An online recording of the full presentation held by Dr Høgset will be made available on PCI Biotech’s website (www.pcibiotech.com) under “Scientific publications & presentations” after the event.
Gleder meg til å se den
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ABG har vel heller ikke inkludert Asia markedet i RELEASE studien (og er ikke det flere tusen nye pasienter årlig)…
?
Samtidig skriver de lovende proof of concept data (mRNA) 
Kursmål er 37kr.
Og 0 verdi tydeligvis på Vacc og Nac. I og med de skriver økt potensialet etter resultater for potensielle Nac avtaler 
Synes 37 er et greit kursmål Jubel.
Tross alt 9 kr over dagens aksjekurs.
Husk 
alle monner drar 
♂
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Although gene insertion into macrophages has proven difficult, the results presented here show that non-viral transfection of the [cytosine deaminase prodrug activating] CD gene into these immune cells can be enhanced via PCI. CD transfected NR8383 cells could efficiently convert 5-FC to 5-FU and export the drug, producing a pronounced bystander toxic effect on adjacent non-transfected glioma cells. Compared to single treatment, repetitive PCI-induced transfection was more efficient at low CD plasmid concentration.
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PCI Biotech: Invitation to fourth quarter 2020 results presentation
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Jeg vet ikke om du er klar over hva du akkurat har gjort?!
Nå har du hele PCIB-gjengen etter deg, you can run but you can’t hide;
We don’t have money. But what we do have are a very particular set of skills; skills we have acquired over a very long career. Skills that make us a nightmare for people like you. If you let PCIB go now, that’ll be the end of it. We will not look for you, we will not pursue you. But if you don’t, we will look for you, we will find you, and we will tickle you.
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Men det er i beste fall dårlig stil å kjøre manøveren du gjør her og nå!
@Savepig kommer vel å rydder opp i fundamentaltråden 
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PCI Biotech fourth quarter and preliminary full year 2020 results
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Kristian Berg med i ny artikkel, sammen med amerikanske forskere. Denne PCI-forskningen snakket han om i podcast 104.
Potential for gene-directed enzyme prodrug therapy of gliomas:
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Angående fimaVacc fase 2. Legger det også her, så det ikke pulveriseres i småprattråden. Hør lydklippet fra DNB Markets Session II with E-health session.
Vær oppmerksom på at dette ble sagt før jul 2020, så «next year» er 2021.
RESULTAT CLINICAL DATA FIMAVACC fase 2 i 2022!! Dette ble også gjentatt av PW under spørsmålsrunden under Q i går. Det betyr at fimaVacc fase 2 snart må offentliggjøres.
Det tar mindre enn 1 minutt å høre lydklippet.
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Man lærer mye av å lese forskningsartikler. Men de er lange som et uår. Her er en slik med noen siteringer fra artikkelen (engelsk), blandet med mine kommentarer (norsk)
Kilde: mRNA vaccine for cancer immunotherapy | Molecular Cancer | Full Text
LNP ble i opprinnelsen laget for å levere siRNA, men brukes nå også for å levere mRNA. Det sier vel litt om at der kan finnes bedre løsninger? Endosomal escape eri så fall et stort problem:
only 1–2% of siRNA delivered by DLin-MC3-DMA LNPs could escape from the endosomes into cytosols. Moreover, the cytosolic release of siRNA/mRNA only occurs during a narrow window of time when the LNPs reside in early matured endosomes.
Moderna har klart å forbedre dette 6-fold, men ikke 200X som PCIB:
Ionizable lipids or helper lipids with increased fusogenicity have been incorporated into LNPs to improve the endosomal escape of mRNA/siRNAs. For instance, Moderna L5 LNPs showed 6-fold higher rate of endosomal escape as compared to the DLlin-MC3-DMA LNPs
Immunresponser er et stort problem for mRNA vaksiner:
Most RNActive® vaccines are well tolerated and immunogenic in patients, some of them have shown moderate antitumor efficacy.
In most clinical trials, mRNA cancer vaccines are further combined with checkpoint modulators or cytokine cocktails to augment antitumor efficacy.
In some cases, CD4+ T cell-mediated immune response is partially involved and required, whereas CD8+ cytotoxic T cells play crucial roles in the clearance of malignant cells with somatic mutations. Thus the anticancer therapeutic vaccine not only needs to boost humoral response, CD4+ T cell response but also needs to activate the MHCI mediated CD+ 8 T cells responses, which further adds to the difficulties for efficient boosting of a robust antitumor immunity.
De som til nå regnes som de store. Altså ingen BP. Paradigmeskifte?:
CureVac, BioNTech and Moderna as pioneers in the campaign.
Der dukket også vår samarbeidspartner i Belgia opp:
One pioneer player in this field is eTheRNA immunotherapies. The company has developed a TriMix mRNA-based adjuvant that consists of three naked mRNA molecules, encoding the costimulatory molecule CD70 to induce activation of CD8+ T cells, the activation stimulator CD40 ligand (CD40L) to activate CD4+ T cells,
mRNA vaksiner spås en lysende fremtid, men der er stort forbedringspotensiale! :
Compared to protein or cell-mediated vaccines, the IVT production of mRNA is free of cellular and pathogenic viral components, with no infectious possibilities.
Another advantage of mRNA cancer vaccine is the rapid and scalable manufacturing. The mature manufacturing process of mRNA and formulation platform allows productions of a same or a new type of vaccine within a very short period.
To further improve the potency of mRNA anticancer vaccines, multiple clinical trials are ongoing to evaluate the combination of mRNA vaccines with either cytokine therapies or checkpoint inhibitor therapies.
Future investigations should continue focusing on (but not limited to) understanding and utilizing the paradoxical inherent innate immunity of mRNA, improving the efficiency of antigen expression and presentation by designing advanced and tolerable delivery systems, and modifying mRNA structures to achieve extended and controlled duration of expression.
Konklusjonen min: her er det stort behov for forbedringer, og det vil bli brukt enorme summer i et kappløp for å få de beste vaksinene, og en bedre levering av mRNA, siRNA, miRNA etc. I tillegg trengst en boost av immunresponser. Har PCIB noe slikt i tillegg??
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Her er litt helgekos for de av dere som interessert i medisinlevering., og paradigmeskiftet vi befinner oss i.
Går ut fra at dette er av interesse for PCIB, i og med de sammenligner sin leveringsteknologi mot LNP. Det ble gjort både under RNA Terapeutics og under sist Q.
Jeg refererer til en forskningsrapport som kom denne uken (23.02.21) av Astrazeneca.
Rapporten omhandler leveringsproblemer (endosomal escape) og bivirkninger (cytotoxicity) knyttet opp mot levering av mRNA med LNP.
For å si det forsiktig: Astrazeneca ser ikke ut til å ha løst leveringsproblemene til LNP, verken for effekt eller bivirkninger! De famler tilsynelatende rundt i blinde (eller «mysterious» som de selv kaller det) , og driver fullskala parametrisering for å løse problemene knyttet til levering og bivirkninger (mRNA på avveie kan gi cytotoxicity). Rapporten er forfattet av AZ sine folk stasjonert i Gøteborg, Annette Bak blant andre.
Alt som står på engelsk er direkte siteringer fra forskningsrapporten, med link helt nederst.
Mine kommentarer er skrevet på norsk med fet type skrift, og er mine tolkninger. Dere står selvsagt fritt til å tolke selv, men essensen i rapporten er ikke til å ta feil av: LEVERING MED LNP SLITER MED DÅRLIG EFFEKT, OG MRNA PÅ AVVEIEI GIR ØKT RISIKO FOR BIVIRKNINGER!
LNP er førstegenerasjons leveringsmetode for mRNA. Parametriseringen de står ovenfor vil bli en enorm jobb, og det er ikke sikkert de vil oppnå ønskede resultat i enden. Jeg ønsker de lykke til med jobben.
——————-
De virker ikke å ha helt oversikt over egen teknologi (LNP), annet enn at det ikke fungerer godt nok verken for effekt eller bivirkninger:
The biggest challenge for the delivery of mRNA, and macromolecular therapeutics in general, is to target them to the correct cells and, once endocytosed, let them cross the endosomal membrane. Only a small fraction of exogenous macromolecules can escape from endosomes via yet unknown mechanisms.
Besides the endosomal compartments granting RNA escape, the underlying mechanisms remain mysterious.
Delivery of exogenous mRNA using lipid nanoparticles (LNP) is a promising strategy for therapeutics. However, a bottleneck remains the poor understanding of the parameters that correlate with endosomal escape vs. cytotoxicity. To address this problem, we compared the endosomal distribution of six LNP-mRNA formulations of diverse chemical composition and efficacy, similar to those employed in mRNA-based vaccines.
LNP had different uptake efficiencies and, most importantly, different endosomal distributions.
However, none of these mechanisms have received compelling experimental support and endosome bursting appears restricted to lipoplexes but not to LNP.
Endosomal recycling tubules are characterized by high positive curvature along the tubules and sharp transition to negative curvature at the neck of the tubules. Exogenous cationic lipids may interfere with the packing of lipids in the membrane bilayer, resulting in local instability and, thus, membrane leakage. In addition, recycling tubule fission could create spontaneous breakage of the membrane favouring macromolecular escape. Therefore, we propose that endosomes with recycling tubules are hotspots for mRNA escape events.
The accumulation of undeliverable LNP-mRNA in endosomes does not support the hypothesis of endosome disruption by the proton sponge mechanism and argues that retarding cargo degradation along the endosomal pathway may not increase the chance for cargo escape but rather contribute to toxic effects.
If the endosomal pH is above the pH required for LNP lipid reorganization, the unpacking of LNP and release of mRNA within the endosomal lumen will fail. In addition, acidification is critical to various endosomal activities, such as protein sorting, endosomal progression, lysosomal degradation and cellular homeostasis, that if compromised will have a series of cytotoxic consequences.
In addition to cytotoxicity, these alterations may cause an inflammatory response, similar to the immune system defects characterizing lysosomal storage disorders. Therefore, defective endosomal acidification may account for a great deal of the cytotoxic effects of LNP.
LNP have different chemical compositions and show vastly different delivery efficiency, toxicity and immunological liability. The mechanistic basis for such differences is unclear.
Besides endocytosis, a major challenge remains the ability of RNA to cross the endosomal membrane
Ineffective escape from endosomes imposes higher dosage, thus causing toxicity. Toxicity is due to both cell autonomous, i.e. cytotoxicity, as well as non-cell autonomous effects, e.g. inflammation
Whether they include alterations of the endosomal system is unknown.
Major improvements towards clinical application have come from chemical modifications of RNAs that increase stability and reduce immunogenicity. Nevertheless, efficacy remains a crucial challenge due to limited or poor delivery
The precise site(s) and mechanisms whereby LNP help mRNA escape from the endosomal lumen are to date mysterious. Escape efficiency arguably depends on the distribution of LNP in various subcellular compartments, of which only a selected few are poised to macromolecule escape. Previous studies have yielded contradictory results on LNP internalization, endosomal distribution and escape of RNA (siRNA). Whereas we and others reported that escape is restricted to an early endosomal compartment prior to conversion into late endosomes.
Despite claims of membrane fusion and imaging mRNA escape into the cytoplasm, the sensitivity and resolution of conventional microscopic techniques are insufficient to visualize escape of a small number of mRNAs
Furthermore, the complexity of the endosomal network cannot be underestimated
Så har det gjort noen grep for å gjøre det problemet mindre:
By super-resolution microscopy we could resolve single LNP-mRNA within sub-endosomal compartments and capture events of mRNA escape from endosomal recycling tubules. Our results change the view of the mechanisms of endosomal escape and define quantitative parameters to guide the development of mRNA formulations towards higher efficacy and lower cytotoxicity.
To address this critical problem, we aimed to determine whether differences in LNP- mediated mRNA (LNP-mRNA) delivery efficacy may originate from variations
To gain insights into this outstanding problem, we performed a comparative analysis of six LNP with distinct chemical composition and delivery efficiency in primary human adipocytes.
Og så har de tydeligvis lært noe nytt om endosomal escape:
Our results change the view of the mechanisms of endosomal escape and define quantitative parameters to guide the development of mRNA formulations towards higher efficacy and lower cytotoxicity.
Men dette leser jeg som at sakte rate av levering kan gi bivirkninger, og PCI gir jo hurtig levering når belysningen skjer, så vidt jeg kan skjønne:
Prolonged uptake impaired endosomal acidification, a sign of cytotoxicity, and caused mRNA to accumulate in compartments defective in cargo transport and unproductive for delivery.
Men jeg tenker at de har lært noe for å muligens gjøre LNPs bedre, men etter min vurdering likevel ikke blir like bra som PCI etter justeringene de gjør, og de gjør det utrolig komplisert med masse parametere de skal holde orden på for å gjøre det litt bedre:
A possible strategy would be to develop LNP that can distribute more evenly between endosomes or even preferentially sorted to recycling tubules. For this, extended binding to LDLR may prolong the resident time in recycling endosomes, increasing efficacy and decreasing toxicity. We suggest the importance to carry out a structure/function relationship analysis of different LNP components, e.g. structure of lipid heads and tails, with respect to the different delivery stages independently of each other, but also with respect to the cytotoxic effects derived from the block of acidification. The assays and parameters to measure them described in this study can therefore complement the chemical optimization of delivery systems.»
Slik jeg forstår dette så dreier dette seg om at mRNAet som kommer på avveie under levering kommer litt mindre på avveie, ref slide 22 på fimaNAC presentasjonen:
Men der foreligger et stort behov i markedet for videreutvikling av RNA terapeutics:
In recent years, RNAs have emerged as potentially powerful therapeutics to inhibit gene expression (splicing modulators, siRNAs and antisense oligonucleotides), express proteins (mRNA) or gene editing (CRISPR/Cas9 system). An increasing number of RNA-based therapeutics have proven effective for clinical treatment. More recently, optimization of chemical and physical properties have focused the attention on mRNA-based therapeutics, including for vaccines
Lenke: https://www.biorxiv.org/content/10.1101/2020.12.18.423541v2.full
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At det nettopp ble kjent at PCIB har en patentsøknad inne med denne beskrivelsen, passer kanskje godt som første innlegg under det ovenfor:
It has been found that the method provides superior in vivo delivery of mRNA to target cells relative to the use of lipofectamine as the gold standard for mRNA delivery. This provides a method suitable for various therapeutic applications.
God helg!
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Imponerende Lenny 
Kan eg spør, er du lege eller jobber du innen feltet ?
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Ikke lege nei. Jeg er utdannet innen biologi, fysikk, kjemi og matematikk, og underviser i disse fagene i tillegg til forskningsfag. Men jeg har gode kontakter, og tilgang til folk i bransjen.
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Dette er småprat prat
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Sørlendingen sitt innlegg
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Hver måned kårer jeg det jeg kaller Teksperter™ for noen av de mest populære investeringene våre
Det er de 3 medlemmene som har fått flest likes på innleggene sine de siste 90 dagene. Teksperter™ får også en unikt merke på profilen sin og et trofé-ikon ved siden av navnet sitt. Du kan bli Tekspert™ i flere aksjer/investeringer, og troféet vil bare vises i tråder der du er Tekspert™.
Her er denne månedens Teksperter™ og det mest likte innlegget deres fra de siste 90 dagene:
- @lenny (3644 likes)
- @Jubel (1280 likes)
- @StockDZ (834 likes)
Resten av topp 10:
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@Sorlendingen (682 likes)
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@Investor (667 likes)
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@magga (651 likes)
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@Snoeffelen (489 likes)
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@ufo (347 likes)
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Gratulerer!
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