Using antibody directed phototherapy to target oesophageal adenocarcinoma with heterogeneous HER2 expression.

// Hayley Pye 1, * , Mohammed Adil Butt 1, 2, * , Laura Funnell 1 , Halla W. Reinert 1 , Ignazio Puccio 1 , Saif U. Rehman Khan 1 , Savvas Saouros 3, 4 , Jared S. Marklew 3 , Ioanna Stamati 3 , Maryam Qurashi 1, 4 , Rehan Haidry 2 , Vinay Sehgal 1, 2 , Dahmane Oukrif 5 , Michael Gandy 1 , Hayley C. Whitaker 1 , Manuel Rodriguez-Justo 5 , Marco Novelli 5 , Rifat Hamoudi 1, 6 , Gokhan Yahioglu 3, 4 , Mahendra P. Deonarain 1, 3, 4 and Laurence B. Lovat 1, 2 1 Department for Tissue and Energy, Division of Surgery and Interventional Science, University College London, London, UK 2 Upper Gastrointestinal Service, University College London Hospitals NHS Foundation Trust, London, UK 3 Antikor BioPharma, Stevenage, UK 4 Imperial College London, London, UK 5 Department of Pathology, University College London, London, UK 6 Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, UAE * These authors contributed equally to this work Correspondence to: Hayley Pye, email: h.pye@ucl.ac.uk Keywords: HER2; antibody drug conjugate; photodynamic therapy; oesophageal adenocarcinoma; heterogeneity Received: January 29, 2018      Accepted: March 28, 2018      Published: May 01, 2018 ABSTRACT Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity. A tumour specific and light targeted therapeutic agent with optimised pharmacokinetics could be used to destroy residual cancerous cells left behind after resection. A small molecule antibody-photosensitizer conjugate was developed targeting human epidermal growth factor receptor 2 (HER2). This was tested in an in vivo mouse model of human OA using a xenograft flank model with clinically relevant low level HER2 expression and heterogeneity. In vitro we demonstrate selective binding of the conjugate to tumour versus normal tissue. Light dependent cytotoxicity of the phototherapy agent in vitro was observed. In an in vivo OA mouse xenograft model the phototherapy agent had desirable pharmacokinetic properties for tumour uptake and blood clearance time. PDT treatment caused tumour growth arrest in all the tumours despite the tumours having a clinically defined low/negative HER2 expression level. This new phototherapy agent shows therapeutic potential for treatment of both HER2 positive and borderline/negative OA.