Siebe. Profile picture
Aug 2, 2023 12 tweets 3 min read Read on X
UCSF, led by @MichaelPelusoMD, is starting this trial with the anti -SARS-CoV-2 spike antibody cocktail AER002.


Why I'm so excited that this can cure viral persistence in Long Covid:classic.clinicaltrials.gov/ct2/show/NCT05…
- AER002 is probably the two mAbs P2G3 LS & P5C3 LS derived from a human, which the inventors of Aerium Therapeutics describe in their paper: ncbi.nlm.nih.gov/pmc/articles/P…
- It has strong neutralization against all SARS-CoV-2 tested (up to BA.5) ➡️ matches the persistent viral stains Image
Both mAbs have Antibody-Dependent Cellular Cytotoxicity (ADCC) & AD Cellu Phagocytosis (ADCP):

mAbs bind to the spikes that are left on the surface of the infected cells and their Fc regions (their tails) act as receptors for NK cells & phagocytes to kill & eat infected cells. Image
That is: they can completely clear out a viral infection, even if there is no detectable viral replication. This circumvents SARS-CoV-2's immune evasion.

PwLC were found to have impaired Antibody-dependent NK cell activation, but not ADCP. medrxiv.org/content/10.110…
The antibodies contain the LS mutation in the Fc region, which appears to confer a half-life on the order of months.

So there's a scenario where it helps to suppress but not fully clear the infection, where you get an infusion 2 or 3 times a year.
The two mAbs given together would also increase the threshold for the virus to develop resistance.

The authors state that the antibodies have good effectiveness against mutations that would escape one or the other.
Downsides:
➡️ Needs IV
➡️ Anecdotally, mAbs sometimes cause inflammation, especially with ADCC. This needs to be managed clinically to prevent collateral damage but not stop the immune system working.
➡️ Can't reach the brain
➡️ If neurons are infected, maar nog want to kill them
They are trialing it in 20 people, with 10 controls with what seems like a pretty high dose (1200mg)
Most other mAbs have very limited ADCC, except for Sotrovimab

CD16 activation is a proxy for ADCC here
ncbi.nlm.nih.gov/pmc/articles/P…
Image
Correction: looks like AER002 only refers to P2G3? (The one with more ADCC & active against BA5, but weaker neutralisation overal)


Not entirely clear thoughlinkedin.com/posts/prakash-…
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More from @PatientPersists

Mar 18
If you want to get better at evaluating science, I can highly recommend the book Science Fictions by @StuartJRitchie

I just finished it, and it has really emphasized the many issues with science & I learned a lot!

A few takeaways 🧵 Image
The image above illustrates it well: looking only at registered trials & their primary outcomes, only 50% of trials found a positive effect of various depression treatments.

However, through publ. bias, outcome switching, spinning results etc, the literature looks much rosier!
Treat every paper with the scepticism for a “CBT for ME/CFS” paper

Just because you like positive results, doesn't mean they're well-supported
Read 14 tweets
Feb 23
This is a great article, worth reading.

A few graphs I noticed in addition to @yaneerbaryam🧵
Quantified BBB per DCE-MRI analysis Image
Read 7 tweets
Feb 14
A great paper on viral persistence, with multiple teams using a variety of methods.

They discovered immune activation, as well as efforts to limit immune activity.

Viral persistence assays (Simoa, nCounter, SPEAR) all pooped out: not finding high levels of antigens or RNA
Sample: they focused on the most severe patients, who had at least some measurable biological dysfunctions (POTS, microvascular, endothelial, pulmonary)

I really like this: presumably easier to find abnormalities in extreme population

Severity doesn't seem measured via scale 🫤 Image
Increased IgG to SARS-CoV-2 in Long Covid vs. convalescent Image
Read 7 tweets
Feb 4
To make LC more attractive to pharma we need

1. A surrogate biomarker

2. An international patient registry ➡️ reduces costly recruitment

3. Public precommitment by FDA for accelerated pathways for the first effective drugs

Explained:

#UniteToFight2024 atelfo.github.io/2023/12/23/bio…
1. A surrogate biomarker

Requires increased (and targeted) government spending.

Patient advocacy groups are clearly focused on this
2. International Patient Registry

Trial enrollment is usually slow and costly to companies.

Patient registries that pre-collect relevant data make it easier for companies to find enough people to match their inclusion criteria.

➡️ Required: ambitious person & bit of funding
Read 5 tweets
Jan 18
This paper has now been uploaded as preprint, and the data is definitely interesting:

➡️ Evidence suggests viral replication in Long Covid
➡️ In whole blood
➡️ In significant fraction of pwLC

Paper:

A summary with graphs 🧵 medrxiv.org/content/10.110…
Sample: 48 pwLC, 12 matched controls. All (but 1) non-hospitalized.
➡️ Bit of a small control group imo

➡️ Analysis done on whole blood, instead of plasma or serum

✅ Significance levels corrected for multiple tests (via FDR)
Transcriptomics measures RNA.

Sense (positive) & Antisense (negative) are the complementary RNA strands.

mRNA (positive), if functional, is needed for a cell to synthesize the particular protein the RNA codes for.
Read 18 tweets
Jan 11
The low serotonin findings in LC & POTS can probably not be treated with SSRIs.

According to my literature search, SSRIs increase serotonin (=5-HT) in the brain but *decrease* peripheral serotonin.

MAOi (and 5-HTP?) may be more effective, but have limitations

🧵
Study 1)

Results
" In 64 SSRI users, median concentrations of plasma-free and platelet serotonin were 10-fold and 14-fold lower, respectively, than in 64 matched controls."
journals.sagepub.com/doi/10.1177/00…
Study 2)

"There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047)."
pubmed.ncbi.nlm.nih.gov/30831543/
Read 12 tweets

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