Genetic Polymer^™ Technology

Streamlining Protein Pharmaceutical Development

In the first half of 2007, we formed a spin-off company, Aequus BioPharma, Inc., to further develop a technology created by CTI scientists that extends the plasma half-life of recombinant DNA (rDNA) derived protein pharmaceuticals. This technology, called Genetic Polymer^™ technology, may simplify the development and manufacture of biologics reducing time to market and lowering costs.

Biologics, especially pharmaceuticals derived from recombinant DNA (rDNA), represent the fastest growing segment of pharmaceutical sales. Current sales reach $51 billion worldwide and expected to hit $87 billion by 2010. Industrial-scale protein production technologies are currently being applied to the development of a wide variety of these drugs, including hormones, growth factors, antibodies, and cytokine modulators, to treat a vast range of human diseases.

Extending Plasma Half-life

Frequently, rDNA-derived protein pharmaceuticals have a relatively short plasma half-life. To rectify this problem, several physical, genetic, and chemical approaches have been developed to extend plasma half-life—without compromising efficacy or introducing safety issues such as immunogenicity and other off-mechanism toxicities.

The most successful of these approaches include site-specific amino acid substitution, conjugation to carrier domains, and post-expression chemical conjugation. Genetic Polymer technology may simplify the use of chemical conjugation technology to extend plasma half-life by genetically attaching an amino acid polymer domain to a biologically active protein sequence to create a novel, unique, and patentable gene.

Mechanism of Action

To construct a Genetic Polymer, the DNA sequence encoding a specific amino acid polymer is ligated, or attached, to the DNA sequence encoding a biologically active peptide- or protein-based drug moiety in an expression vector designed for use in a bacterial, yeast, mammalian, or other recombinant protein expression system. The amino acid polymer can be attached to either the N-terminus, C-terminus or both termini of a protein. Typically, DNA encoding a secretion-leader sequence is included in the expression vector to drive secretion of the expressed protein to the extracellular space to facilitate recovery and purification.

A prototypical Genetic Polymer protein is depicted in the schematic shown below. It should be noted that potential post-translational modifications (PTM) present on more than one amino acid repeat are omitted for clarity.

Schematic of a Genetic Polymer™ Protein

Strategic Significance

In addition to its potential for producing lower cost follow-on biologics, we believe this recombinant DNA technology might be used to develop novel biologics, in a wide array of malignant, inflammatory, or infectious diseases. The Genetic Polymer technology platform should be applicable to many different protein pharmaceuticals. This, in turn, may eliminate the need to develop individualized technology for extending the plasma half-life of each protein pharmaceutical, allowing for more convenient dosing.

Our data also suggest that biosynthesis in traditional mammalian cell protein expression systems will allow for the production of a protein pharmaceutical with prolonged plasma half-life, but without the requirement for further chemical modifications subsequent to protein expression.

It is our opinion that this proprietary Genetic Polymer technology creates novel compositions of matter, allowing for the commercialization of protein pharmaceuticals without infringing on the patents of other companies with competing technologies. The first protein pharmaceutical the company plans to move into preclinical and chemical development studies is a novel, long-acting G-CSF biosimilar.