NorthWest Biotherapeutics Inc (NWBO)

[biosectinvestor]

It appears to me that it is like PD-L1 and PD1 inhibitors. There are a number of patents for companies and universities and others who make it by various means. Yes, a Poly ICLC version, is branded Hiltonel, which is marketed by Oncovir. These are specifically called TLR3 Agonists, and those brand names are just names for a specific iteration, like Keytruda and Pembrolizumab are the two names for Mercks drug. I believe it can be sourced from potentially a variety of sources or possibly licensed for manufacturing. I have not done a thorough review, just going off some quick research. But I see that different versions claim to have fewer side effects or to be manufactured more consistently or to be water soluble.

So keep in mind we are discussing a TLR3 Agonist, not a brand name or generic named drug from a particular source necessarily. Even Dr. Liau uses the TLR term and of course NWBO's patents refer to the various TLR's.

Research on TLR3's goes back at least 40 years I see, so there are maybe even versions with no patent protection at this stage.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213534/

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that play a crucial part in the commencement of responses of the innate immune system by sensing conserved pathogen-associated molecular patterns (PAMPS) for early recognition of a particular pathogen and recruiting the innate immune cells such as monocytes, dendritic cells, and macrophages [1, 2]. This family comprises ten members in humans and thirteen in mice [3, 4]. The typical TLR is a type I transmembrane protein consisting of three structural domains: a leucine-rich repeats (LRRs) motif that plays a vital part in the recognition of a pathogen, the toll-interleukin 1 receptor (TIR) domain for interaction with signal transduction adaptors, and a transmembrane domain [5].

TLR3 is mainly expressed in neuroectodermal and myeloid cells. TLR3 of myeloid cells favorably acts as a receptor for the surface recognition of viral double-stranded RNA [6]. The worth of dsRNA in oncology has been assessed by randomized trials carried out in the 1990s. The reproducible effects observed in patients suggest dsRNA to be remarkably effective in the subsection of individuals that remained to be determined. Identification of TLR3 as the exclusive target of dsRNA along with the portrayal of its expression in cancer cells led researchers to conclude that TLR3 expressed by cancer cells is highly sensitive to dsRNA [7].

Since then many TLR3 agonists have been designed to mimic the dsRNA and have been studied indicating that numerous mechanisms subsidize the efficacy of TLR3 agonists. A novel therapeutic approach involves aiming TLR3 receptor expressed by tumor cells to induce apoptosis. It directly interferes with the progression of cancer especially in patients that have a compromised immune system. TLR3 is being widely studied by oncologists all over the world since its significant role in antiviral immunity has been discovered. Currently, its agonists are being exploited in vaccine development. Several non-clinical, preclinical, and clinical studies have inspected the potential of these agonists as adjuvants [8].

In this review comparison of three of the extensively studied TLR3 agonists RGC100, ARNAX, and polyinosinic:polycytidylic acid (poly-IC) along with their dissimilar pathways contributing to tumor regression has been made.

RGC100 https://www.riboxx.com/rbx-media//RIBOXXOL/Riboxxol_biotin_20160914.pdf

https://www.futuremedicine.com/doi/10.2217/imt.10.8

In addition to the two historical modified polyIC compounds, an additional TLR3 agonist, IPH3102, is reportedly in preclinical development at Innate Pharma (Marseille, France). Further details regarding the specificity, structure and function of this molecule has yet to be published.

ARNAX may be patented by the institute of advanced immunotherapy and BD Biosciences may be associated with it.

Looks like Poly ICLC has numerous trials, with many different inconsistent sponsors trying to see if it works against different cancers.

Some universities have versions of TLR3 Agonist patents in process as well.

Looks like there are many different ways to make it. Probably won't be difficult to find someone who wants to work together but Poly ICLC looks pretty much all over the place so they are probably interested in getting it used.

Adjuvants are not looked at as combinations. I believe they are considered likely a part of a potential improvement process rather than a "new drug". It seems likely that there would be motivated parties to work with NWBO to address the interest. But they have a trial already with Poly ICLC, multiple trials, so they likely have a good idea of how to proceed by now with thise. Poly ICLC is not approved for anything yet and has never succeeded as a single factor I believe. Though I had thought I had seen them approved for something in past research. There are a lot of trials, many sponsored by academic institutions, with various TLR3 Agonists, and also specifically with Poly ICLC. I don't think it's going to be an issue to give someone a big win working with NWBO or whomever might own DCVax at such date as that becomes relevant. And, in fact, I'd expect that someone has probably already been in communication with Oncovir, as they are using their version and the company knows the implications. But also, they very likely could use other versions of TLR3 Agonists, if they needed to do so, as a vaccine adjuvant.

And this is something to keep in mind:

$NWBO Kevin Duffy came from Merck, did some spying, went back to Merck, and is now with Regeneron who bought Checkmate and it’s Toll Like Receptor 9 Agonist. Dr. Liau presented data at Pitt showing 50% survival at 10 years with #DCVax plus TLR agonist. Just thinking…

— Gregory Zivic, MD (@metacollectiveG) November 18, 2022

A variety of companies make various TLR's and some companies may be motivated to see if theirs would work with DCVax in some way or another. UCLA has run these various trials with various TLR's and DCVax-L, but the best seems, so far, from what we can see, to be TLR3 Agonist, and in this case that was Poly ICLC or Hiltonel.