The protein pharmaceutical market is driven increasingly by the development of next-generation proteins. Many of these products are derivatives of natural proteins in which the parent molecule has been chemically modified to improve its physical, chemical and pharmacological properties. For example, the covalent attachment of polyethylene glycol chains (i.e., PEGylation) to proteins such as interferon, G-CSF and erythropoietin improved the product profiles of the parent proteins. A growing number of proteins, particularly antibodies, are modified with polymers, toxins, radiolabels and other functional groups.

Current approaches to PEGylation and other posttranslational modifications are limited to a restrictive set of chemistries that are compatible with the 20 natural amino acids. Because these residues are present at multiple sites throughout the protein, it is very difficult to modify proteins with the efficiency and selectivity that is possible with small synthetic molecules and peptides. As a result, chemical modification of proteins typically generates heterogeneous mixtures. This heterogeneity affects the potency and safety of the resulting products.

Ambrx uses an expanded set of amino acids to address the limitations intrinsic to the 20 natural amino acids. Our approach, termed protein medicinal chemistry, combines the power of medicinal chemistry with recombinant biosynthesis. This represents a new paradigm in protein engineering. Ambrx can optimize the pharmaceutical properties of lead candidate proteins, much as medicinal chemistry has been used for decades to improve properties of small molecules and peptides.

Ambrx's ReCODE™ (reconstituted chemically orthogonal directed engineering) technology provides an unprecedented ability to incorporate new chemical functionality into proteins while preserving protein function. Ambrx uses directed evolution and selection strategies to evolve enzymes capable of introducing a novel amino acid at specific sites within proteins. The cell's translational apparatus then incorporates the Ambrx amino acid into the elongating peptide sequence at positions designated by the amber stop codon.