Protein Optimization

Future growth in the protein pharmaceutical market will be driven increasingly by the development of next-generation proteins. First generation protein therapeutics were based upon naturally occurring wild-type proteins harvested from animals or produced through recombinant DNA technology, examples include: tissue plasminogen activator (TPA), erythropoietin (EPO), insulin, G-CSF and interferon-alpha. These naturally occurring proteins in most cases have significant limitations when used as drugs requiring frequent injections with preparations comprised of mixtures of numerous protein species. Second generation protein therapeutics: PEG-Intron®, PEGASYS®, Neulasta®, Aranesp® are based upon a limited set of chemistries that are compatible with the existing 20 natural amino acids and most commonly involve the conjugation of a polyethylene glycol polymer (PEG) to a cysteine or lysine amino acid. This approach, while creating molecules with significantly enhanced time of action, results in a significant loss of potency making it suboptimal for the optimization many classes of protein drug candidates. Thus the optimization of proteins with traditional chemistries is inefficient and limiting when attempting to generate proteins optimized for drug-like properties: preservation of potency, dosing frequency and homogeneity of drug substance.

Ambrx uses an expanded set of amino acids to address the limitations intrinsic to the 20 natural amino acids. Our pioneering protein medicinal chemistry™ drug development process combines the power of medicinal chemistry with recombinant biosynthesis. Through the application of Ambrx’s proprietary technology, numerous variants of the naturally occurring wild-type protein can be generated, each variant containing a single Ambrx Amino acid incorporated into the protein backbone at a location selected by an Ambrx Scientist. This allows for the rational design of molecules in the event that structural information is available, or an empirical approach through substitution at every position and subsequent structure-activity-relationship analysis similar to the approach taken to optimize small molecules or synthetic peptides. This level of control in the application of selective chemistries to proteins represents a new paradigm in protein engineering and allows Ambrx to pursue a broad array of product candidates based upon; proteins, antibodies, antibody fragments and antibody-based bioactive protein and peptide carriers, and tailor them to address specific medical needs of patients. Ambrx will advance molecules that meet or exceed a target product profile through the application of internal resources or though collaboration with other pharmaceutical or biotech companies.