Researchers have discovered that the TLR5 agonist Entolimod (CBLB502, Cleveland BioLabs Inc.), which is in development as a radioprotective agent, work primarily on receptors in the liver, and that it may be useful to fight liver metastases and, more broadly, as a liver-protective agent.
Andrei Gudkov, who is chief scientific officer at Cleveland BioLabs as well as senior vice president of basic science at the Roswell Park Cancer Institute and the paper's corresponding author, told BioWorld Today that after the fact, "from an engineering perspective, it makes sense" that TLR5 agonists should work in the liver, though he also cheerfully acknowledged the findings were at first surprising to him and his colleagues.
They published their work in the April 29, 2013, online issue of the Proceedings of the National Academy of Sciences.
Gudkov likened toll-like receptors (TLRs) to "guardians" that sense pathogens, and mobilize the innate immune system's troops to fight them. The most natural place for those guardians to stand watch is on immune system cells in the bloodstream, where most pathogens are detected. And that is indeed one major site of expression of previously studied classes of TLRs.
But TLRs are also expressed on other organs where infections can establish themselves. And TLR5, whose main natural role is to sense infection with the Salmonella, is expressed in high levels in the liver. Entolimod is a derivative of the Salmonella protein flagellin, and its administration is interpreted by the organism as Salmonella invasion.
"Blood . . . coming from the GI tract goes directly to the liver for purification," Gudkov explained, because in addition to nutrients, food tends to contain any number of poisons, which require detoxification to prevent illness. Salmonella infections are caused by bacteria that take up residence in the liver, and so the liver is a natural place for cells with TLR5 receptors.
Entolimod is in pivotal trials as a radioprotective agent, and earlier studies by Gudkov and colleagues had shown that activating TLR5 leads to the activation of NF-kappaB, which is radioprotective by at least three different mechanisms. (See BioWorld Today, April 11, 2008.)
In their experiments, Gudkov and his colleagues found that overall, Entolimod "dramatically changes gene expression in the liver," Gudkov said. Those changes lead the liver to "pump out proteins, including endogenous antibiotics, antioxidants, and a very interesting spectrum of cytokines, some of which actually have blood-regenerating properties." It is those properties that account for Entolimod's protective effects on blood stem cells after radiation exposure.
In addition to its protective effects on blood stem cells, Gudkov said the cytokine profile that results when TLR5 is activated is unusual in that it does not include either TNF-alpha or interleukin-1 beta, which can lead to septic shock if they are highly activated. Liver cells do not produce those two cytokines, explaining why TLR5 agonists "do not cause cytokine storm and septic shock," Gudkov said.
Liver cells still do, however, produce cytokines that lure immune cells to the liver. That attraction, Gudkov said, is "technically dangerous," since those immune cells can in theory turn on the liver cells themselves.
In the studies now published in PNAS, however, the team also showed that Entolimod activated "a powerful pro-survival pathway," through its effects on one signaling molecule, STAT3. "We now know why such a strong attraction of heavily armed immune cells to the liver is actually benign," Gudkov said.
The attraction of immune cells to the liver means that Entolimod might also be useful for cancer treatment in another way than via its radioprotective effects. The authors showed that through its recruitment of immune cells to the liver, the compound helped mice fight off liver metastases derived from cell lines of colon, lymphoma, and breast cancers.
Based on those results, the company is now also testing Entolimod for the treatment of liver metastases of solid tumors. The agent is in a Phase I trial, and the company is currently determining when to start a Phase II. Gudkov declined to say when such a trial might start, but did say that the company is "going full speed" in this additional indication.