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Updated: Jun 30, 2026
Isolation and Characterization Of Chimeric Human Fc-expressing Proteins Using Protein A Membrane Adsorbers And A Streamlined Workflow
Published on: January 8, 2014
Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to
Chandra B Prabaharan1, Sabeena Giri2, Kevin J H Allen2
1Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Abstract:
Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, that binds to insulin-like growth factor 2 receptor (IGF2R). IF3 was used in TRT to effectively inhibit tumor growth in osteosarcoma preclinical models. However, IF3's relatively short half-life in mice raised the need for improvement. We generated an Fc-engineered version of IF3, termed IF3δ, with amino acid substitutions known to enhance antibody half-life in human serum. In this study, we confirmed the specific binding of IF3δ to IGF2R with nanomolar affinity, similar to wild-type IF3. Additionally, IF3δ demonstrated binding to human and mouse neonatal Fc receptors (FcRn), indicating the potential for FcRn-mediated endocytosis and recycling. Biodistribution studies in mice showed a higher accumulation of IF3δ in the spleen and bone than wild-type IF3, likely attributed to abnormal spleen expression of IGF2R in mice. Therefore, the pharmacokinetics data from mouse xenograft models may not precisely reflect their behavior in canine and human patients. However, the findings suggest both IF3 and IF3δ as promising options for the RIT of osteosarcoma.
Insights
Researchers engineered an antibody, IF3δ, to improve targeted radionuclide therapy for osteosarcoma. This enhanced antibody shows promise for radioimmunotherapy, potentially offering better treatment options for patients.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Osteosarcoma treatment requires novel therapeutic strategies.
- Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) offer precise radiation delivery to tumors.
- A previously developed antibody, IF3, targeting insulin-like growth factor 2 receptor (IGF2R) showed efficacy in preclinical osteosarcoma models but had a short half-life.
Purpose of the Study:
- To develop an improved antibody with enhanced pharmacokinetic properties for osteosarcoma treatment.
- To evaluate the binding affinity, Fc receptor interaction, and biodistribution of the engineered antibody IF3δ.
Main Methods:
- Fc engineering of the IF3 antibody to create IF3δ, incorporating substitutions to prolong serum half-life.
- In vitro assessment of IF3δ binding to IGF2R and human/mouse neonatal Fc receptors (FcRn).
- In vivo biodistribution studies of IF3δ and wild-type IF3 in mouse models.
Main Results:
- IF3δ maintained specific binding to IGF2R with nanomolar affinity, comparable to IF3.
- IF3δ exhibited binding to human and mouse FcRn, suggesting potential for FcRn-mediated recycling.
- Biodistribution revealed higher accumulation of IF3δ in spleen and bone in mice, potentially due to mouse-specific IGF2R expression.
Conclusions:
- IF3δ is a promising candidate for osteosarcoma radioimmunotherapy, demonstrating specific IGF2R targeting and potential for improved pharmacokinetics.
- While mouse biodistribution data may not fully predict human/canine pharmacokinetics, both IF3 and IF3δ show potential for RIT in osteosarcoma.
