Safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies in healthy adults: a phase 1 trial, 2025, Tebas et al.

[Chandelier]

Safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies in healthy adults: a phase 1 trial - Nature Medicine

In a phase 1 trial, intramuscular injection of synthetic plasmid DNA encoding monoclonal antibodies against SARS-CoV-2 was safe and well tolerated and did not elicit antidrug antibodies.

www.nature.com

Spoiler: Authors

Pablo Tebas, Ami Patel, Joseph T. Agnes, Elizabeth M. Parzych, Amanda Baer, Maria Caturla, Sukanya Ghosh, Mansi Purwar, Nicole Bedanova, Chungdhak Tsang, Knashawn Morales, Dinah Amante, Paul D. Fisher, Joseph R. Francica, Laurent Humeau, Daniel W. Kulp, Jesper Pallesen, Paul Leon, Mark Esser, Trevor R. F. Smith & David B. Weiner

Abstract​

Local intramuscular administration of synthetic plasmid DNA (pDNA) encoding monoclonal antibodies (mAb) offers an alternative to recombinant protein-based mAb delivery.
In this phase 1 dose-escalation study, we evaluated the safety, tolerability and pharmacokinetics of a pDNA cocktail encoding AZD5396 and AZD8076, modified versions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing mAb cocktail tixagevimab/cilgavimab in healthy adults.

Participants received up to four intramuscular doses of pDNA encoding both DNA-based mAbs (DMAbs), administered using CELLECTRA electroporation.
The primary endpoints were safety and pharmacokinetics.
All 44 participants received at least one dose; DMAbs were detected in 100% of evaluable participants (n = 39), with serum concentrations reaching a peak of 1.61 µg ml−1.
Sustained expression was observed in all participants during the 72 weeks of follow-up.
The study product was well tolerated, with no product-related serious adverse events reported.
Exploratory analyses demonstrated binding to multiple SARS-CoV-2 Spike protein variants and neutralizing activity in a standard pseudovirus assay.
No antidrug antibodies were detected across approximately 1,000 serum samples using validated tiered assays.

To our knowledge, these data represent the first-in-human proof-of-concept that synthetic pDNA DMAb technology permits the durable in vivo production of a functional mAb cocktail.
This study further underscores the collective importance of synthetic design, formulation and delivery to achieve biologically relevant expression of gene-encoded biologics.
DMAb delivery may represent a long-acting, scalable, cold-chain-independent platform against a wide range of diseases that can be targeted with mAbs and their derivatives.

 

[Chandelier]

@ZdenekVrozina on X:

For the first time ever, a human body was instructed to make lab-designed antibodies against SARS-CoV-2 - by itself - from synthetic DNA.
One shot.
No virus.
Protection lasting over a year.

A new Nature Medicine study tested something called DNA-encoded monoclonal antibodies (DMAbs).
Instead of injecting ready made antibodies, scientists injected synthetic DNA that tells your cells how to make them.
Your muscle becomes a mini factory for antibodies.
The DNA carried blueprints for tixagevimab and cilgavimab - the antibodies used in Evusheld.
It was delivered intramuscularly, with short electric pulses (electroporation) that help DNA enter cells.
The results were remarkable.
Every participant developed measurable antibodies
Those antibodies neutralized multiple SARS-CoV-2 variants (Wuhan, Delta, Omicron BA.5)
Levels stayed detectable for 72 weeks (that’s 1.5 years!)
No serious adverse events
Crucially, no participant developed anti-drug antibodies (ADA) - immune reactions that often sabotage gene-based or protein therapies.
That means the DNA platform triggered expression, not inflammation.
This is a proof of concept that humans can safely express foreign genes from DNA
without integrating them into our genome and without immune rejection.
It’s controlled gene expression, virus-free and clean.
Why this matters
cheaper and more stable than traditional monoclonal antibodies
no cold chain needed
rapidly adaptable to new viral variants
potentially usable for autoimmune or cancer therapies
It’s a small phase 1 trial (44 healthy volunteers) and doesn’t prove real world protection yet.
But it’s the first clinical proof that DNA-coded antibodies can work in humans.
A short flight - but like the Wright brothers, it changes everything.
Immunologically, this is a new form of passive immunity
instead of teaching your body to make antibodies (as vaccines do),
you simply give it the genetic instructions.
And those instructions can last a year or more.
If this platform expands, it could redefine how we produce biologics.
No massive bioreactors. No frozen proteins.
Just a few milligrams of DNA and one injection.