DARPin Targeted Magnetic Hyperthermic Therapy for
Glioblastoma
FP7
 
   Partner: University College London  

   
Introduction

Our research goal is to use antibodies, fragments thereof or antibody-like frameworks (DARPins) as a base for medicines to be used for imaging and therapy of cancer. The antibody fragments we use consist of the smallest antibody segment (scFv) that recognises the target (antigen).

Figure - Molecular model of MFE23. MFE-23, our most characterised scFv, reacts with CEA and was the first scFv to target cancers in man.

We focus on design and construction of these molecules and their interaction with cancer targets. Our primary cancer targets are the epidermal growth factor receptor family (EGFR) for breast /brain cancers; carcinoembryonic antigen (CEA) which is a glycoprotein expressed in colorectal adenocarcinomas; and the avß6 integrin which is present on head and neck cancers.

A strong translational theme is central to our research thinking. We aim to bring the therapeutics designed by our team from bench to bed side. To facilitate this process, the group has a dedicated facility which can produce clinical grade microbial-expressed recombinant proteins in compliance with Good Manufacturing Practice (GMP).

The group has a developmental laboratory which harbours equipment similar to that in the GMP clean rooms. This layout simplifies throughput from developmental to GMP production stage of a lead molecule.

To date some 150 GMP batches have been produced, using the yeast Pichia pastoris as a production platform. The facility, the UCL Cancer Institute Research Trust GMP Facility (CIRT GMP Facility) generates so-called investigational medicinal products (IMPs) for early phase trials. The site is licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) to produce these IMPs.

We have coupled some of our antibody-targeting moieties to superparamagnetic iron oxide nanoparticles (SPIONs), yielding a paramagnetic particle covered with antibodies. As a consequence, these 'functionalised' particles can be selectively targeted to cancers and improve the sensitivity of magnetic resonance imaging (MRI). Interestingly, SPIONs can be induced to generate heat when subjected to an alternating magnetic field (AMF). Thus functionalised SPIONs can be used in heat treatment (hyperthermic) cancer therapies !   We are currently developing this therapy within the DARTRIX project, making use of SPIONs functionalised with DARPins.

Role of UCL within the “Dartrix Consortium”

Our part in DARTRIX is the production of seed lots and subsequent prodcution of GMP compliant 'Dartrix'-therapeutics. Furthermore, the clinical trial will be performed by UCL.


Making recombinant therapeutics in GMP facility.


Project Leader
Kerry Chester

Selected publications
Kinna A, Tolner B, Rota EM, Titchener-Hooker N, Nesbeth D, Chester K. (2015) IMAC capture of recombinant protein from unclarified mammalian cell feed streams. Biotechnol Bioeng. Pubmed

Boonstra MC, Tolner B, Schaafsma BE, Boogerd LS, Prevoo HA, Bhavsar G, Kuppen PJ, Sier CF, Bonsing BA, Frangioni JV, van de Velde CJ, Chester KA, Vahrmeijer AL (2015) Pre-clinical evaluation of a novel CEA-targeting near-infrared fluorescent tracer delineating colorectal and pancreatic tumors. Int J Cancer 137(8):1910-20. Pubmed

Maruani A, Smith ME, Miranda E, Chester KA, Chudasama V, Caddick S (2015) A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy. Nat Commun 6:6645. Pubmed

Goldstein R, Sosabowski J, Livanos M, Leyton J, Vigor K, Bhavsar G, Nagy-Davidescu G, Rashid M, Miranda E, Yeung J, Tolner B, Pluckthun A, Mather S, Meyer T, Chester K (2015) Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging. Eur J Nucl Med Mol Imaging 42 (2):288-301. Pubmed

Abdollah MR, Kalber T, Tolner B, Southern P, Bear JC, Robson M, Pedley RB, Parkin IP, Pankhurst QA, Mulholland P, Chester K (2015) Prolonging the circulatory retention of SPIONs using dextran sulfate: in vivo tracking achieved by functionalisation with near-infrared dyes. Faraday Discuss 175:41-58. Pubmed

Hull EA, Livanos M, Miranda E, Smith MEB, Chester KA, Baker JR (2014) Homogeneous Bispecifics by Disulfide Bridging. Bioconjugate Chemistry 25 (8): 1395-1401. Pubmed

Kogelberg H, Miranda E, Burnet J, Ellison D, Tolner B, Foster J, Picon C, Thomas GJ, Meyer T, Marshall JF, Mather SJ, Chester K (2013) Generation and Characterization of a Diabody Targeting the alpha(v)beta(6) Integrin. Plos One 8 (9):e73260. Pubmed

Schumacher FF, Sanchania VA, Tolner B, Wright ZV, Ryan CP, Smith ME, Ward JM, Caddick S, Kay CW, Aeppli G, Chester KA, Baker JR (2013). Homogeneous antibody fragment conjugation by disulfide bridging introduces 'spinostics'. Nature Scientific Reports 3:1525. Pubmed

Vigor KL, Kyrtatos PG, Minogue S, Al-Jamal KT, Kogelberg H, Tolner B, Kostarelos K, Begent RH, Pankhurst QA, Lythgoe MF, Chester KA (2010) Nanoparticles functionalized with recombinant single chain Fv antibody fragments (scFv) for the magnetic resonance imaging of cancer cells. Biomaterials 31:1307-15. Pubmed



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