Member Info for Burble

Darloman23

I'd be keen too. I sat there last night trying to work out how best to do this, to ensure my CGT is reported properly.

Nomlungu,

Codagenix has some really interesting technology and demonstrate how far synthetic genetic construct technology has come in the last 10-15 years or so. Their codon de-optimisation goes against the flow in some sense of the word. Globally people are always trying to optimise the coding sequence for a DNA/RNA construct to improve yields etc, so going the opposite direction is an interesting take on things.

From a first glance, there are a number of things which stand out for me - firstly, they are using an attenuated live vaccine - which in a way is probably the best in class in some sense of the word. All the proteins are folded correctly, it looks like C-19, it just doesn't replicate as well as C-19. So what immune response that is raised against their version is likely going to be as close to a normal immune response as you could see. All proteins are there, folded in the right way and presented to the immune system how they would be if you were infected with the virulent strain of C-19.

I have a few hesitations though with the set-up. Intranasal means that the control of dosage that actually reaches deep into the lungs is difficult to control. I would imagine they would dose at a higher amount than you would normally. As such, the patient may end up with a higher initial viral load early on, which you would imagine would decrease as the virus replicates slower. The virus does replicate, so in a patient with a limited/suppressed immune system may be problematic (unsure without knowing this field better). A non-replicating virus wouldn't have that same problem, though whether you would be able to obtain a robust immune response in an immunocompromised patient is difficult to say.

Live vaccine manufacture, I would assume is more difficult as there is a chance (though maybe small) that your culture is infected with something else or worse, infected with the real C-19. You also run into problems with delivery of those virus particles to the end patient. So whilst they say that the intranasal is more efficient at mass vaccination, the fact you will probably have to cold chain the vaccine from start to finish will make it difficult to do at any scale. Especially if the virus does not remain active for long after manufacture (meaning you can't bulk store vaccine doses, they're made to order). This in turn will increase costs.

IMHO, novel idea, has potential to raise good immune response, mass delivery and cost may be the issue for more broad deployment.

C7

That makes 3 of us! Got to be a round number, can't be having any of these odd number shares lying around. I have the same for my bank account. It always rounds up my transactions to the nearest pound and throws the rest into a savings account. Means when you look down the statement it's all £X.00 across the board.

AB

Will try to attend where possible. Happy to do some of the science, though I suspect Inan will also join from a technical perspective if he is able to attend.

Do we know when the AGM is yet? I haven't seen anything, but hoping that I've not missed something in the most recent news.

RP,

This is a question that I would like to ask at the AGM if I can make it. Do SCLP see the role of FG2811 as a tool to make better CAR-T/TCR products through it's ability to select TSCMs or do they envisage it instead to be developed into a product in it's own right targetting SSEA-4 on cancer cells? Which route holds the bigger value to the company vs which holds the bigger value to the patient?

Sophie/Cat

Following on from this discussion, Apple filed a patent a few months back for incorporating solar panels in places to recharge batteries. One of the things covered in this application was automobiles. https://bit.ly/37dvkWa so it wouldn't surprise me if as this technology becomes more prevalent it is rolled out across across the EV motor industry, especially once one manufacturer starts to include them, many would rush to follow.

Following on from Crumbs post on ADC.

Antibodies - highly specific, can be tuned to exist in circulation for long periods of time.
Small molecules - highly toxic, but work systemically.

Standard chemotheraphy uses highly toxic agents, generally given orally or by IV which blanket target any dividing cell. They have horrible side effects related to this - hair loss, gut problems, mouth ulcers etc.

ADC technology harnesses the targetted nature of antibodies, with the cytotoxic nature of the chemotherapy drug. This means a range of things - less side effects, more targetted action of the chemo drug, the ability to reach a therapeutic dose inside the cancer cell, whilst limiting off-target effects.

The key to these is stated in Crumbs post. Highly defined target which ideally is expressed only on cancer cells OR is over expressed above normal levels on the cancer cells. An antibody which is specific to that target and is able to reach the cells in high enough numbers to deliver their toxic payload. A toxic payload which is capable of killing the cell when internalised.

I emailed Sclp this morning. Just received confirmation back which says the following:

‘Thank you for your message. The correct date for the admission is Wednesday, October 14th.’

May see a corrective RNS later today.

BW
Owen

Botaki,

They can add value by building on the work that they have done so far, but in a focussed way. Hence it wouldn’t surprise me if this is why they are hiring currently. It’ll give them the hands on the job to be able to actually say ‘yes these antibodies are worth an investor buying/licensing’

The trading update at the bottom is very interesting to read. Will make for some good questions at the AGM I hope

RP

If FG2811 was used to isolate TSCMs destined for CAR-T or TCR therapy, then IMHO I would argue significant. As the timelines for this involve patient T-cell harvesting, in vitro lab modification and then reinfusion back into the patient, the time those cells are capable of remaining viable could impact the quality of that treatment (e.g. the chance it passes quality control) and/or therefore chances of success of engraftment in the patient. Furthermore (and this is pure speculation) if additional doses were required, it would be preferable for you to hold these cells in reserve in a viable state, rather than re-harvest (as by this point the patient's disease may have progressed). This is speculation.

https://www.sciencedirect.com/science/article/pii/S1083879118311868 this article suggest a mean time of around 22 days from harvest to receiving final product back, with a min of 20 days and a max of 57 days. https://www.stemcell.com/media/files/wallchart/WA27041-Production_of_Chimeric_Antigen_Receptor_T_cells.pdf this is also a great poster explaining exactly what CAR-T is for people who want to understand more.

I will add two things though. Firstly, currently SCLP is *NOT* a CAR-T Biotech, though they do have links with other groups/biotech which are. Secondly, I am making a purely speculative guess as to the role that FG2811 has to play. There may be other applications which it could be used for that have not been thought of due to the limited material out there on this mAb. I hope that we hear more over the coming weeks/months about the application of this mAb to the SCLP pipeline/platforms.

That makes more sense now. If that's the case then the potential for moditope is even bigger than I imagined. Kudos to the patent attorney who wrote that one!

WF.

Oh definitely - without a patent you are going to struggle to commercialise something.

I wasn't meaning to be accusatory, I was just confused as to what you were referring to with regard to the eprint when you said land grabbing. I didn't know whether it was in reference to the mAb itself, the avidimab technology which was discovered and is described in that PhD thesis, the use of it in an ADC format.

If it was a more broad comment regarding patent space, then yes all these discoveries form new packets of land that are now fenced off from competition and able to be leveraged when it comes to commercialisation.

I hope there was no offence caused through this confusion!

That's the poster for it. https://www.jbc.org/content/early/2019/12/12/jbc.RA119.011518.full.pdf this is a paper with the crystal structure of the antibody on.

WF

When you say land grabbing, what are you specifically referring to?

For those of you non-scientifically minded reading my previous post. I ran out of characters so here are a few definitions.

Tn - Naive T cells
An immature T cell which has not been activated and is not a memory T cell. This type of cell has not encountered a target antigen within the rest of the body. But has undergone selection positively and negatively within the thymus to remove self T-cells. This set also includes CD4 (helper) and CD8 (killer) T cells.

Tscm - T memory stem cells
T memory stem cells are a rare subset of the memory T cells. These have a stem-cell like capability e.g. are able to self-renew and have the capacity to differentiate into the entire spectrum of memory and effector T cell subsets.

Tcm - Central memory T cells
A memory T cell subset which is able to migrate to secondary lymphoid tissue.

NSG mice - a highly immunodeficient genetic mouse (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ)
These mice have a genetic immune deficiency that affects their B and T cells. Due to the lack of mature B and T lymphocytes, these mouse models are ideal for xenoengraftment of human cells and tissue e.g. transferring human cells into a mouse and seeing what they do/where they grow/do they differentiate etc.

Crumbs 1412.

This post is interesting, from all I have seen across the years SCLP has never really been interested in CAR-T technologies. After all, if you want to engage the immune system and target it to a specific target you would use immunobody. It's far cheaper to produce, scaleable and is an off the shelf therapy (in the sense you don't have a bespoke treatment made per patient using their own cells).

The fact FM2881 targets T memory stem cells suggests this may be the focus of this position. A quick literature search reveals a few different interesting nuggets. In reported CAR-T trials, patients receiving their transfected T-cells (the CAR-T therapy itself), receive a mix of different T- cell subtypes. This variation may be the reason why some CAR-T products fail to engraft in some patients and not in others. https://go.nature.com/34KCJtl this paper describes (quote) 'we found that TSCM cells engrafted with 10- to 100-f old more progeny than Tcm or Tn cells in both lymphoid and non-lymphoid tissues. Notably TEM cells, which resemble cell populations used in current clinical trials for adoptive immunotherapy [read CAR-T], had a poor proliferative and survival capability resulting in negligible engraftment 1 month after transfer' with the caveat added which says 'this humanised mouse model, however, is inadequate to test T cell self-renewal in vivo because we found that all CD8+ T cell subsets uniformly differentiated into effector cells, perhaps as a result of encounter with homeostatic cytokines and with xenogenic MHC antigens.' before finishing with 'nontheless, adoptive transfer in NSG mice suggests that TSCM cells have enhanced replicative and survival capabilities compared with naive and conventional memory subsets'.

https://go.nature.com/3dhs3pP this paper has a lovely section on 'targetting TSCM cells for therapy' that is well worth a read. Interesting to read this 'clinical trials have largely employed unselected intratumoral or
peripheral blood mononuclear cell (PBMC)-derived T cell populations. Tumor-infiltrating lymphocytes are typically in a state of terminal differentiation and functional exhaustion, which makes the isolation of early memory T cell subsets impractical. However, the selection of less differentiated T cell subsets becomes realistic
and desirable in the context of immunotherapies that are aimed at conferring tumor reactivity to circulating T cells via TCR or CAR gene engineering. The isolation of less differentiated T cell populations also has the advantage of reproducibly generating more defined T cell products'.

So in brief - I suspect that this FG2811 has massive potential in the CAR-T field. Hence why SCLP are hiring somebody for a position to solely work on this. If this is the case, I would hope that they go down the route of non-exclusive licensing access to this mAb. That way no-one company benefits, meaning patients ultimate benefit from the many CAR-T products in development .

Quick glance, some interesting points to take on board.

The section around manufacturing is interesting. 'Not all platforms under development, such as RNA vaccines, have a proven ability to upscale.'

Oxford vaccine snapshots '1500-3500 doses per L of culture' and '2000 L culture, a batch takes 26-30 days'...'100-150m doses annually at this scale' though this is dependent on losses in downstream processing'.

RNA based vaccine (BioNTech and Moderna et al.) '2-3 million doses per L of culture' with 'a single batch taking between 40 and 50 hours to complete' and 'between 5-7 bn doses of drug annually' again dependent on losses in downstream production. However in the section on challenges in manufacture it says 'For the RNA platforms, the material costs are the major contributor to the operating costs and to the overall production costs. The highest cost material is the 5’ cap analogue, for example the CleanCap sold by TriLink Biotechnologies, which is required for the RNA to function in the cells of the human body'. So additional costs there for BioNTech and Moderna. In addition 'However, filling in such large containers might be limited by the thermostability of some of the vaccines, such as the RNA vaccines. If RNA and/or other vaccines need to be lyophilised [freeze dried], this would further slow down and decrease the production volumes'.

Take home from this section - DNA is scaleable, it's cheaper to produce than an mRNA vaccine. It also doesn't need additional chemical reagents to be added to make it function, is chemically more stable than RNA. As we seemingly no longer need electroporation we also don't have that problem to contend with. Hence, SCLP have a clear benefit on all these points than many of the teams out front.

Will have a proper read later.

An interesting article on patients who are reinfected with covid. https://www.theguardian.com/world/2020/oct/06/flurry-of-coronavirus-reinfections-leaves-scientists-puzzled

More talk about T-cells and lasting immunity. I highly suspect first to market, may not be best in class.

C7

Good luck at the doctors! Wishing you the best.