Background GS-1423 is a first-in-class bifunctional molecule comprised of an anti-CD73 antibody fused to the extracellular domain of TGFβ receptor II (TGFβRII). GS-1423 is designed to inhibit CD73-mediated adenosine production and neutralize active TGFβ within the tumor microenvironment. Dual antagonism of these 2 broadly immunosuppressive barriers is anticipated to facilitate productive anti-tumor immunity.
Methods This open label Phase 1a study (NCT03954704) evaluated the safety, tolerability, and pharmacokinetics of GS-1423. Exploratory biomarkers included the evaluation of the inhibition of GS-1423 targets, i.e.CD73 and TGFβ, in the periphery. Biomarker assessments were performed in serial blood samples from patients receiving GS-1423 every two weeks (Q2W). Biomarker assays, unless otherwise stated, were custom built and qualified to measure the following: 1) TGF-beta 1/2/3 (Luminex, Bio-Rad) in platelet poor plasma, 2) CD73 target occupancy (TO) on B and CD8 T cells in whole blood, 3) free soluble CD73 (sCD73) not bound to GS-1423, and 4) sCD73 activity in platelet poor plasma. Biomarker values were plotted longitudinally by patient and by dose.
Results A dose dependent decrease in TGF-beta 1/2/3 in plasma of patients was observed on treatment. There was no detectable TGFβ at the 20 mg/kg dose level and above at 2 hours post first dose and for the duration of the Q2W dosing interval. A dose dependent increase in CD73 TO on B and CD8 T cells was also observed with treatment, and complete TO was achieved at 20 mg/kg and above at 2 hours post first dose for the duration of the Q2W dosing interval. Free sCD73 decreased at 2 hours post first dose, while remaining above the lower limit of quantitation, and then increased above baseline after 24 hours post-dose at the 3 mg/kg dose level and above. The sCD73 activity in blood correlated with changes in free sCD73 levels.
Conclusions Blood biomarker analyses of GS-1423 in patients with advanced solid tumors demonstrated undetectable soluble TGFβ1/2/3 and complete TO of CD73 on B and T cells at the 20 mg/kg dose level and above. The mechanism underlying the increase in sCD73 following GS-1423 treatment remains to be elucidated.
Ethics Approval The study obtained ethics approval from the IRB/IEC and all participants gave informed consent before taking part in the study.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.