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Molecular imaging of mesothelin expressing cancers

University of British Columbia

Mesothelin is a cell surface glycoprotein highly expressed in mesothelioma, ovarian cancer, pancreatic cancer and some other malignancies. It is a promising candidate for tumour specific therapy and diagnosis, given its limited expression in normal tissues. The purpose of the work presented in this dissertation is to develop and characterize a molecular imaging bioprobe that targets mesothelin. We radiolabelled fab and f(ab´)₂ fragments of the anti-mesothelin antibody mAbK1 with ⁹⁹mTc- tricarbonyl core using a histidine-modified tridentate ligand, while whole mAbK1 was radiolabelled with ⁹⁹mTc using a direct labelling approach. In vivo evaluation of these ⁹⁹mTc labelled radioimmunoconjugates in mesothelin expressing NCI-H226 tumour model, revealed low mesothelin specific tumour uptake. These findings were attributed to low expression of mesothelin on NCI-H226 cells as well as to the low affinity of mAbK1. An anti-mesothelin antibody mAbMB, with higher mesothelin affinity than mAbK1 was labelled with ¹¹¹In and evaluated in A431K5 tumour model which expresses clinically relevant levels of mesothelin. Biodistribution studies and SPECT imaging revealed specific localization of ¹¹¹In-mAbMB in mesothelin expressing A431K5 tumours. An interesting finding with ¹¹¹In-mAbMB was its preferential localization in spleen, which suggests a role of circulating mesothelin antigen in forming immune complexes with ¹¹¹In-mAbMB. In comparison, control studies with ¹¹¹In-mAbK1 revealed low specific uptake into A431K5 tumours. These studies provided evidence that ¹¹¹In-mAbMB is a better choice than ¹¹¹In-mAbK1 for imaging mesothelin expression in tumours. A dual-modality SPECT/MR imaging bioprobe was further developed by conjugating ¹¹¹In-mAbMB with SPIONs (superparamagnetic iron oxide nanoparticles) which demonstrated specific targeting and MR imaging capability in A431K5 tumour bearing mice. The work in this dissertation for the first time demonstrates successful SPECT imaging of mesothelin expressing cancers using radiolabelled antibodies. The radiopharmaceutical ¹¹¹In-mAbMB developed in this work holds promise for clinical use as a radioactive imaging bioprobe. Additionally, bioconjugates of ¹¹¹In-mAbMB and SPIONs are promising as dual-modality SPECT/MRI imaging bioprobes, which may be beneficial in improving the imaging outcomes of these difficult to treat tumours. In conclusion, our studies demonstrate that molecular imaging agents targeting mesothelin have a role to play for the detection and monitoring of mesothelin expressing cancers.

Text

2010-12-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/30461

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/