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Preclinical data support in-human studies of CD38 T-cell engager ISB 1342 for RRMM
ISB 1342 is a bispecific antibody that simultaneously targets CD38 and CD3 on multiple myeloma (MM) and T cells, respectively. Created using bispecific engagement by antibodies based on T-cell receptor (BEAT®) technology, ISB 1342 was designed to demonstrate low immunogenicity and binds to an alternative epitope on CD38 to daratumumab1. Previously known as GBR 1342, the agent received orphan drug designation in 2019 for the treatment of relapsed/refractory MM (RRMM), in the hope to overcome resistance to daratumumab.
At the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Marie-Agnès Doucey presented preclinical data surrounding ISB 1342 for the treatment of RRMM.1 The topline findings from across the preclinical studies are summarized below:
- ISB 1342 demonstrated higher in vitro potency towards MM cells compared with daratumumab, irrespective of CD38 expression.
- Potency of ISB 1342 was sustained when applied in combination with daratumumab and soluble CD38 in MM cell models.
- The killing potential of ISB 1342 was not significantly impacted in vitro following addition of dexamethasone, suggesting that the agent could maintain potency if administered alongside glucocorticoids.
- CD38+ T-cell fratricide was not detected following treatment with ISB 1342, indicating high specificity for CD38+ MM cells.
- ISB 1342 exhibited higher in vivo potency compared with daratumumab, demonstrating full tumor control in mice xenograft models.
- ISB 1342 administration in mice MM xenograft models resulted in elevated levels of cytokines and immune effector molecules, such as granzyme A and B, TNF-α, and CXCL10 within the tumor microenvironment.
ISB 1342 represents a promising agent for the treatment of patients with RRMM, demonstrating encouraging in vitro potency and in vivo efficacy. Data from preclinical studies support the ongoing clinical evaluation of the T-cell engager: ISB 1342 is currently being evaluated in a phase I dose-escalation study (NCT03309111) in triple-class exposed/refractory patients,2 which represent a current unmet medical need.
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