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Development of targeted radioimmunotherapy for osteosarcoma using a comparative oncology approach

Date

2024-02-23

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

Type

Thesis

Degree Level

Doctoral

Abstract

This study sheds light on the potential of developing targeted antibody-based therapies for osteosarcoma (OS) - a malignant bone tumor that affects both canines and humans. Researchers focused on a cation-independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R), known for its overexpression in various OS cell lines. They utilised phage display libraries to create antibodies that recognise IGF2R in human, canine, and murine models, including a promising antibody named IF3. The antibodies were then radiolabeled and characterised in vitro and in vivo using patientderived tumor models in SCID mice. The results demonstrated the specific binding of these antibodies to tumours and their potential for effective tumour uptake, which are crucial aspects of antibody-based radioimmunotherapy (RIT). An innovative aspect of the study involved using 177Lu-labeled IF3 in mice with canine-patient-derived tumors, which showed high uptake in both the tumor and spleen, leading to significant inhibition of tumor growth. However, the study also revealed spleen-associated toxicity, indicating the need for careful clinical evaluation in future applications. The findings from the use of IF3, both in its radiolabeled form and various animal models, hold promise for developing targeted antibodybased therapies for OS in both humans and canines. Further modifications to IF3 were made by engineering an amino acid substitution in the Fc region and creating IF3δ, demonstrating the potential for FcRn-mediated endocytosis and recycling. However, biodistribution studies in mice revealed unexpected spleen and bone accumulation, highlighting the distinct pharmacokinetics between mouse models and potential human and canine applications. Lastly, we used a cell-based phage display method to identify CB01, an antibody that selectively binds to OS cell lines with minimal affinity to normal cells. CB01's interaction with glycosaminoglycans (GAGs) revealed the crucial role of glycans in OS and posits GAGs as novel therapeutic targets. MicroSPECT/CT imaging underlined CB01's efficacy in tumor targeting and biodistribution, emphasising its potential in precise cancer treatment through RIT. In conclusion, this study makes significant strides in understanding and treating osteosarcoma, introducing novel therapeutic approaches and insights into the roles of IGF2R and GAGs in cancer progression. The development of IF3 and CB01 antibodies represents a promising advancement in targeted therapies, offering hope for improved management and treatment efficacy in osteosarcoma across species.

Description

Keywords

IGF2R, RIT, antibody engineering, Phage display

Citation

Degree

Doctor of Philosophy (Ph.D.)

Department

Pathology and Laboratory Medicine

Program

Health Sciences

Citation

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DOI

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