Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

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Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

Background: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. Results: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. Conclusions: Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

Purpose: 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2′-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [18F]FLT in tumor xenografts. Methods: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[125I]iodo-2′-deoxyuridine biodistribution measurements. In [18F]FLT studies, FdUrd pretreatment was generally performed 1h before radiotracer injection. [18F]FLT biodistributions were measured 1 to 3h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [18F]FDG tumor uptake. Using microPET, the dynamic distribution of [18F]FLT was followed for 1.5h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation. Results: FdUrd induced an immediate increase in tumor uptake of 5-[125I]iodo-2′-deoxyuridine, that vanished after 6h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [18F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [18F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [18F]FLT uptake in all tumors increased steadily up to 1.5h. MRI showed a well-vascularized homogenous lymphoma with high [18F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis. Conclusion: We showed a reliable and significant uptake increase of [18F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [18F]FLT PE

Branched KLVFF tetramers strongly potentiate inhibition of beta-amyloid aggregation

The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of beta-amyloid (Abeta) peptides into toxic aggregates. Molecules that interfere with this process might act as therapeutic agents for the treatment of AD. The amino acid residues 16-20 (KLVFF) are known to be essential for the aggregation of Abeta. In this study, we have used a first-generation dendrimer as a scaffold for the multivalent display of the KLVFF peptide. The effect of four KLVFF peptides attached to the dendrimer (K(4)) on Abeta aggregation was compared to the effect of monomeric KLVFF (K(1)). Our data show that K(4) very effectively inhibits the aggregation of low-molecular-weight and protofibrillar Abeta(1-42) into fibrils, in a concentration-dependent manner, and much more potently than K(1). Moreover, we show that K(4) can lead to the disassembly of existing aggregates. Our data lead us to propose that conjugates that bear multiple copies of KLVFF might be useful as therapeutic agents for the treatment of Alzheimer's disease

CERN-MEDICIS: une nouvelle infrastructure pour la production de radioisotopes à usage médical

CERN-MEDICIS is a facility dedicated to research and development in life science and medical applications. The research platform was inaugurated in October 2014 and will produce an increasing range of innovative isotopes using the proton beam of ISOLDE for fundamental studies in cancer research, for new imaging and therapy protocols in cell and animal models and for preclinical trials, possibly extended to specific early phase clinical studies (phase 0) up to phase I trials. CERN, the University Hospital of Geneva (HUG), the University Hospital of Lausanne (CHUV), the Swiss Institute for Experimental Cancer (ISREC) at Swiss Federal Institutes of Technology (EPFL) that currently support the project will benefit of the initial production that will then be extended to other centers