Member Info for Burble

C7

Am out this evening and on my phone currently, though will put pen to paper later as to what I believe are the many positives Scancell has over the competition as it currently stands and where the market is moving. Rather than just writing these down, I will try and offer clear points as to why I think this is a positive and where there could be drawbacks to their platforms/patents.

Inan, can I also add I apologise if my posts have come across overly critical of you. There wasn't any hostility behind them in the slightest.

Thank you Inan, and yes - you're correct and I am entirely in agreement. If I make a point, as any good scientist should be able to, we should present our references and place them within the context of science both from a general perspective and in this case from SCLPs perspective.

I would add that as with all forms of text based communication, the way things are read by others may not be the way they were intended. As such, clarification may be needed on posts and that should not be dissuaded. As I have always said, if people do not understand one of my posts or would like further information, they only have to ask - I'm always more than happy to talk through my workings and invite people to challenge me on my assumptions and conclusions.

I would like to think that I have acted with humility (and I offer anybody the right to tell me if that isn't the case). If I am wrong and someone has corrected me then great - it's all part of being a scientist.

We make assumptions based on the data we have in front of us. When someone comes along and presents conflicting evidence, we weight it up against what we know and then decide whether it challenges our own assumptions of the subject. The same goes for when somebody presents supporting information. The great thing with science is that it is not just black or white, it has many shades of grey....but fundamentally we don't know how many.

Something that we believe is fact and has been for many years, may change. Someone will come along and present a whiter white, or a blacker black. That doesn't change the knowledge or results in front of us, it just changes the context. The shade of grey, has suddenly become slightly closer to black than we thought it was or slightly closer to white than we thought it was. Fundamentally the shade hasn't changed. This is what's so fun about science, it's never ending.

The reason I am saying things like 'have we considered whether Mab 2811 could cause cancer', is because it's me trying to contextualise data put in front of me and highlight that there is always a risk that this could happen. It's not me stating that is *is* going to happen, it's me stating that based on the evidence in front of us that is a *potential* risk.

Science demonstrate that T memory stem cells have the potential to be harnessed for use in T-cell based therapies against cancer and infectious disease (white). It also demonstrates that TSCMs play a role in autoimmunity, T-cell leukaemia and T-cell based infections (HIV etc) (black). Hence, my question could be posed in a different way.

Based on the limited data we have on Mab 2811, it's effects can be placed somewhere along that gradient from black to white. At the moment, it could be closer towards white (good end). It might also have the potential to move towards black (bad end). Until we have further data on it, on its effects and on long term effects in vivo using it, we just don't know where on this spectrum it lies. Rather than looking at it through the eyes of the ever optimise 'this will only ever go towards white' we should think of it more through the eyes of a realist 'it has every potential to go either way'.

Inan

I'm not trying to pull you down a peg in the slightest. Please do not think that is my motive because honest to god it isn't. I have far more important things to do than get into stupid petty slanging matches on an investors bulletin board. If it has come across that way then I do apologise. To be honest with you, if it makes you happy I can just as easily stop posting and leave you to it - I have far more important things to be doing with my life than arguing with a glowing set of pixels.

'Its a BB for investors ........... Science light'

But without the science and a full understanding of the science, people cannot fully comprehend risk/reward. They cannot understand the potential for success, equally they cannot understand the potential for failure. The latter could be a technical failure (it doesn't work as we expected) or a market failure (e.g. there are others in the same market which do the job better, cheaper, safer, quicker etc).

'Many do not understand what Burble is posting anyway .. even in laymans terms so it makes little difference'. Maybe so, it is highly likely that many people do not understand what I am saying. We all know many people invest with zero understanding of what they are investing in - that's not my problem.

What I will say though is if a single person understands the science that SCLP are doing a bit better than they would have without reading my or any other person on this boards posts, then the SCLP bulletin board will have been a success.

I'm not out to make personal attacks on people or play dirty. What I will do however, is continue to challenge posts I feel may need further questions asked about them, I will continue to ask questions of the points that I myself do not understand, I will continue to reflect on others posts and also question my own understanding of the science behind SCLP. I hope others will do the same. A bulletin board inherently is for everyone to read, to post, to understand, to question and to digest information. It's not a place for infighting. Life is too short for that.

Inan,

I'm not going to argue with you or Lindy, however in essence she has confirmed some of my points and also highlighted her ingenuity as a scientist.

It works with IB - confirms my statement that 'pre-moditope epitopes are able to be inserted into a DNA construct'
The protein does not fold and is degraded via autophagy which causes siPTMs - 'For citrullination to occur, you need cell-stress to occur (e.g. be hypoxic, nutrient deficient or be in some form of oxidative stress)'. The unfolded protein response that is generated by the IB peptides, results in ER stress - confirming that for moditope to be generated from these pre-moditope peptides stress has to occur.

Which in turn means that this statement 'Therefore the only way you would be able to obtain citrullinate ‘moditope’ peptides in vivo using a DNA vaccine would be to *have a way to target the DNA vaccine to a stressed cell*, express these peptides (as unmodified amino acid sequences) AND then expect it to be modified – #something you have no guarantee of happening#.'

The sentence highlight by asterisks highlights Lindy's skill as a scientist. She has realised that you can induce a stress response inside of a cell using the unfolded protein response and the autophagy mechanisms that this induces.
However
She has also confirmed my final statement (bracketed by #) when she says 'However, peptide is more efficient.'. With a chemically synthesised peptide drug you can ensure that citrullination has occurred. You cannot guarantee 100% citrullination of your IB delivered peptide inside a cell, hence why I suspect they have gone down the peptide delivery route rather than the IB route.

Not a problem in the slightest! Please do ask is there is anything you don't understand. At times, I do find myself flipping into scientific terminology, even when trying to write a lay response.

2/2/end

For citrullination to occur, you need cell-stress to occur (e.g. be hypoxic, nutrient deficient or be in some form of oxidative stress). Therefore the only way you would be able to obtain citrullinate ‘moditope’ peptides in vivo using a DNA vaccine would be to have a way to target the DNA vaccine to a stressed cell, express these peptides (as unmodified amino acid sequences) AND then expect it to be modified – something you have no guarantee of happening.

Taking the above into account. If you use the term Moditope you are specifically talking about a siPTM modified peptide. You cannot encode a siPTM peptide into a DNA vaccine, hence Moditope is not able to be delivered as DNA based vaccine. You can however deliver pre-cursor peptides in a DNA based format, but you are then expecting it to be modified in vivo – something you have limited control over.

Inan,

Firstly, as with all inventions an inventor will patent not just the invention specifically but also a wider patent space surrounding your invention.

through this you see a range of thing and I’ll break them down for the rest of the readers to understand:

The patent covers a broad range of epitopes from different proteins including NYESO, Cytokeratin, HSP90, BiP, ING4, CXCL10 and CXCL12 as well as vimentin (the main focus).

Clause 12 – lists the epitopes the patent covers, then details which arginine residues are modified (citruillinated). Then finishes with the preferred vimentin residue.
Clause 13 – highlights the preferred citrullinated epitope from vimentin and that it can be used to raise an immune response to a range of cancers but not limited to just those listed.
Clause 14 – Goes into further detail regarding the preference for which one, two or three arginines are citrullinated and also says that additional residues can flank the epitope.
Clause 15 – Highlights alternative preferred epitopes of vimentin and then details which of the arginines within these should be citrullinated.
Clause 16 – Highlights further epitopes from vimentin that are also included within this patent and highlights the arginines which could be citrullinated. Note however, that they have not specified which ones are preferred (e.g. these could be moditope targets, but they haven’t done any/limited work on the immunogenicity of these, so have included them in the patent just in case’.

Clause 17 and 18 are an interesting one. You’ll note that these specify the same epitopes that were listed in clause 14 and 15, but this time without mentioning the citrullination however these clauses do include the sentence ‘and/or a nucleic acid encoding such an epitope, for use in a method of treating cancer.’

Now why would they include the same clause twice?

The answer is because they are patenting the preferred epitopes without the citrullination modification in both peptide and DNA form. As I said in my earlier post you can’t encode the post translational modification in a DNA vaccine – that statement still stands.

As Moditope (in thise case I’m talking about modi-1) specifically relates to citrullinated vimentin and alpha-enolase proteins. Your statement saying ‘moditope was inserted into a DNA construct using whole length vimentin’ is incorrect. You would be correct though in saying unmodified vimentin (peptides or full length protein) or specific ‘pre-moditope epitopes) are able to be inserted into a DNA construct – that is true. But to call that moditope would be factually incorrect because moditope specifically refers to the citrullinated form or stress-induced post-translational modified (siPTM) peptide form.

1/2

Yup, was a lovely site. Such a shame Pfizer had a poor track record in their R&D sector during Ian Read's tenureship. Very short sighted decisions were made which cost the company - one was the loss of the Sandwich site.

Bermuda

Labs run of coffee. You should see the panic in a department when the coffee machine breaks! Just after they announced we were being put on redundancy notice at Pfizer, they closed all the on-site coffee shops within weeks! Every single meeting was done over a coffee (if you organised the meeting it was expected you would buy coffees) and the panic that spread across site was pretty funny to watch.

Entrepreneurial me realised there was a gap in the market, went to Argos and purchased 10 filter coffee machines and dotted them over site with honesty boxes. Cost of a bag of coffee from Asda was around £2 a day per machine. The honesty boxes were making upwards of £50 a day....was a tidy little profit maker for the last three months of my contract there!

'Why did they chose only to run with a peptide vaccine ... ?'

My guess is a very simple reason.
- Immunobody - amino acid target.
- Moditope - amino acid target with post-translational modifications

Post-translational modifications are difficult to encode within a DNA construct in the lab (requires many modifications and additions to expression systems). Impossible to do in vivo. Hence PTMs required for moditope to work cannot be encoded within a DNA based vaccine, hence the need to go down the peptide route.

That makes sense. I apologise! I read so many manuscripts with work that it all blends into one at times!

I thought that was in relation to this paper https://cancerres.aacrjournals.org/content/80/16/3399 and the corresponding RNS https://www.lse.co.uk/rns/SCLP/publication-highlights-potential-of-avidimab-hl98138qyipcdc0.html, unless i am wrong this looks to be a new publication which goes into more detail about the molecular mechanisms behind the FG88.2 and chimeric ch88.2 mAbs.

A very interesting read, especially the comparison between the murine and the chimeric antibodies and the differences these are presenting at an experimental level.

Inan

I hate to nitpick, but if you’re going to copy and paste information, can you please reference the source. By referencing your source, not only does it allow others to read further into the article, but it also is good practise to highlight where you have obtained this information from rather than passing it off as your own.

Reference to where Inan lifted his previous post from for transparency. https://www.frontiersin.org/articles/10.3389/fimmu.2018.01963/full

Immunology can sound like a foreign language at times!

Yardstick

Welcome!

Inan,

Partly correct. Generally, DNA vaccination harness the use of cells within the body to produce proteins - but more often than not those are not antibodies themselves. They would more likely be proteins (be that from viruses, bacteria or possibly cancer targets) which are therefore presented to the immune system inside the vaccinated patient. Once (and if) the immune system responds, the body then produces a number of antibodies and other immune responses against those 'foreign' targets.

DNA vaccination with immunobody vaccines result in the generation of an engineered antibody with T-cell epitopes and and cancer antigen sequences. So slightly different in the sense they don't present whole protein to the immune system and wait for the immune system to react. The protein produced by vaccinated cells inside SCIB patients is engineered to ensure an immune response against a specific target epitope on a protein and directly engage and generate a high affinity T-cell response.

Whilst I appreciate your understanding of this, many on this board may not understand the nuances and differences between DNA vaccines as a whole and the technicalities and benefits of the SCLP immunobody platform over other forms of DNA/RNA based vaccinations.