Increased affinity by dimerization of radiolabeled Affibody molecule ATH001 targeting PDGFRβ

Area of Science:

• Radiopharmaceutical development
• Molecular imaging
• Cancer biology

Background:

• Platelet-derived growth factor receptor-β (PDGFRβ) is a key marker in the tumor microenvironment, making it a target for cancer therapies.
• ATH001 is an Affibody molecule targeting PDGFRβ, with potential for anti-cancer drugs and radioligand therapy (RLT).
• Dimerization of ATH001 was hypothesized to enhance PDGFRβ targeting efficacy.

Purpose of the Study:

• To evaluate a novel dimerized construct, ATH022, for targeting PDGFRβ.
• To compare the in vitro and in vivo performance of Gallium-68 and Indium-111 labeled ATH022 against the monomeric ATH001.

Main Methods:

• Synthesis of dimeric ATH022 by conjugating two ATH001 binders to a linker with a DOTA chelator.
• In vitro and in vivo evaluation of Gallium-68 and Indium-111 labeled ATH022 and ATH001.
• Assessment of PDGFRβ antagonism and binding affinity, including off-rate determination.
• Cellular and tissue-based binding studies, including blocking experiments.

Main Results:

• DOTA-ATH022 demonstrated PDGFRβ antagonism and a tenfold increase in affinity compared to DOTA-ATH001, primarily due to a reduced off-rate.
• Radiolabeled DOTA-ATH022 exhibited enhanced specific binding and retention in U87 cells and PDGFRβ-positive spleen tissue.
• While spleen binding was threefold higher and retention fivefold longer for ATH022, solid tumor uptake in U87 models was not improved.

Conclusions:

• DOTA-ATH022 represents a dimerized Affibody molecule with significantly enhanced affinity for PDGFRβ.
• Increased retention in PDGFRβ-avid tissues was observed for radiolabeled DOTA-ATH022.
• The dimeric construct did not lead to improved uptake in solid tumor tissue despite enhanced affinity.