DAC™ and PC-DAC™ Technologies

DAC™ and PC-DAC™ Technologies

Background

The field of peptide therapeutics has been largely unexplored in the clinic despite tremendous progress made in the generation of leads coming from advances in phage display, combinatorial libraries, and the advent of proteomics. The main impetus for the rapid diversion from peptide leads to peptidomimetic small molecules early in the discovery stage comes from the justified belief that no short-acting peptide can overcome patient compliance and manufacturing costs associated with a very brief exposure; most peptides have a plasma half-life of a few minutes.

Direct efforts to block peptide cleavage by altering peptides or inhibiting peptidases have had mixed success and have not provided general solutions to the problem. While these methods have slowed metabolic cleavage, they have not been able to address rapid kidney clearance of small peptides of up to 20 kDa by glomerular filtration. Therefore, from a pharmacokinetic viewpoint, even the modified peptides are not fully satisfactory.

ConjuChem Model

ConjuChem is founded on powerful core technology platforms bonding therapeutic molecules—principally peptides—to albumin. Much smaller than proteins, peptides are well-characterized compounds with very specific and often highly potent activity.

The Drug Affinity Complex (DAC™) and Preformed Conjugate-Drug Affinity Complex (PC-DAC™) technology platforms developed by ConjuChem address the longstanding challenges of protecting peptides from peptidase degradation and preventing their rapid kidney excretion. Achieving this can help to make the development of peptide drugs a practical reality.

Technology Features

Our DAC™ and PC-DAC™ technology platforms and resultant strategies are based on two features:

  • A synthetic modification of a well characterized peptide moiety can yield a modified peptide analogue containing a reactive chemical group but still retaining most of its original biologic activity; the modified peptide is called a drug affinity complex (DAC™).
  • The attachment of the DAC™ through reaction of the active moiety with the free thiol of cysteine-34 of albumin forms a therapeutic bioconjugate. This reaction occurs either in vivo using endogenous albumin (for DAC™) or ex vivo using recombinant albumin (for PC-DAC™).

By bonding to albumin, the DAC™ and PC-DAC™ peptides are protected from rapid degradation and excretion. In addition, these peptides effectively adopt the beneficial pharmacokinetic properties of albumin. They:

  • Are distributed throughout nearly all tissues and organs in the body
  • Do not easily cross the blood-brain barrier, thus preventing most central nervous system side effects
  • Have a long half-life—from 8 to10 days in humans

The attachment to albumin can occur in two independent ways: in vivo to circulating albumin following parenteral administration (DAC™), or ex vivo to recombinant albumin, which is then administered by injection as a preformed conjugate (PC-DAC™). The covalent attachment of a DAC™ to albumin is permanent, and the peptide does not need to be released from the albumin in order to perform its biologic function.

The plasma half-life of peptides can be measured in minutes. The plasma half-life of albumin varies within species: 40 to 48 hours in rats, approximately 60 hours in dogs, and around 15 days in humans.