Forimtamig: a potent GPRC5D-targeted bispecific antibody in multiple myeloma
Hafsa Alia, Hiba Hilalb, Maliha Gulc, Maham Asadb, Mohammed Hammad Jaber Amind
- aDepartment of Medicine, Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan
- bDepartment of Medicine, Karachi Medical & Dental College, North Nazimabad, Karachi, Pakistan
- cDepartment of Medicine, Khyber Girls Medical College, Hayatabad, Peshawar, Pakistan
- dDepartment of Medicine, Faculty of Medicine, Alzaiem Alazhari University, Khartoum, Sudan
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Abstract
Multiple myeloma is a malignancy of clonal plasma cells characterized by progressive bone marrow infiltration, commonly presenting with anemia, bone pain, hypercalcemia, and renal dysfunction. T-cell bispecific antibodies (TCBs) have emerged as an effective therapeutic option in relapsed and refractory multiple myeloma, with G-coupled protein receptor, family C, group 5, member D (GPRC5D) representing a promising target due to its high expression in myeloma cells and limited presence in normal tissues. Forimtamig is a next-generation GPRC5D-targeting TCB with a novel 2:1 binding format - bivalently engaging GPRC5D and monovalently binding CD3ε on T cells. This structural advantage enhances avidity, stabilizes immunological synapses, and enables potent T-cell activation and cytotoxicity, even against low-antigen-expressing cells in immunosuppressive bone marrow environments. Preclinical studies show that forimtamig outperforms earlier 1 + 1 TCB formats by 50-200-fold in cell-killing efficiency. When combined with standard agents such as daratumumab, pomalidomide, or cereblon E3 ligase modulatory drugs, forimtamig has shown improved tumor clearance and reduced relapse rates. Its design also minimizes tumor escape by targeting the N-terminal region of GPRC5D. Currently undergoing phase 1 trials, forimtamig is being evaluated both as monotherapy and in combination regimens. Its high potency, favorable safety, and durable immune engagement make it a promising candidate in the evolving treatment landscape of multiple myeloma.
TL;DRForimtamig is a next-generation GPRC5D-targeting TCB with a novel 2:1 binding format that enhances avidity, stabilizes immunological synapses, and enables potent T-cell activation and cytotoxicity, even against low-antigen-expressing cells in immunosuppressive bone marrow environments. (Semantic Scholar)