Development of targeted radioimmunotherapy for osteosarcoma using a comparative oncology approach
Date
2024-02-23
Authors
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