GPRC5D overexpression

Compared with blank control group and negative control group, the siGPRC5D-AS1 group showed a significant decrease in the relative expression of lncRNA GPRC5D-AS1 (P<0.05), a significant increase in the number of proliferating cells and migrating cells (P<0.05), a significant increase in the tumor volume of nude mice (P<0.05), a significant increase in β-catenin, Ki67, PCNA and N-cadherin protein expression (P<0.05), and a significant decrease in E-cadherin protein expression (P<0.05); conversely, these results were opposite for the eGPRC5D-AS1 group. Silencing the expression of lncRNA GPRC5D-AS1 can enhance the proliferation, invasion, and migration ability of renal cancer cell line 786-0, which can be weakened by the overexpression of lncRNA GPRC5D-AS1.

GPRC5D, FcRH5 and BCMA are highly prevalent across MM patient subgroups, including high-risk patients who may warrant targeted therapy approaches. Based on our data and previously published work for FcRH5- and BCMA-targeted T-cell bispecifics (Sumiyoshi et al. EHA 2021; Cortes-Selva et al.

And the cytotoxicity was much stronger than that of BCMA-CD3 (Teclistamab analogue) and/or GPRC5D-CD3 (Talquetamab analogue) treatments. We have developed a novel dual-targeted T cell engager for MM treatment, which showed strong tumor killing effect in in vitro and in vivo models with low CRS risk. The toleration of high dosage in cynomolgus suggested the good safety performance. Above all, the preclinical study illustrated SCR-8572 can be a promising therapeutic candidate in treatment of MM patients.

Biomarker analysis indicates that RG6234 leads to T-cell engagement in the BM of patients with RRMM and demonstrates rapid and effective T-cell mediated anti-myeloma activity irrespective of the route of administration. Cytokine release, T-cell activation followed by BM infiltration, and MM cell depletion are early PD changes after IV and SC administration and precede clinical responses. Compared with IV dosing, SC administration reduces peak cytokine levels in Cycle 1, suggesting a more subtle immune activation and a potential safety benefit for patients.

Moreover, LM-305 showed good safety profile in the animal studies. In conclusion, this preclinical data suggested that LM-305 is a novel GPRC5D targeting ADC with best-in-class potential, and therefore it can be a promising therapeutic candidate for the treatment of RRMM patients expressing GPRC5D.

Compared to the GPRC5D antibody in clinical (JNJ-64407564), this antibody has a higher affinity to 293T cells overexpressing GPRC5D (EC50=1.9nM vs. 3nM), MM cell lines, and MM patient samples...At last, MM patient bone marrow samples cultured in vitro with this bispecific antibody increased cell death of the CD138+ population. In summary, the GPRC5D antibody could efficiently target Multiple myeloma tumor cells.