Near-infrared Photoimmunotherapy Targeting Cadherin-17 for Gastrointestinal Cancer Treatment

In an ageing society, cancer incidence rate would continue to rise. Better cancer treatment to reduce disease burden and improve patients' quality of life is in urgent need. Photodynamic therapy (PDT) was discovered as a cancer treatment about 30 years ago. Photosensitizer (PS), light and oxygen are the three essential elements in PDT. Illumination can activate PS which then reacts with oxygen to generate singlet oxygen. Singlet oxygen would induce cellular damage in cancer cells, leading to cell death. An ideal PS for effective PDT should have a maximum excitation light wavelength within the near infrared region (650 nm - 850 nm) to facilitate deeper light penetration into body tissue. Additionally, the PS should be preferentially taken up by cancer cells. Despite having high cancer killing potency, PDT's clinical application has been limited. One reason is that patient receiving PDT treatment could suffer adverse effect when exposed to external light. Another concern is that PS could also be taken up by normal tissue albeit at a lower level. The current project aims to develop a novel cancer therapy by conjugating a cancer specific antibody with PS for targeted PDT, termed photoimmunotherapy (PIT). ; The gastrointestinal (GI) cancer biomarker cadherin-17 (CDH17) is the focus in this project. CDH17 is overexpressed in GI cancers with normal tissue expression limited only to small intestine and colon. A humanized monoclonal antibody targeting CDH17, namely ARB102, was conjugated with IR700, a phthalocyanine PS. The water-soluble IR700 can be easily conjugated to the antibody by the N-hydroxysuccinimide amine reaction. IR700 has a maximum excitation light wavelength at 689 nm which has good tissue penetration properties. SDS-PAGE results confirmed the successful conjugation of ARB102-IR700. The degree of labelling was calculated to be approximately four IR700 molecules to an antibody molecule. Characterization of the conjugate ARB102-IR700 indicated that it could bind to CDH17 with high affinity and specificity, ...