4 research outputs found
Pretargeting of internalizing trastuzumab and cetuximab with a 18F-tetrazine tracer in xenograft models
Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab. Bioorthogonal reaction between tetrazine and trans-cyclooctene (TCO) was used for tracing cetuximab and trastuzumab in vivo with a fluorine-18 (t (A 1/2) = 109.8 min) labelled tracer. TCO-cetuximab or TCO-trastuzumab was administered 24, 48, or 72 h prior to the injection of tracer to A431 or BT-474 tumour-bearing mice, respectively. With cetuximab, the highest tumour-to-blood ratios were achieved when the lag time between antibody and tracer injections was 72 h. With trastuzumab, no difference was observed between different lag times. For both antibodies, the tumour could be clearly visualized in the PET images with the highest tumour uptake of 3.7 +/- 0.1%ID/g for cetuximab and 1.5 +/- 0.1%ID/g for trastuzumab as quantified by ex vivo biodistribution. In vivo IEDDA reaction was observed in the blood for both antibodies, but with trastuzumab, this was to a much lower degree than with cetuximab. We could successfully visualize the tumours by using cetuximab and trastuzumab in pretargeted PET imaging despite the challenging circumstances where the antibody is internalized and there is still some unbound antibody circulating in the blood flow. This clearly demonstrates the potential of a pretargeted approach for targeting internalizing antigens and warrants development of pharmacokinetic optimization of the biorthogonal reactants to this end.Peer reviewe
Pretargeting of internalizing trastuzumab and cetuximab with a 18F-tetrazine tracer in xenograft models
Background: Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab.
Results: Bioorthogonal reaction between tetrazine and trans-cyclooctene (TCO) was used for tracing cetuximab and trastuzumab in vivo with a fluorine-18 (t½ = 109.8 min) labelled tracer. TCO-cetuximab or TCO-trastuzumab was administered 24, 48, or 72 h prior to the injection of tracer to A431 or BT-474 tumour-bearing mice, respectively. With cetuximab, the highest tumour-to-blood ratios were achieved when the lag time between antibody and tracer injections was 72 h. With trastuzumab, no difference was observed between different lag times. For both antibodies, the tumour could be clearly visualized in the PET images with the highest tumour uptake of 3.7 ± 0.1%ID/g for cetuximab and 1.5 ± 0.1%ID/g for trastuzumab as quantified by ex vivo biodistribution. In vivo IEDDA reaction was observed in the blood for both antibodies, but with trastuzumab, this was to a much lower degree than with cetuximab.
Conclusions: We could successfully visualize the tumours by using cetuximab and trastuzumab in pretargeted PET imaging despite the challenging circumstances where the antibody is internalized and there is still some unbound antibody circulating in the blood flow. This clearly demonstrates the potential of a pretargeted approach for targeting internalizing antigens and warrants development of pharmacokinetic optimization of the biorthogonal reactants to this end
Synthesis and in vitro evaluation of a novel PET radiotracer for imaging androgen lesions in metastatic prostate cancer
Prostate cancer is the most common cancer in male population in the western world. In Finland around 5000 men are diagnosed with it every year. Most patients are diagnosed with localized prostate cancer, when the prognosis is good: the relative 5-year survival is over 90%. The metastasized form of prostate cancer can be considered fatal, since the 5-year survival rate for patients with metastases in distant organs is about 29%. Early diagnosis and clear and definite understanding of patient's tumor profile are fundamental parts of optimized treatment of prostate cancer. Proliferation and antiapoptotic characteristics of prostate cancer tissue is caused by altered androgen receptor signaling. Many treatment forms of prostate cancer are concentrating on inhibiting this signaling pathway. Furthermore expression of androgen receptors is increased in prostate cancer tissue compared to healthy tissue. These factors corroborate that androgen receptor is a good candidate for targeting and imaging prostate cancer. With positron emission tomography tracers it is possible to quantitatively detect receptors in vivo. Selective androgen receptor modulators are class of drug molecules that alter androgen receptor activity. They have high affinity to androgen receptor. The aim of this master's thesis was to produce a fluorine-18 and/or iodine-131 labelled selective androgen receptor modulator derivative that could be used for imaging androgen receptor lesions in metastatic prostate cancer. Two different selective androgen receptor modulators were investigated. The second one, a 4-(pyrrolidin-1-yl) benzonitrile derivative was labelled successfully with iodine-131. Its binding to androgen receptor was tentatively shown with LnCapAR cell line. The radiolabelled compound showed binding to androgen receptor with IC50 value of 0.1903 nM
Additional file 1: of Pretargeting of internalizing trastuzumab and cetuximab with a 18F-tetrazine tracer in xenograft models
Supporting information contains the PET images of 89Zr-radiolabelled cetuximab and trastuzumab; description of the purification of mAbs, immunoreactivity testing of modified mAbs, cell uptake assay, in vitro pretargeting assay, and radiosynthesis of [18F]TAF; and ex vivo biodistribution results for pretargeted experiments and 89Zr-radiolabelled cetuximab and trastuzumab. (PDF 1832 kb