The binding of PD-1 increases VEGF by fourfold, and the binding of VEGF increases PD-1 binding by 18-fold. And so theoretically, what you’re going to have is the tightest binding in a location where both antigens exist, which is a tumor microenvironment. Now the other thing to think about is that ivonescimab is a tetravalent molecule, so it has two binding sites for PD-1 and 2 binding sites for a VEGF. VEGF is a secreted dimer by the tumors. And because of that, it can lead to potential cross-linking of two ivonescimab molecules and actually multiple ivonescimab molecules. This is well described in the literature for bevacizumab, and we believe the same thing is happening for ivonescimab. And that actually leads to a possibility of an increased avidity.
So there’s affinity, the tighter binding between the cooperative binding, but then there’s a possibility for avidity as well. So the easiest way to think about this is if you think about one hand holding a handle bar with a tight grip, using two hands to hold that sort of bar with both hands, that’s the avidity phenomena. So there’s a tighter binding for affinity and a tighter binding for avidity as well. And so we believe that this will have important differences in giving — as opposed to giving both of these agents separately and the clinical data seems to support that. And we’re moving very aggressively forward.
Dave Gancarz: Thank you, Allen. And I think you’ve mainly addressed this. And then another question with respect to how does this differentiate from just a PD-1 agent on its own. So a lot of approved PD-1 agents to exist pembrolizumab, durvalumab. If you can just kind of speak to a little bit of the difference there in terms of how it works.
Dr. Allen Yang: Yes, so I thought I’d described that pretty well. But if you want more detail. We could talk about the three-hour answers, I’ll try to get the 30-second answer here. Maybe focusing on the MOA, where we have both an affinity and avidity sort of phenomenon playing on with ivonescimab, we’ve been moving very aggressively based on the clinical trial data. If you look at all the PD-1s and less so the PD-L1s out there, they’ve pretty much done the same thing. They’ve gone into non-small cell lung cancer, they compare themselves to chemotherapy. We believe that ivonescimab is superior to PD-1 and PD-L1 therapy, okay? To prove that there are four Phase IIIs running two global ones that are being conducted by Summit and then two Chinese specific studies that are being run by Akeso.
The partnerships, you’ve heard about the HARMONi and HARMONi-3 and EGFR progressors and frontline squamous non-small cell lung cancer. These are ones we’re conducting globally with our partners, Akeso, in China, but Akeso actually has, as Dave alluded to, a treasure trove of data across multiple different tumor types. And they’ve advanced into two additional Phase III that are China specific. One is called the 306 study, which is a frontline squamous cell non-small cell lung cancer against tislelizumab with BeiGene PD-1 for their markets. So it’s a Chinese-specific squamous cell frontline study, but they’re also running a frontline study of monotherapy ivonescimab against pembrolizumab in frontline non-small cell lung cancer. So if you look at the four studies we’re conducting, three of them are against PD-1, and 2 of them are specifically against pembrolizumab or KEYTRUDA.
So we are going to sort of differentiate this molecule from PD-1s dramatically by clinical data.
Dave Gancarz: Thank you, Allen. Really appreciate that. And so that concludes the list of questions that we have received today. So I do want to thank everyone very much for attending this morning’s earnings call. As I mentioned earlier, an archived version of the webcast will be available on our website, www.smmttx.com. And I’d like to thank you, and wish you all a great day.
Operator: And this concludes today’s conference call. Thank you for your participation. You may now disconnect.
