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Background <p>Platelet-derived growth factor receptor–β (PDGFRβ) is a canonical marker of pericytes and stromal cells in most tissues. It is present on cancer associated fibroblasts (CAFs) in the tumor microenvironment and has thus been proposed as a potential therapeutic target both for anti-cancer drugs as well as for radioligand therapy (RLT). ATH001 is a novel Affibody molecule-based radiopharmaceutical in clinical development for targeting of PDGFRβ. We hypothesize that dimerization of ATH001 could improve affinity to PDGFRβ, leading to better characteristics for in vivo targeting. The dimeric construct, named ATH022, was generated by conjugation of two chemically synthesized ATH001 binders to a tri-functional linker comprising a DOTA chelator. Here, we present a comprehensive in vitro and in vivo evaluation of Gallium-68 and Indium-111 labeled ATH022, in direct comparison with ATH001.</p> Results <p>DOTA-ATH022 acted as a PDGFRβ antagonist and competed dose-dependently with the endogenous ligand PDGF-BB. Affinity of the dimer was improved approximately tenfold compared to DOTA-ATH001, mainly due to strongly decreased off-rate. Radiolabeled DOTA-ATH022 demonstrated higher specific binding and longer retention to U87 cells in vitro. Radiolabeled DOTA-ATH022 also exhibited elevated binding in PDGFRβ-positive tissues spleen and U87 tumors, that could be blocked by ATH001 in excess. Binding of DOTA-ATH022 in PDGFRβ avid and well-perfused spleen was 3 times higher than for DOTA-ATH001, but tumor binding was lower. In vivo retention in spleen was 5 times longer for Indium-111 labeled ATH022, in agreement with its in vitro binding characteristics.</p> Conclusions <p>DOTA-ATH022 is a novel dimerized version of ATH001, with significantly improved affinity towards PDGFRβ. Retention of radiolabeled DOTA-ATH022 in PDGFRβ-avid tissues and tumors was increased, however uptake in solid tumor tissue was not improved.</p>

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Increased affinity by dimerization of radiolabeled Affibody molecule ATH001 targeting PDGFRβ

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月16日

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  • Ayman Abouzayed,
  • Hugo Olsson,
  • Natalia Papadopoulos,
  • Bogdan Mitran,
  • Hemantha Mallapura,
  • Tahmida Akter,
  • Irina Velikyan,
  • Olle Korsgren,
  • Carl-Henrik Heldin,
  • John Löfblom,
  • Michael Wagner,
  • Olof Eriksson

摘要

Background

Platelet-derived growth factor receptor–β (PDGFRβ) is a canonical marker of pericytes and stromal cells in most tissues. It is present on cancer associated fibroblasts (CAFs) in the tumor microenvironment and has thus been proposed as a potential therapeutic target both for anti-cancer drugs as well as for radioligand therapy (RLT). ATH001 is a novel Affibody molecule-based radiopharmaceutical in clinical development for targeting of PDGFRβ. We hypothesize that dimerization of ATH001 could improve affinity to PDGFRβ, leading to better characteristics for in vivo targeting. The dimeric construct, named ATH022, was generated by conjugation of two chemically synthesized ATH001 binders to a tri-functional linker comprising a DOTA chelator. Here, we present a comprehensive in vitro and in vivo evaluation of Gallium-68 and Indium-111 labeled ATH022, in direct comparison with ATH001.

Results

DOTA-ATH022 acted as a PDGFRβ antagonist and competed dose-dependently with the endogenous ligand PDGF-BB. Affinity of the dimer was improved approximately tenfold compared to DOTA-ATH001, mainly due to strongly decreased off-rate. Radiolabeled DOTA-ATH022 demonstrated higher specific binding and longer retention to U87 cells in vitro. Radiolabeled DOTA-ATH022 also exhibited elevated binding in PDGFRβ-positive tissues spleen and U87 tumors, that could be blocked by ATH001 in excess. Binding of DOTA-ATH022 in PDGFRβ avid and well-perfused spleen was 3 times higher than for DOTA-ATH001, but tumor binding was lower. In vivo retention in spleen was 5 times longer for Indium-111 labeled ATH022, in agreement with its in vitro binding characteristics.

Conclusions

DOTA-ATH022 is a novel dimerized version of ATH001, with significantly improved affinity towards PDGFRβ. Retention of radiolabeled DOTA-ATH022 in PDGFRβ-avid tissues and tumors was increased, however uptake in solid tumor tissue was not improved.