higher avidity against heterogeneous targets. In conclusion, dual‐antigen targeting with ramantamig represents a significant advancement in overcoming tumor heterogeneity and preventing antigen escape‐mediated resistance.