Abstract
Simple SummaryOsteosarcoma (OS) is the most common type of bone cancer and mainly affects children, teens and young adults. The overall survival rate is ~67%, but patients with distant metastases have poor prognosis. Insulin growth factor 2 receptor (IGF2R) is a protein that has been shown to be expressed widely in human patient-derived OS cells and is a suitable for target for monoclonal antibody-based therapies. Given the similarities between canine and human OS, IGF2R is also overexpressed in canine OS. Towards the goal of one-health approach, we generated human antibodies that bind with similar affinities to IGF2R expressed in human, murine and canine tissues. We demonstrate tumor accumulation of radiolabeled antibodies in mice bearing human and canine patients derived tumors. Therefore, these antibodies show promise for development into the agents for radioimmunoimaging and radioimmunotherapy of OS in human and canine patients.Etiological and genetic drivers of osteosarcoma (OS) are not well studied and vary from one tumor to another; making it challenging to pursue conventional targeted therapy. Recent studies have shown that cation independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) is consistently overexpressed in almost all of standard and patient-derived OS cell lines, making it an ideal therapeutic target for development of antibody-based drugs. Monoclonal antibodies, targeting IGF2R, can be conjugated with alpha- or beta-emitter radionuclides to deliver cytocidal doses of radiation to target IGF2R expression in OS. This approach known as radioimmunotherapy (RIT) can therefore be developed as a novel treatment for OS. In addition, OS is one of the common cancers in companion dogs and very closely resembles human OS in clinical presentation and molecular aberrations. In this study, we have developed human antibodies that cross-react with similar affinities to IGF2R proteins of human, canine and murine origin. We used naïve and synthetic antibody Fab-format phage display libraries to develop antibodies to a conserved region on IGF2R. The generated antibodies were radiolabeled and characterized in vitro and in vivo using human and canine OS patient-derived tumors in SCID mouse models. We demonstrate specific binding to IGF2R and tumor uptake in these models, as well as binding to tumor tissue of canine OS patients, making these antibodies suitable for further development of RIT for OS
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumor and the fifth most common primary malignancy among adolescents and young adults [1]
The extracellular domain of insulin-like growth factor-2 receptor (IGF2R) contains 15 cation-independent mannose receptor (CIMR) domains repeats and one FNII domain located between CIMR domains 12 and 13
To generate human antibodies that bind to conserved regions of IGF2R, we developed both synthetic and naïve antibody Fab-fragment libraries
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumor and the fifth most common primary malignancy among adolescents and young adults [1]. Patients with metastases to the lungs and to the bone have an unfavorable prognosis with an overall survival of less than 40% and. Unlike some cancers, which share a common genetic signature, OS demonstrates sweeping genetic variability from one tumor to the marked by complex karyotypes and substantial aneuploidy [4]. This has made pursuing a conventional targeted treatment approach challenging and has led recent cooperative efforts to consider alternate approaches that involve commonalities such as metastatic patterns and tumor microenvironment [5]. IGF2R expression appears to be both essential to and associated with the development of OS, making it an ideal therapeutic target
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