Discovery of AB680: A Potent and Selective Inhibitor of CD73

Extracellular adenosine (ADO), present
in high concentrations in
the tumor microenvironment (TME), suppresses immune function via inhibition
of T cell and NK cell activation. Intratumoral generation of ADO depends
on the sequential catabolism of ATP by two ecto-nucleotidases, CD39
(ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73
eliminates a major pathway of ADO production in the TME and can reverse
ADO-mediated immune suppression. Extensive interrogation of structure–activity
relationships (SARs), structure-based drug design, and optimization
of pharmacokinetic properties culminated in the discovery of AB680,
a highly potent (Ki = 5 pM), reversible,
and selective inhibitor of CD73. AB680 is further characterized by
very low clearance and long half-lives across preclinical species,
resulting in a PK profile suitable for long-acting parenteral administration.
AB680 is currently being evaluated in phase 1 clinical trials. Initial
data show AB680 is well tolerated and exhibits a pharmacokinetic profile
suitable for biweekly (Q2W) iv-administration in human.