Dual-Targeted ISB 2001: A Trispecific Approach to Combat Treatment Escape in Multiple Myeloma

Recent advances have led to the development of innovative treatments for multiple myeloma (MM), focusing on antigens like CD38 and BCMA. Despite the effectiveness of CAR T-cell therapies and bispecific antibodies, achieving long-term remission remains challenging, with progression-free survival (PFS) rates dropping below 40% after two years of treatment with certain drugs. One hypothesis suggests that the relapse may be due to a decrease in target antigen expression or the growth of MM cells with insufficient target expression. This phenomenon has been observed post-treatment with daratumumab and BCMA-specific CAR T-cells.

A novel trispecific molecule, ISB 2001, has been designed to address this issue by simultaneously engaging BCMA and CD38, using the TREAT technology. This molecule is unique in that it targets CD3 on T-cells and both BCMA and CD38 on MM cells, with its binding arms derived from a synthetic phage display library and featuring a modified Fc region to minimize immune cell interactions.

In vitro studies have shown that ISB 2001 significantly enhances binding to MM cells with low antigen expression, demonstrating superior potency with an EC50 ranging from 0.4 to 1.2 pM, which is considerably better than a BCMA-targeted T-cell engager. It also shows robust activity against tumor cells in the presence of soluble BCMA or APRIL.

Importantly, ISB 2001 has been shown to activate T-cells and induce cytokine secretion only in the presence of tumor cells, suggesting minimal off-tumor activity. This was confirmed by its low binding to T-cells and negligible binding to healthy circulating CD38+ BCMA- cells.

Preclinical studies indicate that ISB 2001 has a half-life of 7 days and can induce tumor regression at doses as low as 0.02 mg/kg in a therapeutic PBMC-humanized mouse model. The in vivo efficacy was linked to T-cell infiltration and activation at the tumor site without systemic effects.

The data presented suggest that ISB 2001 holds promise as a potent MM treatment through its dual targeting approach, offering potential benefits for patients with relapsed/refractory MM who may have developed resistance through antigen downregulation. Preparations for a Phase 1 clinical trial are currently underway.