Member Info for Blownitalready

It will be amusing if there is a good RNS out in the morning....I really have no idea why people would want to sell right now.
Hold for gold !

May need to turn phone on side to view fully

Biotech M&A, is picking back up. Here are the latest deals.
Dealmaking is essential to the business of drug development. Keep track of M&A as it happens with this database.
Updated October 3, 2022

https://www.biopharmadive.com/news/biotech-pharma-deals-merger-acquisitions-tracker/604262/

Fibroblast activation protein (FAP) is best known for its heightened expression in tumour stroma. This atypical serine protease has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. FAP expression is difficult to detect in non-diseased adult organs, but is greatly upregulated in sites of tissue remodelling, which include liver fibrosis, lung fibrosis, atherosclerosis, arthritis, tumours and embryonic tissues. Due to its restricted expression pattern and dual enzymatic activities, FAP is emerging as a unique therapeutic target. However, methods to exploit and target this protease are advancing more rapidly than knowledge of the fundamental biology of FAP. This review highlights this imbalance, emphasising the need to better define the substrate repertoire and expression patterns of FAP to elucidate its role in biological and pathological processes.

https://pubmed.ncbi.nlm.nih.gov/24470260/

Old research, but has opened my eyes to the possibility of more ailments that could be targeted.

The money would also be stretched further with additional milestone hits .....

Loving it -

The Company looks forward to providing a full technical update to shareholders on the Affimer immunotherapy and pre|CISION chemotherapy programmes as part of a Science Day event when the data sets from the pre-clinical and clinical programmes are in hand, so that the data can be presented and the development path and associated risks for the programmes can be described in detail.

Full report for anyone who's not seen it

https://www.trinitydelta.org/research-notes/fy21-results-a-year-of-frustrations-and-opportunities/

Once AVA6000 has established the clinical proof of concept, we expect increased industry interest in the pre|CISION platform. Avacta has been exploring other single-agent chemotherapies whose clinical utility would similarly benefit from improved efficacy and reduced toxicities. The most advanced is a FAP-activated proteasome inhibitor, AVA3996, a prodrug of an analogue of Takeda’s Velcade (bortezomib), which is commonly used for multiple myeloma. AVA3996 offers the prospect of reducing the dose limiting toxicities, principally peripheral neuropathy and thrombocytopenia, that constrain Velcade use to multiple myeloma and mantle cell lymphoma.

Velcade’s efficacy, particularly when used in combination regimens, could broaden its use into additional hard-to-treat indications, such as pancreatic cancers. Animal studies have shown encouraging results, with selective drug delivery to tumour sites and reduced systemic exposure. Despite approaching patent expiry in 2022 and limited clinical indications, Velcade continues to post blockbuster sales of c $1bn. Similarly, the overall protease inhibitor market is expected to post an 8.4% CAGR growth and reach $2.3bn in 2026. ***Avacta has earmarked funds from the June 2020 raise to complete the preclinical package *** and is on track to start the first-in-human Phase I clinical trial in H223.

yngladbuys - sit on your shares as long as you can and hopefully we will get an RNS that locks everyone in/out and a slice of this company gets taken/bought for a very large amount.

Treated myself to a few more....

At these crazy prices it has given long term shareholders a chance to fill their boots .
Not long to wait for the almost inevitable!

Partial excerpt:-

An online resource that logs side effects in cancer patients to help assess their quality of life will benefit from a new framework, thanks to researchers.

The European Organisation for Research and Treatment of Cancer (EORTC) has an Item Library that offers coverage of side effects – also called adverse events, AEs - important to cancer patients and the impact they have on their quality of life and emotional wellbeing.

Researchers from the University of Leeds’ School of Medicine and the EORTC have now created a new framework to systematically classify and improve searchability and item selection for relevant AEs in the Item Library after clinicians, researchers and regulatory authorities highlighted an increasing need for a patient-centred approach in measuring AEs and their burden on patients.

The framework developed by study, published in the Journal of Clinical Oncology, will now be integrated into the Item Library’s online searchable database.

Gold standard for side effects reporting
The gold standard for the classification of side effects reporting in cancer clinical trials is the Common Terminology Criteria for Adverse Events (CTCAE). Used by clinicians, it includes more than 835 different side effects, including using laboratory and imaging findings.

Patient-reported outcomes (PROs) complement clinician reporting by directly capturing the patient perspective. The EORTC Item Library supplements the standard PRO questionnaires and modules developed by the EORTC QLG to assess quality of life for cancer patients. The Item Library allows for more flexibility through customised lists of questions (item lists) that can be used to better cover new disease and treatment contexts.

It covers symptoms and treatment-related burden, emotional functioning and overall quality of life.

https://medicinehealth.leeds.ac.uk/faculty-/news/article/573/new-framework-for-cancer-patient-side-effects-to-help-assess-quality-of-life

The pharmaceutical industry has sustained momentum since the vaccine bounce - are they a recession-proof investment?

The pandemic shone a spotlight on the pharmaceutical and biotech industry and their share prices hit new highs as a result.
Big pharmaceutical players have continued to perform well into 2022 even as other sectors flounder in the face of the cost of living crisis and rising inflation.

Broad exposure to the sector means investors can capitalise on the increased long-term demand for healthcare solutions.

The pharmaceutical industry has undergone significant change over the past few years.

While the Covid vaccines made headlines, years of research are starting to bear fruit for big players like AstraZeneca and GlaxoSmithKline.

But with a recession looming will pharmaceutical players be able to sustain their momentum? And could it be a good time to invest in biotech firms, which have seen their shares languish?

The Covid vaccine has raised AstraZeneca's global profile significantly and in February it reported a record quarter for revenues including $1.8billion from the Covid vaccine and sales from its $39billion acquisition of Alexion. It also increased its dividend for the first time in a decade.

AstraZeneca is now the second largest FTSE 100 company by market cap after doubling its share price in five years and is a popular holding among income funds including Artemis and Columbia Threadneedle UK Equity Income fund.

'Big pharma as represented by FTSE 100 constituents AstraZeneca and GlaxoSmithKline have performed well in the wider market slump this year. Their shares are up 28 per cent and 8 per cent, respectively, in the year-to-date,' says Garry White, Charles Stanley's chief investment commentator.

'Covid-19 related sales are slowly unwinding, but the loosening of pandemic restrictions have boosted sales of other vaccines, sales of cancer drugs have been rising - and the major players have good pipelines of potential new products in development.'

https://www.thisismoney.co.uk/money/investing/article-11024301/Is-good-time-invest-pharmaceutical-biotech-stocks.html?

ico=mol_mobile_moneyinvesting-newtab&molReferrerUrl=https%3A%2F%2Fwww.dailymail.co.uk%2Fmoney%2Finvesting%2Findex.html

5. Conclusions
Affimer reagents have been shown during this project to be able to bind to VIM-1, and in preliminary
experiments show inhibitory effects on its rate of hydrolysis of nitrocefin. The modification of a
target protein by inclusion of a biotin acceptor peptide tag has also been demonstrated to be a
useful technique to assist in screening, though further investigation may be needed on resultant
orientation of a BAP-tagged protein when bound to streptavidin.
Future work needs to be done to characterise the type of inhibition witnessed during these results,
as well as a given Affimers ability to inhibit VIM-1 in vivo. When coupled with prior work on NDM-1,
these are good steps towards verifying Affimers as desperately needed inhibitors of metallo-ß?lactamases in the ongoing struggle against antibiotic resistant pathogens. The rapid screening of
Affimer libraries against a target alongside their low cost and ease of manufacturing make Affimers
useful tools for the future

.....told yer it was a lot to take in ..

4.4. Continuation of the Project and Future Applications
Affimer61 was shown to bind to VIM-1 and successfully modulate its activity in an n=3 series of
experiments. Further work is required to establish an IC50 of this Affimer as well as its effectiveness
against VIM-1 expressing bacteria in vivo, and a crystal structure of VIM-1 with Affimer bound would
help to elucidate its method of inhibition, and possible application to other VIM-variants.
Work to express VIM-1 variants and test Affimer cross reactivity is also necessary, as there is a great
need for cross-reactive metallo beta lactamase inhibitors. Further phage display screening could also
be used to select cross-reactive Affimer binders in the hope of isolating a broad range inhibitor.
4.4.1. Ongoing work using reagents created in this project
Since the conclusion of research on this project, L. Medinger (University of Leeds) has continued
testing for Affimer reagent inhibitors of VIM-1. Using the purified phage from the second round of
phage display and stocks of BAP-tagged VIM-1 created during this project he has performed the
third pan of phage display and phage ELISA to try and identify unique Affimers that target VIM-1.
In early tests, one such Affimer appears to have an inhibitory effect on VIM-1 at 33-fold
concentration (50 nM VIM-1, 1.5 µM Affimer14)

4.3.3. Development of resistance
Bacteria have the ability to acquire resistance to new methods of inhibition, in ways previously
described in 1.1.2. It is important to consider how the use of Affimer proteins as VIM-1 inhibitors
could exert a selective pressure which may lead to the evolution of resistance, it is possible bacteria
could develop such mechanisms of resistance to any Affimer reagents.
The evolution of resistance can only be tested in longitudinal studies of Gram-negative bacteria by
treating VIM-1 expressing cells with various concentrations of Affimer61 and antibiotics then
passaging over a number of weeks to assess whether any strains were capable of evading Affimer
inhibition by acquiring resistance. An adaptive library evolution, similar to those used in 2014 by
Jahn et al. could be utilised, whereby increasing antibiotic drug concentration in set stages over a
period of two weeks resulted in cells expressing increased resistance to the antibiotics used [109]
.
4.3.4. Immunogenicity
The ability of a substance to provoke an immune response in a host is referred to as
immunogenicity, and this is another important consideration when developing novel reagents such
as the Affimer [110]. Anti-drug antibodies (ADAs) can be expressed in response to a therapeutic, and
bind in a tiered response that can cause immune complexes to be formed, and can result in
erroneous activation of the complement cascade [111]
.
With regards to the immunogenicity of the Affimer structure, Avacta Life Sciences Ltd published
observations using human ex vivo samples. Three different structures of Affimer scaffold were
tested at five-fold the concentration of Avastin after a period of seven days in T-cell cultures, and
analysed by flow cytometry [110]. It was found that all three structures elicited low levels of immune
response, among these the type 2 Affimer structure that was used in this thesis[110]. These results
give hope to the future use of Affimer technology in therapeutics.

4.3.2 Intracellular Delivery
One challenge to overcome for the use of Affimers as therapeutics is the use of a reliable system for
intracellular delivery. Due to their size and polarity, proteins are more challenging to diffuse across a
cell membrane than small molecules. A protein such as an Affimer is around 12 kDa, and is therefore
unlikely to passively diffuse across a membrane in great enough numbers to elicit an efficacious
response [101]. The added complexity of a double-membrane cell envelope in the case of Gram?negative bacteria means it is increasingly difficult. There is evidence to suggest though that MBL’s
like NDM-1 and VIM-1 are localised to the periplasm, such that an inhibitor need only permeate through the outer membrane of a Gram-negative bacterium to be effective thereby indicating a
higher level of target accessibility compared to cytoplasmic targets [101], [102]
.
Cell-penetrating peptides (CPP’s) are water soluble, partly hydrophobic peptides that have the ability
to penetrate a cell membrane without causing significant damage, and have the capacity to deliver
an internalised covalently bound biologically active cargo with low toxicity [103]. In 2004 TP10 CPPs
were shown to deliver SYTOX Green - a nucleic acid stain – preferentially to S. aureus cells when
incubated with both HeLa and non-invasive S. aureus, fluorescence increased in S. aureus without
increasing at the same rate in HeLa cells [104]. In 2015, CPPs were covalently conjugated to peptide
nucleic acids (PNAs) to target intracellular RNA polymerase a subunit (rpoA) expression, and found a
50% reduction in gene expression at 1 µM[105]
.
Polymersomes are lipid based delivery systems that can release their encapsulated molecule under a
variety of conditions such as change in pH, redox potential, ionic strength or instability within the
design of the system[106]. Polymersomes have the ability to encapsulate amphiphilic, hydrophobic,
and hydrophilic molecules making them well suited to carrying proteins [107]. They have been shown
to have the capacity to deliver drug mixtures of doxorubicin (DOX) and paclitaxel (TAX) into tumour
tissues in hours at a low pH and 37°C [108]
.

4.3.1. Affimers as Therapeutics and Diagnostics
As discussed in the introduction (see 1.5.2) there are currently no clinically approved metallo-ß?lactamase inhibitors currently in use, though some are in late-stage clinical trials. This goes to
demonstrate the potential impact a successful inhibitory Affimer could have clinically. If it could be
shown that inhibition is possible through the use of an Affimer reagent against a single MBL, tests
could be performed to identify any potential inhibition of related MBLs. If it was not applicable due
to the binding location varying between tangentially related MBLs, the high variability in binding
potential for the rest of the phage library could be screened in a similar way against a new target or
ranges of targets, in order to try and identify a specific binder – and potential inhibitor – for each.

hydrolyse the nitrocefin reagent
independently or inhibit VIM-1 activity.