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ASH 2024 | First-in-human Phase I Study of SAR442257, a tri-specific antibody, in R/R multiple myeloma and NHL
Fredrik Schjesvold, MD, PhD, Oslo University Hospital, Oslo, Norway, comments on the development and Phase I testing (NCT04401020) of a tri-specific antibody targeting both T-cells and myeloma cells, with a dual target on T-cells (CD3 and CD28) and a single target on myeloma cells (CD38). Although the study showed some responses, the high rate of viral infections and reactivations due to the aggressive activation of T-cells led to the drug’s development being stopped. This study highlights the challenges of this novel therapeutic strategy for multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This interview took place at the 66th ASH Annual Meeting and Exposition, held in San Diego, CA.
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Transcript (AI-generated)
Yeah, this is a poster I’m presenting at this Congress. This was a quite a novel product. It’s based on the bi-specific principle where you target both T-cells and myeloma cells. It’s been a major success with bi-specifics with BCMA, which are now on the market and in studies in earlier lines. But this was an attempt to make that T-cell efficacy even higher, even more potent...
Yeah, this is a poster I’m presenting at this Congress. This was a quite a novel product. It’s based on the bi-specific principle where you target both T-cells and myeloma cells. It’s been a major success with bi-specifics with BCMA, which are now on the market and in studies in earlier lines. But this was an attempt to make that T-cell efficacy even higher, even more potent. So the target on the T-cells were two, so it’s both CD3, which is standard, but also CD28, which is sort of the second signal, so increases the efficacy or the activation of the T-cells more. On the other hand, it was not BCMA they used, they used CD38 to target myeloma cells.
So all together, this was a Phase I trial, it was monotherapy, late-line patients exposed to most other drugs. And the study wasn’t a great success. We had some responses, but not many. So probably CD38 is maybe not such a good target for this therapy. We haven’t seen so many others, even though there are coming some tri-specific, including CD38.
But I think the main problem was actually on the safety side, because the very aggressive activation of T-cells with two markers or two targets on the T-cells led to many viral infections, CMV reactivations, EBV reactivations. So in the end, this was too toxic, too many patients had to stop. And since the responses weren’t that great, in the end, the development of this drug was stopped. But I think it’s immunologically really interesting because it’s the first example of double targeting T-cells in a sort of bispecific setting. And seeing that that’s too much, even with a really efficacious target on the other side, this would lead to too much viral reactivation and viral disease. So we presented and published it later mainly for this effect to sort of visualize and demonstrate how this principle, what the problems were with this principle.
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