Chimeric Antigen Receptors are an impressive first step into designed biological technologies. There are new challenges associated with their design and deployment - but there are also a lot of theoretical capabilities that are unmatched non-protein therapeutics. It's very much a new paradigm in treatment. These are 'cures' to human misregulations very much like how small molecules 'cured' patients of foreign diseases a century ago (and do not cure patients of regulatory diseases).
If you want to build your own chimeric antigen receptors we've built a digital infrastructure to allow you [1]. Though we just made public our generic protein design software (thanks ShowHN! [2]), we're employing the same underlying digital infrastructure to build, evaluate, and manage CAR designs in high throughput [3]. The drug approved here was painstakingly designed by hand [4], while we think the technology now exists to permit many more such advances to be created at a much more rapid pace.
Wow, this seems really amazing. I read some background from your show HN, but does your software mostly make DNA plasmids? How would you go about integrating that into a eukaryote? I think in the article they used a retrovirus. Also, plasmids have a maximum size for proteins, do you have a vector to incorporate larger proteins?
The software 'compiles' down to DNA - which can be produced and delivered in any form useful to clients. Most of the time that deliverable is a plasmid.
The plasmid DNA is then used as a reagent to manufacture the physical retroviruses that are used to transduce the extracted T-cells which are then reimplanted into a patient.
Practically, multiple plasmids, each containing a single component of a synthetic retrovirus are given to 'viral manufacturing cells', and the output is pool of virus that is infectious only once, and has DNA that encodes the CAR design as its payload. That virus is then given to the extracted T-cells, where it infects them with the viral payload and integrates its genetic payload into their genomes. Once integrated, the cells are tested to ensure they are not further infectious, then reimplated - newly 'upgraded' with DNA that encodes a synthetic CAR protein that is now capable of homing in and killing the target cancer.
Getting all that payload into a plasmid is certainly an art. A lentiviral capsid has a physical pressure capacity such that it can hold <13kb of DNA. This is precisely why it's so important to have good ways of testing/pruning/evaluating new protein designs so that you can prune down a theoretical design into precisely the minimal design required for effect.
Thanks for this highly informative answer. I'm particularly interested in vaccine-based cancer immunotherapy. Do you know of any good survey papers covering that?
If you want to build your own chimeric antigen receptors we've built a digital infrastructure to allow you [1]. Though we just made public our generic protein design software (thanks ShowHN! [2]), we're employing the same underlying digital infrastructure to build, evaluate, and manage CAR designs in high throughput [3]. The drug approved here was painstakingly designed by hand [4], while we think the technology now exists to permit many more such advances to be created at a much more rapid pace.
[1] https://serotiny.bio/pinecone/
[2] https://news.ycombinator.com/item?id=14446679
[3] https://serotiny.bio/notes/applications/car
[4] https://serotiny.bio/notes/proteins/car19/