Initial insights into the interaction of antibodies radiolabeled with Lutetium-177 and Actinium-225 with tumor microenvironment in experimental human and canine osteosarcoma

Abstract

Background: Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human monoclonal antibody IF3 to an insulin-like growth factor 2 receptor (IGF2R) radiolabeled with either alpha-emitting Actinium-225 (²²⁵Ac) or beta-emitting Lutetium-177 (¹⁷⁷Lu) radionuclides with the OS cells and tumor microenvironment (TME) in experimental human and canine OS.

Basic procedures: SCID mice bearing canine Gracie or human OS-33 OS tumors were treated with ¹⁷⁷Lu- or ²²⁵Ac-labeled IF3 antibody, sacrificed at 24, 72 or 168 h post-treatment and their tumors were analyzed by immunohistochemistry (IHC) for the presence of OS cells, various elements of TME as well as for the double DNA strand breaks with γH2AX and caspase 3 assays.

Main findings: IHC revealed a reduction in IGF2R-positive OS cells and OS stem cell populations post therapy with ²²⁵Ac- and ¹⁷⁷Lu-labeled IF3 antibody. Notably, radiolabeled IF3 antibody effectively diminished pro-tumorigenic M2 macrophages, highlighting its therapeutic promise. The study also unveiled varied responses of natural killer (NK) cells and M1 macrophages, shedding light on the intricate TME interplay. Time-dependent increase in γ-H2AX staining in canine Gracie and human OS-33 tumors treated with [¹⁷⁷Lu]Lu-IF3 and [²²⁵Ac]Ac-IF3 was observed at 24 and 72 h post-RIT.

Principal conclusions: These findings suggest that radiolabeled antibodies offer a hopeful avenue for personalized OS treatment, emphasizing the importance of understanding their impact on the TME and potential synergies with immunotherapy.

Keywords: Actinium-225; Immunohistochemistry; Lutetium-177; Osteosarcoma; Radioimmunotherapy; Tumor microenvironment.