An Interview with Lewis Gruber of SIWA Therapeutics

SIWA Therapeutics is one of the few senolytics biotech companies founded prior to the past few years, invigorated with new funding now that the clearance of senescent cells as a basis for rejuvenation is an area of intense interest for the research and development community. The company is also, I believe, running the only senolytics program based the use of monoclonal antibodies. This is a way to encourage the immune system to destroy cells bearing specific surface markers, in this case a form of advanced glycation endproduct that is found on cancerous, senescent, and otherwise dysfunctional cells.

Many of our readers are familiar with CAR-T immunotherapy, which has enjoyed some success, but it's not without considerable challenges. How does your approach differ?

We are using a simpler approach of just manufacturing a monoclonal antibody. Of course, we do that in Chinese Hamster Ovary (CHO) cells and purify and produce a monoclonal antibody product so that we don't have to modify patient cells or any other cells in order to apply our treatment. It's just a straight typical monoclonal antibody product, the same sort of immunotherapy that's used in a variety of cancer therapies. In this case, we've found a marker that's on cancer cells and senescent cells because of the way the markers are produced, and therefore the monoclonal antibody can enable removal of those cancer cells.

Can you summarize a bit more how that antibody SIWA 318H works?

It binds to proteins on the surface of oxidatively damaged cells that may be senescent or cancerous, or just very dysfunctional. By doing so, it provokes an immune response, initially an innate immune response with the natural killer cells. The bottom line is, the immune response not only destroys and removes the cells to which the antibody binds, but immune cells also secrete factors that promote regeneration. So, while we're removing cells that are not going to function properly, we're promoting their replacement with new cells from adult stem cell populations. The interesting thing about the markers is that they are a product of glycolysis, and high levels of glycolysis were associated even back before World War Two by Otto Warburg. They were shown on cancer cells. Cancer cells and senescent cells have their peculiarities, and they are high producers of this particular marker; therefore, we can hone in on those two types of cells.

Is it a coincidence that the marker is present on both senescent and cancerous cells? Or is there a reason for that?

Both types of cells conducted an elevated level of glycolysis and there are various explanations in the scientific literature. Both are highly metabolically active. Some people think of senescent cells as almost dead, but, in fact, they are among the most metabolically active of cells, and cancer cells are as well because of high proliferation. Both types of cells have a high need for ATP. One explanation in the literature is that they both resort to glycolysis to get additional ATP. The senescent cells put all of their efforts into the senescence associated secretory phenotype, so they're producing a lot of cytokines and other molecules, so they need to use glycolysis, but they're not using it to divide. A simplified way of looking at it is that senescent cells grow, and they need energy for growth; they basically get to the size that a cell would normally be when it divides, and then they just don't divide. When you look under the microscope, you see large, flattened cells that are senescent cells, because they've grown but they just didn't divide. Cancer cells, of course, will go ahead and do the division and you'll have two daughter cells. The bottom line is that they both have to grow to that large size.

Does this mean a vaccine might be developed for senescent cells or even cancer?

Yes, and we are working on what we have. We've done preliminary studies in mice, and now we're looking at expanding it into other species, even beyond humans, but we do have a candidate vaccine already in the works. As with any drug, you do want to be careful about certain conditions, pregnancy or other conditions where you don't want to disrupt any things happening. For example, senescent cells have been found in fetuses. The one common thing, strangely enough, with senescent cells is every situation in which they're beneficial, they're removed. After they form the different structures in the fetus, they're eliminated. The same thing is true in wound healing, which is often given as an example of a beneficial effect. Initially, senescence promotes proliferation of repairing cells, but if that's allowed to go on too long, the wound tends to produce scar tissue, fibrosis, and the bottom line is that in the natural healing process, senescent cells appear for a time and then are removed. Although you do have to be somewhat careful, you don't want to interfere with the initial stage of wound healing or with fetal development, otherwise, it's a good rule of thumb that removing a senescent cell or a cancer cell is not a bad thing.



Alas they don't mention human trials roadmap. I would expect the early comers to have been progressed further

Posted by: Cuberat at February 19th, 2020 8:26 AM
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