Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma
However, patients who become refractory to these therapies have a very poor outcome. This underscores the need for additional targets for immunotherapy in MM. GPRC5D, an orphan G-protein coupled receptor, is such a promising novel target.
We assessed GPRC5D cell surface protein expression levels and mRNA expression levels in bone marrow (BM) samples derived from MM patients and healthy donors, using flow cytometry and gene expression profiling, respectively. Furthermore, we evaluated the activity of the new GPRC5D-targeting, T-cell redirecting bispecific antibody talquetamab against MM cell lines and in fully autologous MM patient-derived BM samples, containing not only tumor and effector cells, but also immunosuppressing cells.
Expression levels of GPRC5D are significantly higher on MM cells, compared to normal plasma cells or other immune cells. Talquetamab effectively kills GPRC5D MM cell lines in the presence of T-cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in BM samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T-cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with BM stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated MM cell lysis in an additive fashion.
In conclusion, we show that GPRC5D is promising novel target for MM immunotherapy with the T-cell redirecting bispecific antibody talquetamab. These results provide the preclinical rationale for an ongoing phase 1 study with talquetamab in relapsed/refractory MM.