For Ichnos Glenmark Innovation, good things come in threes. The alliance between Ichnos Sciences and Glenmark Pharmaceuticals has developed a trispecific, T-cell activating antibody that shrank multiple myeloma tumors in mice and killed cancer cells in human tissue more effectively than Johnson & Johnson's Tecvayli.
The results were published in Nature Cancer on Sept. 11. The drug candidate, ISB 2001, is now in a phase 1 clinical trial.
“This is our lead asset, so it's important for us as not only our contribution to the myeloma therapeutic space, but also it's an opportunity to demonstrate the value of our platform,” IGI President and CEO Cyril Konto, M.D., told Fierce Biotech in an interview.
That platform, called BEAT (Bispecific Engagement by Antibodies based on the T Cell Receptor), enabled the team to attach binding sites for a T cell surface protein called CD3 onto an antibody heavy chain that also had a binding site for B-cell maturation antigen (BCMA), a known target on multiple myeloma cancer cells. The other heavy chain of the vaguely Y-shaped antibody targets CD38, another myeloma target.
Binding to all three targets brings the T cell and the tumor together, Konto said. From there, the T cells can attack and kill the cancerous cells.
When pitted against bispecifics such as Janssen's Tecvayli and Bristol Myers Squibb’s candidate alnuctamab in human cell lines, ISB 2001 had a 20-to 260-fold stronger cancer-killing potency. The trispecific also beat Tecvayli at killing tumors taken from multiple myeloma patients.
To further test ISB 2001’s cancer-killing prowess, the researchers grafted human myeloma tumor cells onto mice and treated them with the antibodies. At a 0.1-mg/kg dose, ISB 2001 completely eradicated the tumors of all eight mice; Tecvayli, meanwhile, had no complete regressions and showed 30.8% tumor growth inhibition.
T-cell activators like ISB 2001 run the risk of over-activating the immune cells and sparking cascades of inflammatory cytokines.
“Often, greater potency comes at the cost of more side effects,” Sigrid Ruuls, Ph.D., and Paul Parren, Ph.D., wrote in a Nature Cancer commentary piece on the new study. “Even though ISB 2001 showed greater T cell-mediated cytotoxicity of tumor cells than that of teclistamab and another control CD3xBCMA bispecific, T cell cytokine secretion was not higher. Thus, there could be a larger therapeutic window for ISB 2001 than for other TCEs.”
Ichnos has enrolled about 20 patients in the phase 1 trial so far, Konto said, and the company hopes to present preliminary data in multiple myeloma patients at a conference later this year.
Glenmark, a multinational company with headquarters in India, is the sole backer of IGI. Ichnos was originally spun out of Glenmark in 2019.
IGI has another antibody, a bispecific called ISB 1442, currently in a phase 1/2 trial for relapsed or refractory multiple myeloma. And a small molecule from the Glenmark side of the collaboration targets the T-cell regulator CBL-B, which Konto said could potentially be used in combination with ISB 2001 down the line if all goes well.
“We're bringing the T cell and the tumor all together, and with a small molecule, we could improve the potency of the T cells themselves,” Konto said. “On paper, it looks great.”