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| Title | Sym024 interacts with a unique epitope on the CD73 homodimer, favoring effective bivalent binding to improve anti-PD1 therapy. |
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| Journal, issue, pages | Clin Cancer Res, Year 2026 |
| Publish date | Jan 9, 2026 |
 Authors | Janus S Jakobsen / Michael M Grandal / Randi W Hansen / Harsh Bansia / Emily Armbruster / Isabelle Theret / Niels Jørgen Ø Skartved / Rikke Hald / Maria C Melander / Anne Worsaae / Matteo Riva / Kristian Reckzeh / Laurent Vuillard / Johan Lantto / Amedee des Georges / Camilla Fröhlich /    |
| PubMed Abstract | PURPOSE: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical ...PURPOSE: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of PD(L)-1 immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. Here, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action. EXPERIMENTAL DESIGN: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys. RESULTS: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No pre-clinical safety flags were observed, and the pharmacokinetics profile of Sym024 supported a standard clinical dosing regimen. CONCLUSIONS: The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD(L)-1/anti-CD73 combination treatment. |
 External links | Clin Cancer Res / PubMed:41511395 |
| Methods | EM (single particle) |
| Resolution | 2.66 - 3.2 Å |
| Structure data |  EMDB-71123: CD73-Sym024 focused map 1  EMDB-71125: CD73-Sym024 consensus map  EMDB-71126: CD73_Sym024 focused map 2  EMDB-71127: CD73-Sym024 focused map 3 EMDB-71128, PDB-9p1m: |
| Chemicals |  ChemComp-NAG:  ChemComp-ZN: |
| Source |
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 Keywords | HYDROLASE / Antigen-Antibody Complex / Drug Target |
homo sapiens (human)