Based on a technology that expands the genetic code of E. coli, Ambrx was founded in 2003. The technology was created in the laboratory of Peter Schultz, Ph.D., a chemist at Scripps Research Institute, who started the firm along with Richard DiMarchi, Ph.D., and Troy Wilson, Ph.D. (Dr. DiMarchi, now at Indiana University in Bloomington, co-developed the recombinant insulin Humalog while at Lilly Research Laboratories.)
Ambrx researchers improved Schultz’ prokaryotic process and named it ReCODE™ (reconstituting chemically orthogonal directed engineering). ReCODE combines medicinal chemistry with recombinant DNA-based protein biosynthesis to make next-generation protein therapeutics.
The technology incorporates a novel (non-natural) amino acid at a specific site into proteins like growth hormone. Then polyethylene glycol (PEG) is attached to enhance the protein’s pharmaceutical activity. The PEGylated protein remains active much longer than the native protein.
“We can do once-weekly or even once-monthly dosing compared to wild-type proteins that need daily administration,” says Ho Sung Cho, Ph.D., chief technology officer.
ReCODE improves on first-generation protein therapeutics, such as growth hormone, interferon-alpha, and interferon-beta, Dr. Cho remarks. These proteins are composed of only the 20 natural amino acids and all require frequent injections.
Second-generation protein therapeutics, in which PEG is attached to lysine or cysteine using conventional conjugation, require fewer injections, but they are heterogenous mixtures with suboptimal potency compared to the natural protein.
Ambrx’ ReCODE technology incorporates a novel Ambrx amino acid into a site that preserves protein function and allows site-specific attachment of PEG, explains Dr. Cho. Through directed evolution and selection, specialized orthogonal tRNA synthetases are evolved to selectively modify a similar orthogonal amber stop codon suppressing tRNA. The cell’s translational machinery then incorporates the Ambrx amino acid into a peptide sequence at positions controlled by the amber codon.
“The amber stop codon allows us to expand the genetic code beyond the natural 20 amino acids and code for amino acids of interest,” explains Dr. Cho.
Using ReCODE, Ambrx researchers have incorporated more than 50 new amino acids into proteins in E. coli, yeast, and mammalian cell systems. Ambrx’ method can be applied to multiple protein classes, including cytokines, peptides, and antibodies, to develop treatments for cancer, endocrine disorders, inflammation, and infectious diseases, Dr. Cho claims.