ASH 2024 | The first results of ISB 2001, a BCMAxCD38xCD3 targeting trispecific antibody, in R/R myeloma

At this ASH annual meeting I had the privilege of presenting the first results of a Phase I study of ISB 2001. ISB 2001 is a groundbreaking, first-of-its-kind tri-specific antibody that is designed to treat multiple myeloma. Unlike the traditional bispecific antibody or even CAR T-cells that target one marker on the myeloma cells, ISB 2001 targets two markers, BCMA and CD38 on the myeloma cells, and activates the T-cells by binding to CD3. And this approach directs the T-cells to target and kill the myeloma cells more precisely. And the design of the molecule is in a way such that it minimizes the effect on healthy cells, so overall resulting in a safer and more targeted cancer cell killing. 

The study of ISB 2001 is a Phase I study aimed at finding the optimal dose. And to qualify for the study, patients must have had relapsed/refractory multiple myeloma and have exhausted all prior lines of therapy or available therapy, including three drug classes: the immunomodulatory drugs, the proteasome inhibitors, and the anti-CD38 monoclonal antibody. The study was designed to look at nine dose levels of ISB 2001, and thus far we have completed exploring dose level 7 in 20 patients. 

What was remarkable was that we found people responding at very low doses, as low as dose level 3, which was 50 micrograms per kilogram. And amongst those who received this dose or higher, we found that 83% of the patients responded, and 73% of the patients had a VGPR, that’s a 90% reduction in the myeloma burden. 22% of patients had a complete remission, and even one patient had a minimal residual disease negativity, which is quite profound for this early-phase study. 

Encouragingly, the response was quite durable, in that some patients responded beyond nine months, and what was more important was that ISB 2001 can induce a response in many patients who have had prior T-cell redirection therapy, including CAR T-cells and bispecific antibodies. 

The safety profile of ISB 2001 was quite favorable, in that there were no side effects that led to death or treatment discontinuation. And remarkably, the infection rate was quite low. Severe infections only occurred in three patients, which again is quite remarkable for this type of immune therapy. Cytokine release syndrome, which is quite common for this type of immune therapy, occurred in 75% of patients, but the majority were mild, Grade 1. Only two patients had grade 2 CRS, but one was doubtful because it occurred quite late and coincided with the diagnosis of COVID-19 infection. The treatment was quite simple, we used tocilizumab and low-dose dexamethasone, which are common treatments for these types of issues, but only half of the patients required that treatment. 

So overall, I think the early findings of ISB 2001 in this first-in-human study are amongst the most promising I’ve seen in this group of heavily pre-treated patients, and I think that ISB 2001 has the potential to transform the outcome and treatment of patients with multiple myeloma who’ve exhausted all lines of therapy.

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