Trispecific Antibody from Ichnos Glenmark Outperforms J&J's Tecvayli in Treating Mouse Multiple Myeloma

Ichnos Glenmark Innovation has achieved a significant milestone with its latest development. The collaboration between Ichnos Sciences and Glenmark Pharmaceuticals has produced a trispecific, T-cell activating antibody known as ISB 2001. This antibody has demonstrated remarkable efficacy in shrinking multiple myeloma tumors in mice and killing cancer cells in human tissues more effectively than Johnson & Johnson’s Tecvayli. The findings were published in Nature Cancer on September 11th, and ISB 2001 is currently undergoing a phase 1 clinical trial.

IGI President and CEO Cyril Konto, M.D., emphasizes the importance of ISB 2001, describing it not only as a key contribution to multiple myeloma therapeutics but also as an opportunity to showcase the innovative potential of their BEAT (Bispecific Engagement by Antibodies based on the T Cell Receptor) platform. This technology allows the attachment of binding sites for a T cell surface protein called CD3 to an antibody heavy chain that also binds to B-cell maturation antigen (BCMA), a recognized target on multiple myeloma cells. The other heavy chain of the antibody targets CD38, another myeloma-specific marker. By binding to all three targets, the antibody brings T cells and tumor cells into close proximity, enabling T cells to eliminate the cancerous cells effectively.

In comparative studies using human cell lines, ISB 2001 demonstrated a 20- to 260-fold stronger cancer-killing potency than Johnson & Johnson’s Tecvayli and Bristol Myers Squibb’s candidate alnuctamab. Furthermore, ISB 2001 outperformed Tecvayli in killing tumors extracted from multiple myeloma patients.

The researchers also tested ISB 2001’s efficacy in mice grafted with human myeloma tumor cells. At a 0.1 mg/kg dose, ISB 2001 completely eradicated tumors in all eight mice, whereas Tecvayli showed no complete regressions and only a 30.8% tumor growth inhibition.

Despite the promise of T-cell activators like ISB 2001, there is a concern about over-activating the immune cells, which can lead to inflammatory cytokine cascades. However, Sigrid Ruuls, Ph.D., and Paul Parren, Ph.D., noted in a Nature Cancer commentary that ISB 2001’s greater T cell-mediated cytotoxicity did not result in higher T cell cytokine secretion, suggesting a potentially larger therapeutic window for ISB 2001 compared to other T-cell engagers (TCEs).

Currently, about 20 patients have been enrolled in the phase 1 trial of ISB 2001, and the company aims to present preliminary data on multiple myeloma patients at a conference later this year.

Glenmark Pharmaceuticals, headquartered in India, is the sole financial supporter of IGI. Ichnos Sciences was spun out of Glenmark in 2019. In addition to ISB 2001, IGI is also developing another antibody, a bispecific called ISB 1442, which is in a phase 1/2 trial for relapsed or refractory multiple myeloma. Additionally, a small molecule from the Glenmark side of the collaboration aims to target the T-cell regulator CBL-B. Konto mentioned that this molecule could potentially be used in combination with ISB 2001 to further enhance T cell potency if future developments are favorable.

Konto envisions combining their current antibody technologies with small molecules to enhance the effectiveness of T cells against tumors. “We’re bringing the T cell and the tumor together, and with a small molecule, we could improve the potency of the T cells themselves,” Konto remarked. “On paper, it looks great.”