• Our Science
• What is an Aptamer?
• Key R & D Functions:
• Aptamer Discovery
• Drug
  Metabolism & Pharmacokinetics
• Chemistry, Manufacturing, & Controls
• Selected Publications

Oligonucleotides composed of unmodified RNA or DNA are rapidly metabolized by serum and tissue nucleases. While having rapid drug clearance and a short duration of action is desirable for some clinical applications, most of the time a prolonged duration of action is preferable. Over the past ~20 years a number of chemical modifications have been described that significantly stabilize oligonucleotides to nuclease-mediated metabolism. We have adopted several of these well-characterized modifications in the process of creating aptamers that are highly resistant to nuclease degradation.

During our post-SELEX modification processes, we study metabolic stability of early lead molecules in animal and human serum (a nuclease containing matrix). We assess the rate of disappearance of the full length molecule and then, by liquid chromatography and tandem mass spectroscopy, we identify the specific metabolites and sites susceptible to cleavage. With this information, we can then introduce site specific stabilizing modifications into the parent molecule and retest to confirm that nuclease resistance has been achieved. Once the aptamer core has been sufficiently stabilized, we often conjugate the aptamer with a polyethylene glycol (PEG) moiety to create a larger molecule that will be resistant to renal filtration and clearance via excretion. Large molecular weight PEG has been a commonly used and well validated strategy for increasing the circulation half-life of protein and peptide therapeutics. The PEG conjugated aptamer can then be tested in vivo to establish if the desired pharmacokinetics have been achieved. We have enabled a unique set of technologies and know-how which is highly specific to aptamer discovery and development.

Tuning metabolic stability through chemical modification

Through this combination of optimization of metabolism by chemical stabilization and elimination by PEGylation, we are able to precisely design and then confirm the desired PK properties of the resultant development candidate. There is no analogous therapeutic drug discovery technology that allows such precise control of PK properties by rational design. We refer to this as "PK tunability", and it highlights a key strength of the aptamer technology.

"There is no analogous therapeutic drug discovery technology that allows such precise control of PK properties by rational design."

–Renta Hutabarat, Director, DMPK