So let's start um with uh discussing Nimbaleukin and then potentially talking about uh some of the surprising, I believe surprising uh effects from the preliminary studies. So nimbaleukin is a circularly permuted cytokine, uh, that mimics IL-2, uh, but uh is differentiated from it in a couple of important ways. One is It uh has a fused amino. And carboxyterminus, uh, with a break in this circular molecule now. Um, at a site adjacent to where IO2, uh, binds one of the three chains of the IO2 receptors, specifically the IL 2 receptor alpha chain. And the uh Scientists at uh And now neural, um, uh, inserted the recombinant IO2 receptor alpha chain at that site which would normally bind. Uh, to that end, they have a molecule now that binds apparently solely uh the beta and gamma chain of the IL2 receptor, uh, recognizing that the alpha chain uh is expressed both on activated. Uh, T cells, but also on at high affinity, uh, with high affinity IL2 receptors on the regulatory cells. Um, the, the physiological observation following adaptive or following administration, uh, is quite interesting. What they found is that uh not only could, uh, nimvolleukin be given safely and effectively as an outpatient regimen, uh, but also, uh, Yeah. Uh, at the regimens that they employed at, we're able to see single agent activity, uh, which has been difficult to see in patients with conventional melanoma, much less, uh, a tough melanoma, uh, cadre, um, uh, mucosal melanoma. In this instance, uh, Nimbalekin is Um, um. Demonstrating 3 very surprising and differentiating uh biologic behaviors. One is that it can have any anti-tumor effects in melanoma as an outpatient regimen. The second is that unlike uh high dose IO2 regimens which conventionally are associated with uh a marked increase in Tregs, uh, this is not observed. With administration of Nembalein. And then surprisingly, uh, to me at least, uh, uh, a decrease in neutrophil. Counts in the blood are observed, where that becomes the predominant population in patients getting conventional high dose CO2. This suggests to me, uh, especially given Uh, the widespread expression of the third chain of the IL 2 receptor, the common gamma chain of the IL 2 receptor, which is uh utilized not only by aisle 2, but also by aisle 4, aisle 7, aisle 9, aisle 15, and aisle 21, that um That we should approach nimbaleukin, especially given its clinical differentiating activities, uh, not as a IL2 mimic, but as something quite different that's soliciting very different biology, perhaps borrowing activities from some of the other uh T cell growth factors that I just mentioned, 479, 15, and 21. In addition, Um, the, uh, Um. Ability not to see increase in Tregs is quite interesting. If you look at the data so far, I would say that there are Uh, 3 pieces of data that would suggest that not stimulating T-rex is a good idea. Uh, and those 3 pieces of data are #1, uh, the requirement for high doses of IL-2 in the setting of melanoma, uh, which is one of the two indications for which it's been approved, um, to be used by the FDA, um. Uh, you can get away with lower doses of IL-2 in patients with kidney cancer, but with a lower response rate, but at least you can see some responses. You don't see that in patients with melanoma, only high dose IL2 and now nimbaleukin are associated with responses in patients with melanoma. And this suggests to me that the presence of T. regs in melanoma are limiting the ability. Of IL-2 to mediate important effects until you get to doses higher than the endogenous T-rexs can consume the IL 2. The second piece of data, uh, which was controversial for quite a long while, but is now, I believe, increasingly believed by people in the field, is that the application of the first checkpoint. Uh, blockade, which was antibodies to CTLA4 was originally said to be uh not targeting Tregs which do. Uh, express this molecule, but rather, To be enhancing CDHs and uh conventional CD4 factors. But in actual fact, more recent data suggests both in the mouse and human that uh blocking antibodies to CTLA4 are effective in limiting um the reg functional activity in some instances causing their depletion. And then I think very recent data now being reported by a number of companies including Za Pharmaceuticals, is the targeting of Tregs uh by using an antibody to CCRA, which is important in their biology and their migration, uh, has been in early studies. Uh, wants to keep an eye on are associated with some evidence of anti-tumor effects. So I think those are the three best pieces of data that we have right now. Uh, the T. regs are important in the biology of cancer and, uh, and in melanoma in particular.
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