Acute lymphoblastic leukemia (ALL) is the most common malignant disease affecting children. Although therapy strategies improved, T-cell acute lymphoblastic leukemia (T-ALL) relapse is associated with chemoresistance and a poor prognosis. One strategy to overcome this obstacle is the application of monoclonal antibodies. Here, we show that leukemic cells from T-ALL patients express surface CD38 and CD47, both attractive targets for antibody therapy. We therefore investigated the commercially available CD38 antibody daratumumab (Dara) in combination with a proprietary modified CD47 antibody (Hu5F9-IgG2σ) in vitro and in vivo. Compared to single treatments, this combination significantly increased in vitro antibody-dependent cellular phagocytosis (ADCP) in T-ALL cell lines as well as in random de novo and in relapsed/refractory T-ALL patient derived xenograft (PDX) samples. Similarly, enhanced ADCP was observed when combining Dara with pharmacological inhibition of CD47 interactions using a glutaminyl cyclase inhibitor. Phase II-like preclinical in vivo trials using T-ALL PDX samples in experimental minimal residual disease like (MRD-like) and overt leukemia models revealed a high anti-leukemic efficacy of CD47 blockade alone. However, T-ALL xenograft mice subjected to chemotherapy first (post-chemo MRD) and subsequently co-treated with Dara and Hu5F9-IgG2σ displayed significantly reduced bone marrow infiltration as compared to single treatments. In relapsed and highly refractory T-ALL PDX combined treatment with Dara and Hu5F9-IgG2σ was required to substantially prolong survival as compared to single treatments. These findings suggest that combining CD47 blockade with Dara is a promising therapy for T-ALL, especially for relapsed/refractory disease harbouring a dismal prognosis in patients.

Targeting the tumor vasculature by gene therapy is a potentially powerful approach, but suitable vectors have not yet been described. We have designed a new type of liposomal vector, based on the composition of anionic retroviral envelopes, that is serum -resistant and nontoxic. These artificial virus -like envelopes ( AVEs ) were endowed with a cyclic RGD -containing peptide as a targeting device for the a v û 3 -integrin on tumor endothelial cells ( ECs ) . The packaging of plasmid DNA complexed with low -molecularweight, nonlinear polyethyleneimine into these AVEs yielded artificial virus -like particles ( AVPs ) that transduced ECs with efficiencies of up to 99%. In contrast, transduction of a variety of other cell types by these RGD ± AVPs was comparably inefficient under the same experimental conditions. This EC selectivity was mediated, in part, but not exclusively, by the RGD ligand, as suggested by the reduced, but still relatively high, transduction efficiency seen with AVPs lacking RGD. The interaction of anionic lipids of the AVPs with ECs may therefore contribute to the observed selective and highly efficient transduction of this cell type. These findings suggest that the targeted AVE technology is a useful approach to create highly efficient nonviral vectors.

Die lonisation der R--OR-Bindung bei den Borfluorid-bzw. Antimonpentachlorid-Verbindungen bestimmter Ather, Acetale und Orthosaureester l l R t sich auf Grund der fast momentan verlaufenden Umwandlung der bei der lonisation auftretenden ROBF,bzw. ROSbCI,-Anionen in die zur nukleophilen Anlagerung nicht mehr befdhigten BF,-bzw. SbC16-Anionen praparativ nachweisen. Die Untersuchung d e r Einwirkung von Borfluorid auf verschiedene 2-Alkoxy-1 ,&dioxolane ergab einen Zusammenhang zwischen der lonisierungsfahigkeit d e r Borfluorid-Verbindungen und d e r Elektronendichte an dem Kohlenstoff-und Sauerstoff-Atom der C-OR-Bindung. Im Verlaufe dieser Arbeiten wurde eine neue einfache Methode zur Herstellung von Trialkyloxoniumsalzen gefunden. Die Untersuchung der Einwirkung von Borfluorid bzw. Antimonpentachlorid auf Benzophenonoxim und dessen 0-Methylather lieferte neue Beitrage zur Kenntnis d e r Beckmannschen Umlagerung.

This study aims to evaluate the performance of different leaching schemes with respect to the mobilization of antimony and arsenic from polluted samples collected at different sites in Mansfeld District, Germany. Besides the elution by water the leaching by artificial acidic rain and by two different schemes of sequential extraction were employed for estimation of the mobilization of antimony and arsenic. The samples were characterized by X-ray fluorescence analysis for their total concentration of metalloids, metals and main constituents. It was found that both antimony and arsenic show little mobilization with de-ionized water as well as artificial acidic rain in single step batch procedures (≤ 0.13% of the total content). Although the percentage leached is very low, the concentrations in the resulting solutions are of ecotoxicological relevance. BCR procedure indicate a very strong binding of Sb and of As in the samples. Less than 20% of the total content can be leached in sum in all leaching steps, of it most under strongly oxidizing conditions. This scheme seems not suitable for a detailed investigation of possible mobilization processes under environmental conditions for the metalloids under investigation. The four-step extraction procedure by Wenzel et al. gives a more detailed pattern of the binding of antimony and arsenic. This procedure was found to be a suitable scheme for evaluating the possible mobilization processes from the samples contaminated by ore processing waste, especially by change through other ions or under reducing conditions.