Second Generation pre|CISION^® Peptide Drug Conjugate

In some cases, we believe that the antitumor activity of our small molecule pre|CISION^® drug candidates would be enhanced by altering the pharmacokinetics of both the conjugate and the released warhead to improve tumor exposure. We employ two types of chemical modifications to accomplish this: those that alter the kinetics of cleavage by FAP (kcat/Km) and those that alter the physical properties of the molecule to drive the desired pharmacokinetics. AVA6103 is an example of this approach.

The second generation pre|CISION^® PDC are FAP-enabled warheads with two key advantages over Generation One:

1. Extended capping groups are added to alter the PK of the conjugate and the released warhead, essentially to create a sustained release mechanism and:
2. Additional self-immolative linkers are inserted between the warhead and preCISION^® peptide, allowing an adjustment to the rate of proteolytic warhead cleavage from the peptide (kcat/Km).

These two advances in the pre|CISION^® pipeline allow more tailored delivery of warheads to the tumor microenvironment with the desired PK profile in the tumor v. plasma. With our generation two advances in the platform, warheads that have failed in the clinic due to both therapeutic index as well as PK challenges can be optimized for tumor-specific delivery.