Astatine-211 and Iodine Conjugates: Radiohalogenation and Preclinical Pharmacokinetics for Targeted and Pretargeted Radioimmunotherapy
Doktorsavhandling, 2002

Endoradiotherapy using labelled tumour specific-monoclonal antibodies in the therapy of malignant disease is a therapeutic modality that is coming of age. While clearly defined tumours can be treated with surgery and/or chemotherapy, occult metastases requires adjuvant systemic treatment, e.g. chemotherapy or endoradiotherapy, to prevent or delay tumour progress. To improve the therapeutic efficiency in the treatment of disseminated occult disease, short-range, high-LET .alfa.-emitters such as 211At offers an attractive prospect together with carrier substances such as tumour specific antibodies. The aim of this work were: to establish a convenient procedure to obtain 211At in chemically useful form, to develop routes of synthesis, and the subsequent evaluation in vitro and in vivo, of radiohalogenated conjugates for targeted and pretargeted radioimmunotherapy. Methods. 211At was produced by cyclotron irradiation via the 211At(.alfa.,2n)209Bi reaction, and the astatine was isolated from the irradiated targets using a novel dry-distillation procedure. Antibodies (Mov18, ovarian-tumour-specific, and C215 colon-tumour-specific) or poly-L-lysine of different molecular weights, were radiohalogenated with 125I, 131I or 211At via the intermediate labelling reagent N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE). Radiohalogenated products, labelled antibodies for radioimmunotherapy (RIT) and modified poly-L-lysine as effector molecule for pretargeted radioimmunotherapy (PRIT), were characterised in terms of radiochemical yields, structure, in vitro binding properties, and were subsequently evaluated in vivo with regard to biodistribution or therapeutic efficiency in athymic mice. Results. 211At was isolated at high radiochemical yields (75-85% of the original target activity) with fast kinetics. Subsequent labelling and conjugation to antibodies and polymers were highly efficient with overall labelling efficiencies of 50-70%. In vitro evaluation of labelled products showed that binding properties were retained at present reaction conditions. In short term therapy of 211At-MOv18 in mice with occult intraperitoneal human metastases (NIH:OVCAR-3 cells), 9 of 10 animals were apparently free of tumour after treatment given intraperitoneally. The distribution of modified polymers in tumour-free mice revealed fast whole-body clearance rates and tissue uptakes generally lower than that of labelled antibodies. Conclusions. 211At-labelled tumour specific antibodies are effective in therapy of intraperitoneal human ovarian micro metastases xenograft in nude mice treated intraperitoneally. Improvement of pharmacokinetics, with enhanced therapeutic index, in the treatment of minimal residual disease may be achieved utilising a pretargeting strategy based upon a biotinylated, 211At-labelled and charged modified poly-L-lysine effector molecule.









Sture Lindegren

Institutionen för kärnkemi





Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 1796