Member Info for RayPointer

It would have been interesting if Scancell had invited non-exclusive collaborations for Moditope TCR.
How many takers would they have had.

Yes, on Immunobody and Moditope, I agree. I think we all find that frustrating. The wait for data.
But back in 2017 we had no pre-clinical collaborations with pharmas and now we have 4.

https://www.scancell.co.uk/Data/Sites/1/media/publications/posters/cri-2018-homocit-responses.pdf

This poster explains it well.

Morning Knowlesi

Same in some respects but different in others

SCIB1 - IND approved albeit much, much later than expected
Modi1 - manufacturing problems still to overcome so I will give you that one
SCIB2 - Trial to be funded and monitored by CRUK
Glycans announced (as you say)
Mab2811 - I see that as separate to Glycans Mabs since it targets stem memory TCells
4 collaborations announced
Modi2 announced

I do agree that Scancell is still without deals so the same in that respect.
But would you say that the chances of deals are greater or lesser now when compared to 2017?
I'm interested in your view on this.

2 distinct processes :

One produces citrullination
The other produces homocitrullination

Both common in cancer. I think this is why Lindy is excited at the prospect of combing Modi1 and Modi2.
But it is strength of that CD4+ attack that matters and its ability to persuade the immune system that cancer is non-self.
It is not an attack in large numbers initially, but with the help of clonal expansion close to the tumour it soon becomes an attack in numbers.

I think the answer lies in the potency of the CD4+ Tcells and its hoped-for ability to flip the immune system.
This is the same as Inan hs just pointed out.

Thanks for that Wild.
I will do more investigating.
I have A Level Statistics LOL.

It does seem to me that there are so many criteria used in reporting trial results and so many variables.
For instance, what is the definition of a responder?
And surely the strength of the response is also relevant.

Then, as Inan says
do you exclude those patients with severe side effects and either die or are taken off the trial?

Then you have the strong memory effect of SCIB1?
Is this stronger that a memory effect created by a normal immune response (not enhanced by a vaccine)?
So continued survival of the patient is also important (well it is to the patient but perhaps not so much to the CI manufacturer)

I also think that by combining CIs the law of diminishing returns is important.
2 CIs gives better stats but more side effects. 3 CIs may be a step too far!

In short, you need to look at the whole package of data from a trial. Somebody much more qualified than us will then assess the data in a peer review.
All IMHO

Hi Wild

This seems back to front to me.
What is the definition of "null response rate" in this context

Thanks

It would be interesting to know that when Lindy talks about a 55% target, what is she talking about?
What is the exact definition of success in a patient according to Lindy's criteria.
I suspect different trials use different criteria to measure success when announcing their results.
We need to compare apples with apples.

C7, what on earth was that!

"Hey, great news, morning, time for tea."

I think he's got a woman.

This is their website

https://counterfietsupplier.com/counterfeit.php

So, what you are saying is the amplivant brings something extra to the activation process.

The TCell activated by the Modi1 peptide plus amplivant is somehow enhanced to the TCell activated by the peptide alone.
Activation itself is complex enough but it appears we are now adding to the properties of the TCell.

An example of one of the properties of activation is priming the TCell to promote clonal expansion.
Do you know anything of the extra properties that amplivant provides?

I'm off for a walk now but this does seem to be an interesting discussion.
Catch up later.

Bunsie
You have to pay extra for the un-moderated banter.
But seriously, there are areas of the science that are not that well defined on Scancell's website and the exact way that amplivant works is one such area.
The required dose is reduced 100 fold so my guess is that it makes the binding between the APC and the TCell that much more efficient. Hence we get a much greater chance of the TCells being activated.
Whether it also has the effect of increasing the avidity of the activated TCells is another area for discussion.
ATB

It strikes me that the conjugate has to be precise in where the covalent bond is located
This will then cause the APC to present the exact shape required to maximise the chance of activation.
So the peptide binds with the TCR normally and amplivant binds elsewhere on the TCR, hence I assume this increases the avidity.
That's the way I imagine it anyway.
It must have taken a lot of experimentation to get that covalent bond in the right place.

To my way of thinking it has similarities to Avidimab - more than 1 binding to achieve high avidity. Albeit, the bindings are different in Avidimab but the same general principle.

IMHO.

Sorry, just read your last post.
It's very much how I imagined it to be.
Very clever chemistry that aims to link the APC to the TCell for the optimum time needed for activation.

There are 2 bindings here.

The first is the covalent (chemical) bond that ties the peptide and amplivant together. This is the relevant bond that needs to be achieved in manufacture.
I assume this is aimed to be a strong chemical bond that permanently connects the 2 structures. Definitely not a temporary bond.

Then there is the binding that your links are talking about. I assume in the case of Modi1 it is the binding of the presented conjugate (by the APC) to the appropriate TCell. This, I believe, what the NH bridging is about.
I wouldn't have thought this is a permanent chemical bond since the APC needs to engage with the TCell and then disengage once activation has taken place. What I think is happening is that the adjuvant helps with the attraction between the APC receptor and the TCell receptor giving a stronger temporary attraction more likely to end in TCell activation as compared to the peptide on its own.
I may be going down the wrong track but I haven't got an "Ask Lindy" app on my laptop LOL.

The exact 2 atoms forming the bond is a level of detail we don't need to know.
I'm just speculating on one possible reason for the difficulty in manufacture.

Hi Inan

Covalent bonds are extremely common in nature.

https://www.sciencedirect.com/topics/chemistry/covalent-bond

Its the sharing of electrons between 2 atoms which can be the same or different e.g. Hydrogen binding to Hydrogen.
The shared electrons complete an electron shell in each atom. In the case of hydrogen to hydrogen each atom has 1 electron, so they both share the 2 electrons giving each a completed 2 electron shell in this case. This gives a strong chemical bond.

So, the bond connecting a Modi1 peptide to Amplivant could be any 2 atoms that bond covalently.
But I reckon the bond must be designed to be between a specific atom in the peptide bonding to a specific atom in amplivant. Getting the bond in the exact place may possibly prove challenging given the size of the molecules involved.

Possibly the problem is the formation of the covalent bond between the peptide and the adjuvant in exactly the right place in both of the molecular structures (peptide and adjuvant)
I'm just thinking that forming the bond in the correct place is crucial to the effectiveness of the adjuvant.

I pretty much agree with most of what you say.

One point though, You say:

"Saying they have not sorted out technical difficulties of combining all 3 components is worrying as they have been working it a long time and you cannot out a definitive timeframe on an unknown."

The position is that they have managed to manufacture the first 2 components and are still working on fixing problems with the 3rd manufacture.
I suspect that the actual combining of the 3 components will be the easy part of the process but I don't claim to be correct in this.
But I agree with your point that you cannot put a timescale on this. It obviously presents difficulties that have not previously been encountered by Polypeptide.