ASCO 2024 | The potential of IPH6501, a tetraspecific antibody-based NK cell engager, for NHL

Here at ASCO, we presented the first trial in progress display for a phase one/two open label multicenter trial that’s looking at the safety and tolerability and preliminary anti-tumor activity of a product called IPH6501, which is a first in class NK-cell engager. And we’re testing it in patients with relapsed or refractory CD20-positive non-Hodgkin lymphoma. This drug belongs to the family of NK engagers. The research in the field of NK-cells as a means to, you know, treat hematological malignancies, has been a growing field, first with, chimeric antigen receptor NK-based cell products and also with other modified NK-cell therapeutic, sorry cellular therapeutics. But NK engagers have been a little bit difficult to develop, primarily because, to ensure sustainable and effective NK-mediated cell killing, it really is a hard task.

So this particular product, which we believe is revolutionary in the field, is a tetraspecific antibody-like structure that targets tumor cells through CD20 and engages the NK cells through three different docking sites, so to speak, one is NKp46, one is IL2 receptor, and the other is CD16. By engaging NK-cells through different pathways preclinical data had demonstrated that we’re able to elicit more or more pronounced activation and consequent cell killing. Not only in vitro but also in vivo, experiments had shown that in a dose dependent manner, IPH6501 induced clearance of CD20-positive metastatic lesions in mice in mouse models in a very predictable way.

The other really interesting and exciting aspect of this drug is that there doesn’t seem to be, at least in the preclinical experiments, an increase in the classic toxicities that we’ve been used to seeing for T-cell engaging bispecific antibodies, namely cytokine release syndrome and neurological toxicity. And that’s part of the reason for this is because the types of cytokines that are induced by NK engagement are different than those that are induced by T-cell engagement. And so in the preclinical space, there’s reason to believe that there could be a sort of an uncoupling of activity and toxicity for this very exciting NK engager.

So the study as I mentioned is a phase one/two study. Right now we are in phase one. The study has just began enrolment. The phase one portion consists of a three plus three classic design to determine the maximum tolerated dose. Once the recommended phase two dose will be identified, then we’ll have expansion cohorts in the phase two portion of the trial. There’s a number of dose levels that are being explored, and obviously we will be excited to see at which dose levels we identify the best activity that also has an acceptable safety profile. The study is open internationally, especially in the United States, Australia and France. Other sites may be opening in the future, but we’re very excited to collaborate with colleagues around the world as we discover this first in human NK tetraspecific engager.