Hello,
I thought I’d once again explain my reasoning in simple terms, this time regarding that article. I should mention that I have read the entire article, not just the snippets visible “on this side” of the paywall.
Link to the article:
https://www.sciencedirect.com/science/article/abs/pii/S1368764626000300
What is the essential finding of the article?
The article demonstrated that clever-1/stab1 (a beloved child has many names) affects the SIRP-alpha (SIRPα) expression of macrophages, which in turn affects how well macrophages recognize CD47 proteins on the surface of cancer cells.
So what are CD47 and SIRP-alpha?
CD47 is a protein found on the surface of numerous cells in the body, intended to signal the immune system (macrophages) that “do not eat us, because we are not foreign.” Otherwise, the immune system would start destroying the body’s own cells, which would have dire consequences. Macrophages recognize these CD47 proteins with the help of a receptor called SIRP-alpha, which is located on those macrophages.
The problem in cancer is that if cancer cells express this CD47 structure, then macrophages do not recognize them as cancer cells but mistake them for the body’s own cells, and thus do not engulf them, nor can they present their antigens to other immune cells. This is how cancer “hides.”
CD47 inhibitors have been studied as cancer drugs for a longer time, and they are very effective, but unfortunately, they block CD47 on all cells, so the harms are truly abundant and dangerous, making the drugs clinically unusable. For example, magrolimab.
What is the role of clever-1?
Clever-1 is on the surface of the macrophage (not in the cancer cell) in the same way as SIRP-alpha. The article showed that in a mouse model of lung adenocarcinoma, resistance to osimertinib was mediated by higher clever-1 expression in tumor-associated macrophages, and more specifically that higher clever-1 expression was associated with higher SIRP-alpha expression and more abundant CD47 expression in cancer cells. It was also shown that blocking SIRP-alpha removed this clever-1 mediated effect.
That is, higher clever-1 appears to regulate how much SIRP-alpha a macrophage has, which it uses to identify CD47-positive cells (either its own or cancer cells), so that it knows not to engulf them. Conversely, less clever-1 leads to a lower amount of SIRP-alpha and thus causes the macrophage to also engulf cells that have CD47 expression. That is, it effectively creates local CD47 inhibition.
What does this mean for BEX?
Clever-1 is thus an enhancer of SIRP-alpha and thereby participates in regulating how macrophages recognize CD47-positive cells (and leave them uneaten). So, in summary:
- Lots of clever-1 in the macrophage
- More SIRP-alpha in the macrophage
- Macrophage recognizes CD47-positive cancer cells more effectively
- Macrophage leaves cancer cells uneaten, which is a bad thing
The biological effect of bexmarilimab (which binds to clever-1) is based on the fact that it somehow affects the function of clever-1. It is known that bex transforms macrophages from an immunosuppressive (M2) type to an inflammatory (M1) type, improves antigen presentation, alters lysosomal processing, affects the cytokine profile, and increases T-cell-mediated immunity… but how and why? It’s a bit unclear.
Given the previous background, at least this mechanism seems obvious:
- Bexmarilimab binds to Clever-1 on the macrophage surface, which interferes with clever-1’s function and does not activate it (antagonist)
- The amount of SIRP-alpha in the macrophage decreases as a result of reduced clever-1 function (as the article strongly appears to show)
- The macrophage no longer recognizes CD47-positive cancer cells as it did before
- The macrophage begins to engulf cancer cells again and thus can also present antigens
So how about all those different effects of BEX? My guess is that they are all downstream effects of the main mechanism. If the macrophage begins to effectively engulf cancer cells again, it naturally follows:
- more tumor material inside the macrophage
- more antigens to process
- more antigen presentation
- more T-cell priming
- more inflammatory signals (cytokines)
- less immunosuppressive macrophage state
If a single molecule has abundant effects, in biology it is fundamentally more often a case of several downstream effects of one main mechanism. And this would fit here too. And the clever-1-SIRP-alpha-CD47 pathway shown in the article would indeed beautifully fit as that mechanism.
Why does this matter?
CD47 inhibitors appear effective in cancer treatment, but are primarily unusable due to systemic side effects. But if clever-1 inhibition with BEX effectively creates local CD47 inhibition where there are many TAMs (tumor-associated macrophages in an immunosuppressive environment = macrophages with lots of clever-1), then that would explain how good efficacy can be achieved combined with minimal side effects. It also explains why BEX works specifically in combination therapies: BEX frees macrophages to engulf cancer cells and present antigens (“targeting the target for T-cells”), but in addition to targeting, those T-cells are also needed to “fire.”
PD-1 inhibitors, on the other hand, are effectively brakes on those T-cells. They are effective in metastatic cancers, but the problem is developing resistance as tumors become immunologically cold when macrophages no longer present antigens…
That is, BEX gets macrophages to target and PD-1 gets T-cells to fire.
Makes sense. I emphasize that this is my assessment of what the mechanism could be, not proof. But if it were true, then BEX would practically be a way to utilize CD47 inhibition without its key side effects.