Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
This study characterizes Sym024 (S95024), a novel antagonistic anti-CD73 antibody designed to more completely inhibit adenosine production in the tumor microenvironment and enhance immune checkpoint blockade.
Key points:
- Rationale: CD73 converts AMP to adenosine, a major immunosuppressive pathway in cancer. Partial inhibition of CD73 may limit the benefit of combining CD73 blockade with PD-1/PD-L1 inhibitors, especially in tumors with high CD73 expression and continuous AMP supply.
Methods:
- Sym024 identification: Sym024 was identified via functional antibody repertoire screening.
- Comparisons with other anti-CD73 antibodies in:
- In vitro assays: binding, CD73 enzymatic inhibition, and T-cell activation.
- In vivo models: tumor growth inhibition in human and murine tumor models in both immunocompetent and immunodeficient mice; assessment of intratumoral CD73 inhibition and immune cell recruitment.
- Mechanistic/structural work: surface plasmon resonance, cryo-EM, site-directed mutagenesis, and size-exclusion chromatography with light-scattering mass detection to define the Sym024–CD73 interaction.
- Preclinical safety and pharmacokinetics: evaluated in monkeys.
Main findings:
- CD73 inhibition: Sym024 more effectively blocked CD73 enzymatic activity over a wide range of CD73 expression levels than benchmark anti-CD73 antibodies.
- T-cell activation and antitumor efficacy: It enhanced T-cell activation and improved the antitumor efficacy of PD-1 blockade both in vitro and in vivo.
- Structural analyses: Structural analyses revealed a distinctive one-to-one binding mode between Sym024 and CD73 that underlies its comprehensive enzymatic inhibition.
- Safety and pharmacokinetics: In nonclinical species, no concerning safety signals were identified, and pharmacokinetics were compatible with a conventional clinical dosing schedule.
Clinical implication:
- Further development: The depth and breadth of CD73 inhibition achieved by Sym024 support its further clinical development, particularly in combination with PD-1/PD-L1 inhibitors, with the goal of overcoming adenosine-mediated immunosuppression in solid tumors.