IGF2R-Targeted Alpha Therapy of Osteosarcoma Enabled by Conjugated [²²⁵Ac]Ac-Macropa-PEG₄-IF3

Area of Science:

• Nuclear Medicine
• Oncology
• Radiopharmaceutical Chemistry

Background:

• Osteosarcoma has poor survival rates with limited treatment options.
• Targeted alpha therapy (TAT) offers a potent treatment modality for solid tumors.
• Insulin-like growth factor-2 receptor (IGF2R) is a promising target for osteosarcoma therapy.

Purpose of the Study:

• To formulate and evaluate a chemically optimized [225Ac]Ac-labeled radioimmunoconjugate targeting IGF2R for osteosarcoma.
• To assess the in vitro and in vivo characteristics of the novel radioimmunoconjugate.
• To determine the therapeutic efficacy and toxicity of the targeted alpha therapy in preclinical models.

Main Methods:

• Thiol-selective conjugation of anti-IGF2R antibody IF3 with Macropa-PEG4-maleimide.
• Radiolabeling with Actinium-225 ([225Ac]).
• In vitro evaluation of radiochemical purity, serum stability, receptor binding, and internalization.
• In vivo biodistribution, dosimetry, and therapeutic efficacy studies in osteosarcoma xenograft mouse models.

Main Results:

• The radioimmunoconjugate ([225Ac]Ac-Macropa-PEG4-IF3) showed excellent radiochemical purity (>98.6%) and stability in human serum (>92% at 168 h).
• High affinity for IGF2R (Kd = 3.8 nM) and efficient receptor-mediated internalization were observed.
• Significant tumor uptake (18.7%ID/g at 72 h) and retention (15.2%ID/g at 168 h) with low bone marrow uptake (1.2%ID/g).
• A single dose of 370 kBq resulted in complete tumor regression in 75% of treated mice with no significant systemic toxicity.

Conclusions:

• [225Ac]Ac-Macropa-PEG4-IF3 is a potent and well-characterized targeted alpha therapeutic candidate for osteosarcoma.
• The radioimmunoconjugate exhibits favorable pharmacokinetics, high tumor targeting, and significant therapeutic efficacy.
• This approach represents a promising translational strategy for treating osteosarcoma with low off-target toxicity.