The expansion of the genetic code beyond the 20 canonical amino acids has been exploited to dramatically impact the therapeutic potential of proteins towards a plethora of human health issues. Most notably, the generation of well-defined immunoconjugates (antibodies linked to a variety of chemical entities) can alter the paradigm of cancer treatment, affording an extremely specific and highly regulated mechanism for combating malignant cells.
This research aims to employ non-natural amino acids to develop novel techniques for the generation of immunoconjugates, and investigate their therapeutic potential. Currently there are three conjugated therapeutic antibodies on the market;however, specific issues with the bioconjugation reaction are detrimental to the widespread application of therapeutic immunoconjugates. Most immunoconjugates are generated using chemistries relying upon natural amino acid functionalities (e.g. the amino group of lysine), which results in non-specific labeling of the antibody as it possesses multiple residues which can participate in the bioconjugation reaction. Additionally, the residue may not be solvent-exposed or in an optimal location for bioconjugation. These non-specific reactions produce mixtures of immunoconjugates that possess multiple labels in different locations, which may decrease the functionality of the antibody, as well as lead to issues in regulatory approvals. However, employing the Schultz technology, a unique functionality can be incorporated in a specific location in the antibody, affording a bioconjugation reaction that yields a single product. The incorporation of p-acylphenylalanine into the Fab (fragment, antigen binding) region of an antibody can provide a convenient way to rapidly and efficiently generate immunoconjugates. These antibodies can be coupled to a variety of therapeutic agents such as toxins, radioisotopes, or other biomacromolecules. This approach solves all of the previously noted issues with the generation of therapeutic immunoconjugates and represents the next technological advance for the highly specific treatment of a variety of human health issues.
With the expression of the acylphenylalanine antibody mutant, it becomes feasible to couple a variety of therapeutic agents onto the antibody. Specifically, this research intends to investigate the conjugation of therapeutic small molecules and additional proteins to the antibody to afford targeted delivery and more favorable pharmacokinetic properties.
| Minnihan, Ellen C; Young, Douglas D; Schultz, Peter G et al. (2011) Incorporation of fluorotyrosines into ribonucleotide reductase using an evolved, polyspecific aminoacyl-tRNA synthetase. J Am Chem Soc 133:15942-5 |
| Young, Douglas D; Jockush, Steffen; Turro, Nicholas J et al. (2011) Synthetase polyspecificity as a tool to modulate protein function. Bioorg Med Chem Lett 21:7502-4 |
| Young, Douglas D; Young, Travis S; Jahnz, Michael et al. (2011) An evolved aminoacyl-tRNA synthetase with atypical polysubstrate specificity. Biochemistry 50:1894-900 |
