Why has the, has the world woken up, particularly in the last 5 or 10 years, and, uh, specifically, how did we get to Neveuan? So, uh, 12 years ago, uh, we saw the early development of checkpoints, and all of a sudden the world that had been, uh, largely in my estimation, addicted to cancer biology, using conventional cytotoxics or the more recent targeted agents could now Uh, be convinced for real cancers, not ones on the side like melanoma and kidney cancer that respond to die too. But now you can see responses not only in those diseases, but also in lung cancer and bladder cancer andpatocellular cancer, and gastric cancer. And so all of a sudden, the um world woke up to the fact that cancer was not just a disease of the cancer cell, but also a disease of the host response and that uh by focusing solely on the tumor cell, you are leaving out an awful lot of biology, and particularly ones that could be curative in patients for very common diseases like lung cancer, which arguably is still one of the biggest killers. Of cancer patients in the uh in the world. So much of the world looking for alternatives either look for additional checkpoints like Lag 3, Tim 3, Tidge. To develop uh uh blocking antibodies too, or to develop uh strategies using novel, um, Uh, ADCs or by specific antibodies that would directly or indirectly target these molecules, ultimately culminating on a centrally important molecule, CD28, the second signal in T cell signaling requisite for most T-cell biology. But also started going back and said, well, maybe we were premature and giving up on these novel I dos. Are there alternative ways to do it? Um, so as I understand the story for Nimba Lukin, Uh, is that they had acquired uh at Al Kreme's the parent company, a protein engineering company. Uh, which had, uh, in part in developing novel strategies to try and develop protein therapeutics. And one of the uh strategies is this uh circularization, annealing the aminothermis and the carboxyterminus, and then opening up the molecule in another site that would allow it to maintain some aspects of the original biology, but perhaps acquire new aspects or get rid of uh some aspects. And I think they were quite clever actually, in retrospect. Um, and that they, uh, Use a system which apparently is not unique to the clever uh protein engineers who developed the strategy, but apparently it is fairly common throughout the normal plant biology. I just learned this. And furthermore, that the um Uh, that they decided to really prevent the IL2 from interacting with the IL2 receptor alpha chain based on known biology to try and edit out any potential cryptic sites that might be possible to have the IL to bind to on immune effectors like T cells, B cells, and NK cells, is they introduced the L2 receptor alpha chain directly into The IO2 receptor. Alpha binding site of bile 2. I haven't said That that was a clever idea. I can only claim that it was clever because of its utility, and it's for the first time that I'm aware of that an outpatient regimen of IL2. Could be administered uh safely and get single agent activity. Uh, that doesn't preclude it being combined with things like checkpoints, which, uh, uh, I know they're actively doing. Uh, but it says it, it, it checks a box for me in any drug development that if you don't see single agent activity, the likelihood of seeing activity, in my estimation, in combination with checkpoints or other agents is quite small. Um, The other thing I should mention is that Uh, their internal dialogue, uh, in their so-called artistry studies and their Picasso program was the idea of converting a normal face of a molecule like IL2 into one very much Picasso-like with uh ears or eyes or mouth or nose distorted in a way where it fundamentally changed the appearance of the molecule and When I was talking with them recently, I cautioned them. I said, well you should really do is flip that analogy and say you took a molecule. Which, uh, Um, Was gobbled up by Tregs, now no longer expands those cells and causes uh much of the toxicity you see with high dose I too, but converts a rather deformed and, uh, anatomically incorrect face to one that is quite pleasing. Uh, and I think when I shared that they were. Uh, pleased with that, uh, change in analogy, but I think it goes deeper than that. I think it's possible given that if you step back from cytokine biology, uh, many of these cytokines have synergistic or antagonistic or uh functionalities. Uh, they, um, Uh, are overlapping, uh, as well, where the same, uh, cytokine can have the same function as another cytokine, or the same cytokine can have what's called pleotropy, the ability to have many different functionalities. And I think we should allow the opportunity that by diverting from natural protein structure of IL2, that they fundamentally created a new structure. With new biology, uh, but interacting with differentially with a disparate set of receptors on, uh, different. Um, Uh, immune cells.
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