 HIC Demonstrates Promising Separation of Deaminated and Non-Deaminated AAV Capsids (ASGCT 2024)
Published on: May 10, 2024
Feliza Mirasol
Studies conducted by a team at Oxford Biomedica demonstrated that HIC can be used to effectively separate non-deamidated capsids from deamidated capsids.
In a presentation given at the American Society of Gene and Cell Therapy’s (ASGCT’s) 27th Annual Meeting, Alex Meola, associate director of AAV Downstream Process Development at Oxford Biomedica, shared results from a study he and his team conducted in which theydemonstrated that hydrophobic interaction chromatography (HIC) can be used to separate non-deamidated capsids from deamidated capsids. The ASGCT annual meeting is occurring on May 7–11, 2024 in Baltimore, Md.
Meola emphasized how the focus on post-translational modification of capsid proteins of the adeno-associated virus (AAV) is growing in the process and analytical development space for gene therapies. The industry has been particularly focusing on how the deamidation of capsid protein from viral protein 1 (VP1)-specific residues, including the N57 domain, is linked to a loss of in-vivo potency (1).
“Temperature, pH, and storage time have been identified as key factors causing this phenomenon,” Meola. “In our quest at Oxford Biomedica—to try and resolve this—we have a static binding capacity residence screening protocol that we run where we look at a variety of different residents. In this case, we decided to look at salt-tolerant residents,” he stated.
Besides process control to prevent deamidation, Meola’s team hypothesized (2) that extrusion of VP1 and deamidation of N57 are related phenomenon and result in generating empty, partial, and full capsids, which significantly influences the ability of the anion exchange chromatography (AEX) process. AEX’s ability to remove empty capsids and deliver functional AAV is thus compromised.
Meola noted that charge-driven separation techniques have not provided the resolution required to differentiate between deamidated and non-deamidated capsid species. Because of this, his team highlighted novel approaches that can be applied to the AEX process to address the complex challenge of removing both empty capsids and deamidated intact capsids. “Controlling strategies in the upstream and downstream processes should be studied and defined at the early stage of process development to limit onset of deamidation in order to minimize product related impurities and loss of vector functionality,” Meola stated.
One of the team’s first approaches was to use HIC to separate distinct peaks with near baseline resolution. After separation, each peak was isolated and individually reprocessed with AEX. “Surprisingly, we discovered that HIC resolved two different species of AAV capsids with near baseline resolution. Each species was reprocessed on AEX, and all product quality attributes were assessed for the intermediate peaks that were generated. We found that the capsids that were more hydrophobic were also more negatively charged,” he explained.
Furthermore, data from liquid chromatography–mass spectrometry analysis demonstrated that the more hydrophobic and more negatively charged capsids exhibited significant levels of VP1-specific N57 deamidation, which has been linked to a loss in gene expression. It was demonstrated, therefore, that the extrusion of VP1 exposes the hydrophobic phospholipase A2 domain on the VP1 unique region, a phenomenon that would make VP1 N57 residue exposed to solvent and thus susceptible to deamidation.
The team was thus able to demonstrate that HIC can be a useful method to separate non-deamidated capsids from deamidated capsids. Meola also stated that the team is working on a novel, patent-pending method to remove deamidated species while simultaneously enriching full capsids on the AEX process. |
The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion |
Relatively quiet since the last of the million-plus days on 7th May.
However, the price remains fairly steady; no large retrace - implying that buyers are waiting to take up trader's profit selling. It has not yet formed a significant characteristic pennant and may not be given time to do so.
If next news is good (odds on that), those waiting on the sidelines hoping for a test of a floor (at 300p?) may all rush to get in, reigniting momentum. Then, beyond 400p, thoughts of 350/250 inclusion will begin to beckon. |
I don't have access to trade details but I suspect we are now in a pattern where each morning we get a big deal that they have to pay a premium for followed by a number of small sellers taking the share price down. |
Surely we all know the answer to that one? Big news.
Nobody needs the full history of OXB to know that they were battered by the coronavirus pandemic restrictions on trials, because most of their customers were either working from home (i.e. not working) or had their trials put on hold because the hospital beds which need to be on standby for trials were reserved for covid.
Happily that is consigned to history now and will hopefully never be repeated.
We know from what Stuart has previously told us that OXB's costs for everything are somewhere around £130m per year.
Sales of around that and we roughly breakeven. Anything above that and our EBITDA margin rises ever upwards until we hit full capacity. So better than 20% on 2026 revenue and maybe eventually 30+%.
A couple of minor problems for small shareholders here are that OXB have told us for over a year now that they aren't routinely going to announce normal sized contract wins anymore - unless the customer specifically wants to.
(and)
They will instead keep us up to date with regular updates on this KPI table, but without actually telling us where and when we will get to see it.
So not for the first time we are in a position where all seems good (very good in fact), but we have to trust that it actually is going as OXB have told us (which it should be).
Out of the ordinary (i.e. big) news would help a lot, not just because it changes all previous guidance, but because the last paragraph of any RNS like that is usually a mini trading update on everything else.
Are we due something like that with the directors not buying? Probably. Will it happen sooner rather than later? Probably. Are biotech deal timeframes very long? For a big deal definitely.
I can only repeat my experience of the original Novartis tie-up. That was excitement on prospects, then impatience and repeat, with the price up and down accordingly. Eventually that got us to about £10 pre-covid (remember that much smaller company is no France, no Boston and only a handful of contracts) then covid changes everything (knocked us right down to £3(ish), built us up to £16(ish), knocked us right back down to £3(ish) again) meanwhile 6,000+ people with no previous hope got the Novartis treatment thanks to OXB.
You will have worked out long ago that I think the key to market success for OXB investors is getting back into the FTSE250. That seems to guarantee more of everything - more news coverage in the papers, more broker interest, more institutions who can buy (some in the trackers have to) and so on - and I'm convinced that eventually OXB will get there.
When? I don't know. My target is this year, but it might need the interim results showing that all is well and on track first. Meanwhile a lot of small investors are likely to have got fed up and sold (again).
Next index review is the end of this month but to double the price in 3 weeks would take some epic news. Could a really big deal (big enough for OXB to be in a closed period and big enough for them to have to announce because of changed guidance) do that in such a short time when OXB are in this sandwich year here between loss and profit?
I'm sure it's possible. Will it happen in the next 3 weeks? No idea. |
Besides the potential detriment to drug access as a result of an immediate severance from Chinese CDMOs, industry respondents estimated that it would take up to eight years to switch manufacturing partners, according to a copy of BIO’s report obtained by Fierce Pharma. |
Just for interest:-
Key takeaway 5 -
While the legislation is only under consideration at this point, given the strong bipartisan support for the bill and concerns from the national security community, it is expected that some form of the bill will become law in 2024.
OXB webcast Final question:-
Miles Dixon Question - Thank you and then secondly, if I could ask, I think it was Sébastien that mentioned about biotech still being difficult. I was just wondering if it was too early to see yet or if you are in fact seeing any new emerging pen profile of potential clients given the challenges at WuXi? Thank you.
Dr. Sébastien Ribault Answer - I have not personally been exposed to anyone coming to us and saying we absolutely want to leave competition and we want to work with you because of US political reasons, to put it that way. Are there people concerned about the situation? The answer is yes. Are they looking for backup plans? The answer is yes. Since we're talking about a text that has not been voted yet, we're still talking about people looking for backup plans, but there's nothing that I would consider as an active discussion as of now. |
In a word, would that be stochastic? Cue the call my bluff theme tune ;)
To stay in the same groove on my stuck record here, I think this month will either be ok or brilliant. Yes, I realise that's a rain or go dark prediction, but the likelihood here is that we will either continue to bobble along with 2 forward & 1 back on what they have told us, or...
Something very significant for OXB will drop and at that point our guidance changes and so does the share price.
Might be malaria. As Plutonian pointed out a long time ago, J&J have had very public supply problems in meeting their commercial needs. BMS have also experienced similar woes. Literally too many possibilities to guess from, but OXB are now in a very happy position of being there for anyone (with money and a need of our services). |
It's important to see a distribution/ accumulation phase before the next leg up. There's no predicting SPs, probabilities suggest further pipe laying before the next move all imo dyor ofc. |
My experience of broker targets is that they're rarely worth the paper they're written on. What I do know is that the third attempt at 350 and a close above that will move us significantly higher again |
A good news story there Marcus. There must be a huge amount of satisfaction for the people working in labs everywhere when something like this turns out to be a success.
It's a bit like the story with Emily (first child with the CAR-T linked to us of course) where she awakened out of the post-treatment storm reaction to the sound of the hospital staff all gathered around her bed and singing happy birthday to her.
You'd need a heart of stone not to have something in your eye after that one. |
Spreadbetting and CFD sites carry a health warning.Over 70 per cent of punters lose money.If you're going to actively trade,you are in effect taking on the MMs and proprietary traders.It can be expensive fun. |
I admire folks who trade these shares - buy at the bottom at 3.15 run up to 3.40 go back short and then long again at 3.15 rinse and repeat. It takes a lot more skill, patience and time than a LTBH option that is my way here... |
Target prices were originally employed by US brokers servicing high net worth private clients.Over the years,this rather simplistic methodology,sneaked into the world of research prepared for institutions.The target prices invariably have a greater cognisance of where the existing share price is now than where the price might be in 18 months time.Hence,you get the Investec analyst who simply shifts his target up and down with OXBs price as it moves from £15 to £2.A far from useful exercise.The stock recommendation is clearly key but i've never seen much merit in price targets.They are a broker's marketing tool. |
I find it really odd that we can have joint corporate brokers (RBC and JPM) with respective recent 12 month targets of 740p and 305p.
My honest best stab at an explanation for that one is the smallcap syndrome, where at the moment we remain under the radar and probably not of great interest to JPM.
It's been mentioned / hinted at on here before that OXB likely only retain JPM because the JPM healthcare conference is the biggest / most prestigious and first of the season. It's also the one where you primarily present to investors rather than scientists / medics. Having JPM as joint broker seems to pretty much guarantee a speaking slot there. |
I'm sure you won't be alone Ch1ck, wouldn't surprise me in the slightest if Brucie has done the same thing - but it's all fine and each to their own.
If I had sold at every high and bought at every low over the last 2 decades then I would be a very wealthy man, but I don't have that ability.
What you are essentially gambling against here is that the assumed looming big news which has stopped the directors buying isn't imminent. If it is then you will miss that gain with the strategy to make more. |
Sold 3/4 yesterday looking to buy back lower |
Agree takeiteasy.
Talk is cheap and all that but by all accounts OXB have a dynamic team in place. |
I think after all of the troubles over the past couple of years and collapsing SP, some brokers may take the view that they want to see 2 or 3 sequential reporting periods ticked off with steady progress before committing to a recommend /buy position.
Each may have their own research protocols to follow which we do not know the details so we can only surmise - but in pure numbers a 50% higher share price target seems to be in the right direction ... |
JPMORGAN RAISES OXFORD BIOMEDICA PRICE TARGET TO 305 (210) PENCE - 'NEUTRAL' |
I would imagine a bigger issue arising from Wuxi’s sanctioning might be a firming up of industry pricing |
Catalent are being bought out by NN to make their slimming drug for American compulsive eaters so probably looking in a different direction now.
Wuxi, well I'd imagine that they would be thrilled with Seb's 2 serious enquiries per week, but what if the US votes to put sanctions on them? |
I wonder how many new CDMO clients are looking to place work with Catalent and Wuxi at the current time. |
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