Member Info for Burble

Also just to add you would never be multiplying an antibody in the lab, an antibody cannot replicate.

The cells (and inherently the DNA which encodes this) can replicate. Upregulation of the transcription and translation of the DNA which encodes the specific monoclonal antibody produces more protein which would then be purified out of the expression culture. When they say an antibody is multiplied in the lab, this is what they are saying. Larger volumes of cells are grown, protein expression is induced and the result being an increase in the amount of antibody protein in that culture. The antibody itself does not multiply.

RP
"So scientists "sieve" through them to find the one that’s best at sticking to the spike. The chosen antibody is multiplied in the lab, and produced in huge quantities. This is then given to patients, immediately boosting their immune response."

This has got to be one of the worst examples I have seen of science communication.

A variety of methods of generating monoclonal antibodies - genetic cloning or hybridoma screening.

Genetically - extract white blood cells from a patient, then in a test tube amplify the DNA fragments encoding the binding region (variable) from the entire antibody repertoire. Reformat that into a screening platform, then screen all those antibodies against the spike protein. Select the one which binds the best, then introduce DNA that codes for that into an expression platform such as CHO or HEK cells and use them to produce large amounts of that antibody for purification.

Hybridoma - extract the spleen, fuse it with myeloma cells and then each resulting cell produces an individual antibody. Screen these against spike protein, select the one that binds best and then grow the cell producing that specific mAb in large volumes then purify the antibody of choice.

Avidimab could be applied in either situation, but you need to know at a genetic level the DNA sequence which encodes the mAb before you can genetically engineer in Avidimab functionality.

‘ Immunobody™-based vaccines have been previously found to persist at intramuscular injection sites for 90 days and lymph nodes for 7 days‘

Makes sense entirely, the turnover and replacement of different cell types happens at differing rates. Muscle cells transformed by the vaccine at the injection site will last longer than the white blood cells within the lymphatic system which were also transformed.

However, once the body starts producing the immunobody protein transcript and presenting this to the immune system the real magic begins. Of the T-cell (CD4+ and CD8+ response) you will have the generation of memory T-cells. These last decades and if they re-encounter the target antigen (e.g. tumour with the same surface epitopes) they will proliferate and attack it.

This is why the immunobody concept helps fight not only the primary tumours but also primes the immune system to search for and attack tumour metastasis if those arise. So long as those express the same molecular profile, the immune system will treat as foreign and attempt to kill.

Yeah I've seen Bake Off for SUTC. It definitely puts a lump in your throat, but it also makes you realise how resilient kids are and how they can put up with so much without complaining.

The C4 show has been done really well, would recommend it for sure.

WTP,

Would recommend watching it on 4OD, rather than giving you a plot spoiler.

Kat

Just a quick correction here, to clear up any confusion. I don't treat patients - I'm not a medical doctor, I'm a biochemist by training with a PhD in antibody engineering and pharmacology. My current line of work straddles the interface between clinicians/patients/NHS/clinical trials and research/researchers (be that academic, clinical, biotech or pharma).

RP

Sadly very little if at all. The current trend in conversations is definitely CAR-T, especially the next generation CAR-T and monoclonal antibodies. We've seen CAR-T be a game changer for many of the leukaemia patients who benefit from it, though we are still trying to understand why failures occur and how to treat the patients who will not benefit at the moment from CAR-T technology. The other area that there is increased focus in is CAR-T for solid tumours. Solids are an entirely different disease than the lymphoma/leukaemias.

For me, the excitement with SCLP is around side effects (or lack of). Many of the current chemo drugs have obscene side effects. Take dinutuximab (anti-GD2 antibody for neuroblastoma). The side effects of this are extreme pain, to the point that patients have to be sedated and given morphine to control it. They're also at high risk of infusion reactions hence need to be treated with anti-histamines and anti-inflammatory drugs. Bearing in mind also that NBL is generally diagnosed in patients less than the age of 5 and is one of the highest frequency cancers diagnosed in the first year of life. Children should not have to suffer just for a chance to survive. Hell, nobody should have to put up with side effects and life-long long-term effects from a treatment. Hence my belief that SCLP are onto something here.

RR

Likewise. I remember reading these articles from my desk when I worked at Pfizer. What's even more poignant for me is the fact that the earlier versions were a) used in children at the Royal Marsden and b) by a professor who is an incredible powerhouse in the childhood cancer sector (current president of SIOP) and somebody I can now call a colleague.

Randomly, we first met in person at a pizza express in London soon after I took up my current role, I was attending a childhood cancer conference and a few of us stopped for dinner the night before. That was one of the most enlightening nights of my life sat talking to many of the leaders in the field of paediatric oncology discussing new therapeutics, potentials and drawbacks of the current designs and the direction of travel we are moving in.

An eye opening look into childhood cancer. September is Childhood Cancer Awareness Month, with many events, talks, seminars etc organised to help bring awareness to these devastating diseases. Whilst progress has been made, sadly many of the cancer drugs that we use on children these days to treat these diseases are decades old and repurposed from adults. The side effects alone are enough to kill children. Hence why safer, less toxic, more targetted drugs are needed. Drugs which not only work on primary tumours, but also prevent the devastating news that a cancer has returned and spread.

Inan,

I'll lay my cards on the table, I've been invested here for 10 years, I've not sold my originally holding but have continued to add in small amounts as and when I feel that I can afford to. My current line of work involves working with children, teenagers and young adults as they go through cancer treatment for a vast array of cancers, sadly many of them succumb to their disease. The devastation, grief and loss associated with any death is immeasurable, more so when it is a child or young adult with years of life ahead of them. I've lost three very close family members to cancer (breast, hepatic and ovarian). Many of these have been given chemotherapy drugs which are 30 years old.

As such, I back SCLP and their vision for cancer therapy. I believe in the science, I believe Lindy has answers that other people possibly haven't considered or haven't attempted. At the end of the day, I'm not in this for the money. I honestly couldn't give two hoots whether I've invested 1% of my salary or 100% of my salary. For me, this is about believing in a company which has a chance at putting an end to the suffering that I at times am part of on a near daily basis. A company with products which could put an end to the endless trips to the clinic for chemo, to put an end to the emotional rollercoaster that repeated routine scans have then waiting for results with baited breath, to put an end to the financial and emotional toll that cancer has on people, to the wasted years spent in hospital waiting rooms rather than with loved ones. If SCIB1 works, then I have every belief that SCIB2, SCIB3, SCIB4 come after and will also work. If Modi-1 works, then similar things will follow. The science is good, but with everything in science you have to play devils advocate. You have to question results, anticipate the problems, highlight the errors and ask yourself 'have I missed something?'. Not everything will succeed, we can game plan every scenario, but the body is a complex thing and cancer is an even more complex beast.

Do I believe in the products/platforms? Yes
Do I believe we can get through phase 1, 2 and 3 clinical trials? Yes, based on the evidence in front of me currently.
Will my view change? Most likely, again based on evidence in front of me and from my own research. As a scientist who works with patients, clinicians, clinical trials units, researchers and other members of the oncology community, if it fails, I'll want to know why it fails so we can do better for the patients who come next.

Inan, there's no need for that.

We're all invested here for many reasons - both from a financial aspect and others from a personal aspect. Science needs balance, you need to have people who critique your findings otherwise science doesn't move forward. People need to understand the science behind SCLP and any other biotech or pharmaceutical company. But they also need to realise that the vast majority of drugs fail to reach the clinic. That's a fact of life.

Based on the information presented to us, we all have to make a decision as to whether we accept and believe it. With anything we do in this world there is risk involved. To determine that risk, we need to know as much information as we can. Hence, I and others will challenge people on this board and in life in general. It's only fair that we present information to others in a balanced and meaningful way such that people can digest it and make their own decisions. It's not their money I'm investing, but at the end of the day I care about the information I put on this board.

It would be entirely wrong of me to advocate something, if I a) didn't believe in it and b) didn't accept and highlight that there are risks and it could fail.

Ignore the last paragraph, I'm typing on my phone and had copied and pasted part of your comment for reference.

Bunsie

Can I just add some clarity to my post. When I mention other mechanisms in reference to Inan's question regarding synergy this was mainly highlighting that PD-1 inhibitors are not a gold bullet, they routinely do fail in patients. That's not to say that they have no therapeutic effect, but I think we should make sure we differentiate a combination trial from a monotherapy trial. Current SCIB1 data looks incredibly promising, PD-1 in late stage melanoma patients could be considered standard of care. Hence if we can join the two together and see a combined response this could be incredibly powerful for patients who routinely will have been given months to live. Without PD-1 they will be dead. Without SCIB1 they would be dead. PD-1 may not be effective in every patient and patients may stop responding, SCIB1 has been shown (albeit in a limited number of patients) to be effective and those patients are still alive to this day.

Cancers evolve, we just don't know in a larger cohort whether the effects we are seeing are representative of a larger cohort. Hence, I guess where I was coming from is part of me would rather see a monotherapy trial before the dual therapy trial. However, the board obviously believe that it is worth persuing this goal. Both for the patients - they believe based on their mouse data that combining PD-1 ihibitors with SCIB1 results in a far better response rate than either individually, and from a business angle - there are PD-1 inhibitors already in the clinic, there are more coming online. Currently they work in a subset of patients. If you combine with SCIB1 you can increase the number of patients who respond and therefore are benefitting from taking your drug.

Add to that, clinical trials are designed to show which drug is causing the responses we see in the clinic. Hence, SCIB1 and PD-1 will have a control arm. If we see the same number of deaths in the PD-1 monotherapy arm as we see in the SCIB1 arm then you could broadly say that it's not the result of the SCIB1 addition that is affecting patients. That's what a clinical trial is about and I'm sure both the clinical trial units, scancell and partners have thought this through long and hard and designed the trial in such a way that patients get the most clinical benefit if it works AND the scientists get the most data out of those who sign up to the trial.

Loss of the interferon-gamma responsiveness also would affect CD8+ cells and could render SCIB1 ineffective entirely), other mechanisms include things like changes to the tumour microenvironment to name a few.

RR

Generally when talking about antibodies in general we use Ab shorthand. Monoclonals in general we use mAb, but if they're in a techincal name (e.g. rituximab) it's non-capitalised. There are so many different short hands in the antibody sphere it makes it easier
(https://bit.ly/3hbJNn1)
- Fab - fraction antigen binding (consists of VL, CL, VH and CH1)
- Fab' - consists of a FAB and part of the hinge region
- F(ab')2 - consists of two Fab molecules joined together by a disulphide bond in the hinge region
- scFv - single chain variable fragment (VH and VL joined together through an engineered chain)
- sdAb - single domain antibody

The list goes on. Generally with these things there is either agreed nomenclature guidelines OR it's done to make it easier to read. Hence Fab = fragment antigen binding, rather than fAb which could be functionalised antibody, fish antibody or any other thing that people may conjure up!

I feel sorry for Putin's daughter. The fact he has two daughters and he's decided to test this vaccine on one of them, suggests either she might not be not the chosen one.

Yup! Scientists are helpful at times when it comes to nomenclature.

Pembrolizumab
Pembro
'Li' - targetting the immune system (immunomodulating)
'zu' - humanised
'mAb' - monoclonal antibody

Trastuzumab (herceptin)
Tras
'tu' - tumour
'zu' - humanised
'mab' - monoclonal antibody

I don't think they will, big pharma has too much to lose to be pressured into approving a drug which hasn't been through clinical trials properly. The fact that they have been quick to pledge not to have external pressure is clear that they're pushing back against political pressure. (https://www.nytimes.com/2020/09/08/health/9-drug-companies-pledge-coronavirus-vaccine.html)

It'll be the Chinese, Russian etc vaccines I would worry about.

Clinical trials in the UK are one of the most robust in the world for two reasons. Firstly, the regulators (MHRA and other organisations) are very good at what they do. Secondly, the NHS being a (relatively) joined up organisation means that patients involved in clinical trials are incredibly well documented even before they start. One of the problems you may have in other countries is that the joined up medical notes aren't there. Hence, if a patient presents with an adverse symptom, clinicians may struggle to obtain a full complete medical history from the patient if they have moved around, changed medical providers or been out of state during their lifetime. The NHS in that sense is one of the best places to run clinical trials.

Not a huge amount to add. With all clinical trials, it is only right for the correct procedures to be followed. A trial being put on hold is not a new thing, but it is the right thing to do.

The appropriate steps will be taken to assess whether this is a direct cause of the vaccine or whether it is something not linked to the trial. It may take a few weeks before appropriate information is obtained and submitted to the regulators. Once that is done, a decision will be made as to whether the trial can restart.

There is obviously a pressure at the moment to restart the trial as soon as possible, so I'm sure the regulators and clinicians involved will be working round the clock to understand this more, but as with any serious adverse effect these things may take time to obtain the data needed to make a decision as to whether or not this is directly linked to the vaccine.

Not a huge amount more to add really, just have to sit and wait for the findings and hopefully see the trial restarted. Now is a critical time for the trial (especially in the UK) as we start seeing infection rates start climbing, the real read out of the success hinges on the trial being performed in regions where people may catch the virus rather than places with low infection rates already.

Oh for sure the antivax brigade will put their spin on this, but fundamentally we just don’t know whether this is vaccine related or not. It may be something, it may be nothing. Until that is confirmed it is only right and proper that the trial is halted.

It means very little at this point in time. People who understand trials will know that they are regularly put on hold and restarted. The reason this is big news is because I think the world wants to get back to normal and this was their main hope currently. Otherwise this wouldn’t be over the news unless it failed to reach its clinical end point or was halted in its entirety early due to poor data or significant adverse effects or death.

What it does highlight is that you can’t rush these things. Phase I (dosage), phase II (activity), phase III (large scale safety), phase IV (monitoring). The idea that Trump will try and rush a vaccine will do more damage by rocking confidence in vaccines than it will save lives. Better to be second to market with a safe product, then rush and get it wrong.

Due to a suspected serious adverse reaction, AZD1222 phase III trial is currently placed on hold. It's unknown how long this hold will go on for and what the impact more broadly will be. Though it's helpful to note that this is not uncommon in clinical trials, especially in phase III where you are dosing more patients than you would have dosed before. This highlights even more so how important late stage clinical trials are, especially how quickly many of these have been taken through early stage trials in small cohorts.

https://www.statnews.com/2020/09/08/astrazeneca-covid-19-vaccine-study-put-on-hold-due-to-suspected-adverse-reaction-in-participant-in-the-u-k/

Will be interesting firstly to know what serious adverse event has been triggered and whether it's caused by a reaction specific to the Covid-19 region or the viral vector they are using to deliver it. Unsure whether we would find out in that level of detail very quickly, but if this appears in more patients as they ramp up the trials, it could be deemed a failure by the FDA/licensing authorities worldwide.