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consideration-synthesis, optimization, and formulation--to
deliver the cargo to the target site.
Although currently best known for their work
with Pfizer on the BNT162b2 mRNA vaccine for
SARS-CoV-2, according to Heinrich Haas, PhD, Vice
President RNA Formulation and Drug Delivery,
BioNTech, one of the company's key areas of
development is cancer immunotherapies.
To achieve this particular type of vaccination an
mRNA that codes for a tumor-associated antigen
(TAA) is transferred into dendritic cells, which
have a key function in tumor therapy. Inside
the cells the mRNA is translated and stimulates
a cascade of immune responses specific to the
TAA in addition to a systemic immune response.
R&D Formulation Development
The coding region of mRNA contains the information
required to synthesize a protein. Other
important elements include the 5' and 3' UTR
regions, a 5' cap and a 3' polyA tail. Synergistically,
the elements make a pharmaceutically-applicable
molecule and need to be optimized
individually to facilitate increased intercellular
half-life, translation, and MHC presentation.
" The good thing is that mRNA can be manufactured
in a cell-free in vitro transcription (IVT)
enzymatic reaction, " said Haas. A DNA plasmid
containing the DNA template is linearized, and
RNA polymerase, nucleotide triphosphates
(NTPs), modified UTP substrates, inorganic
pyrophosphatase, ribonuclease inhibitors,
Heinrich Haas, PhD, Vice
President RNA Formulation and
Drug Delivery, BioNTech
and the cap structure are added. Once the
mRNA is transcribed, the DNA is digested.
Then, importantly, the RNA needs to be
formulated for delivery. " Here the challenges
are a bit higher than for small molecules as
many functions need to be fulfilled by the
formulation, " said Haas. The formulation has
to control serum interactions and protect the
RNA from degradation in circulation, control
biodistribution and deliver the RNA to the target
site, enable and improve cellular uptake and
translation at the target site, and, finally, ensure
protein expression and release into circulation.
Most lipid nanoparticle formulations consist
of four components: the ionizable lipid (e.g.
DODMA, Dlin-MC3-DMA), cholesterol, helper
lipid (DSPC, DOPE) and grafted lipid (PEG-lipid).
The ionizable lipid is positively charged at low
pH and neutral at higher pH. The ionizable
lipids bind the RNA in the positively charged
state through electrostatic interactions and
their pKa values are tailored to favor release | 25


Table of Contents for the Digital Edition of Cytiva_Jan2022_mRNAVaccinesANewEra

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