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IL11 upregulates PDL1 to promote tumour immune escape There will be a lot more coming on this Already heading to clinical trials with Mabwell Therapeutics: aacrjournals.org/cancerres/arti… onlinelibrary.wiley.com/doi/10.1002/ad…

We did epigenetic clock in the mice. Large effect (++). Reviewer 1 made us take it out (despite our protests - see rebuttal at Nature website). Data is shown in our online talks and on BioRxiv (I think). For sure a biomarker of interest for human trials…

A very interesting question. My best guess = nerves. In old IL11-EGFP mice there is big signal in skeletal muscle nerve bundles/NMJ (see Supl figs). Recovery of function with anti-IL11 is > muscle mass effect. So I think innervation is important….

I’ll raise you: How about a clinical trial? We have engineered a super long acting and potent anti-IL11 for human ageing trials at vvb.bio. Faster to humans, not another 5 years in mice Needs investment, build out, approvable endpoints and not easy ++. But..

It is suggested we do more [5 year] mice studies but how about a human trial? We have an anti-IL11 therapy specifically engineered for human ageing trials at vvb.bio. Needs investment, build out, approvable endpoints and not easy +++. But faster to humans…

Stuart Cook Martin Borch Jensen Anissa Widjaja Jamie Timmons Martin Picard Kaitlyn Sadtler, PhD And to keep these thoughts in one🧵: I really think this exciting new understanding of the impacts of IL-11 signaling will help us better understand how Th2-type responses could drive #IACI. There's much metabolic overlap between these illnesses and aging. ncbi.nlm.nih.gov/pmc/articles/P…

💯 We wanted to keep in the clock data, even if pushed to the supplement. We appealed to both the reviewer and [separately] the editor. If something is truly ‘anti-ageing’ it should affect epigenetic clock, across tissues. I think it should be a standard biomarker.

Trametinib common side effects (BNF): Abdominal pain; anaemia; constipation; cough; dehydration; diarrhoea; dry mouth; fever; haemorrhage; hypersensitivity; infection; intracranial haemorrhage; lymphoedema; nausea; dyspnea; stomatitis; vomiting, etc biorxiv.org/content/10.110…

Nice. Check out the GWAS hits for menopause at the IL11 locus… Coincidence?

Pssst - its not just IL11 effects on fibroblasts: “These data show that IL11 inhibits reparative AT2-to-AT1 differentiation in the damaged lung to limit endogenous alveolar regeneration, resulting in fibrotic lung disease” Damaging EMT, as seen in kidney nature.com/articles/s4146…

Timely reminder that the IL-6 (IL-11) trans-signalling idea/field is likely based on an experimental artefact pubmed.ncbi.nlm.nih.gov/38338642/

🙌 IL11 is directly toxic in cardiac myocytes causing calcium handling disturbance and impaired contraction Negatively inotropic in vivo Not just a fibroblast factor Heart failure target? 🤨 academic.oup.com/cardiovascres/…

Nice As predicted: pubmed.ncbi.nlm.nih.gov/36629985/

Clever - non-antibody - ways to inhibit IL11 activity using biased agonist-like modalities to treat fibrotic lung disease: sciencedirect.com/science/articl… And sciencedirect.com/science/articl…

Bi-specific Anti-IL11 + Anti-TSLP Perhaps for asthma? Field moving fast clinicaltrials.gov/study/NCT06612…

Now perhaps the most replicated target gene for lung fibrosis in multiple POC studies Four clinical trials in progress: NCT05331300 NCT05658107 NCT05740475 NCT06612970 All began with PMID: 31554736, just 6 years ago 🚀 pubmed.ncbi.nlm.nih.gov/39791575/

Wonderful leaving dinner with Imperial friends and colleagues last night. Thank you for the kind words and the lovely present, which will be put to very good use! 🤗

Therapeutic (small molecule) inhibition of global gp130 signaling improves right ventricular function in a pig model of RV loading. PAH in humans next? 🙌 scholar.google.com.sg/scholar_url?ur…

Met an “I’m a biotech” guy today. Introduced himself as a ‘serial C-suite’ chap. I thought, what a complete zero-value-add arse. And he was. They mostly are.