Recently, we described a new carbohydrate-induced conformational tumour-epitope on mucin-1 (MUC1) with the potential for improvement of immunotherapies [29, 30]. PankoMab is a novel antibody, which binds specifically to this epitope and was designed to show the highest glycosylation dependency and the strongest additive binding effect when compared to other MUC1 antibodies. This enables PankoMab to differentiate between tumour MUC1 and non-tumour MUC1 epitopes. It has a high-affinity towards tumour cells (e.g. KD [M] of 0.9 and 3x10(-9 )towards NM-D4 and ZR75-1, respectively) and detects a very large number of binding sites (e.g. 1.0 and 2.4x10(6 )for NM-D4 and ZR75-1, respectively). PankoMab is rapidly internalised, and after toxin coupling is able to induce very effectively toxin-mediated antigen-specific tumour cell killing. PankoMab reveals a potent tumour-specific antibody-dependent cell cytotoxicity (ADCC). PankoMab is, therefore, distinguished by a combination of advantages compared to other MUC1 antibodies in clinical development, including higher tumour specificity, higher affinity, a higher number of binding sites, largely reduced binding to shed MUC1 from colon and pancreatic carcinoma patients, no binding to mononucleated cells from peripheral blood (except approximately 7% of activated T cells), stronger ADCC activity and rapid internalisation as required for toxin-mediated cell killing. This renders it a superior antibody for in vivo diagnostics and various immunotherapeutic approaches.
We report on the efficiencies of structurally different but well defined multivalent sLex-ligands (di- and trivalent sLex-peptides and sLexbearing liposomes) to block receptor mediated HepG2-cell binding. Using three types of binding assays with distinct receptor accommodations (soluble anti-sLexmonoclonal antibody CSLEX1, immobilized E-selectin, activated HUVECs), we quantified considerable differences of the inhibition efficiencies for the same multivalent sLex-ligands. Compared to the monovalent sLexthe inhibition powers of both (sLex)2-peptides and (sLex)3-peptides were enhanced up to 50-fold for cell binding to the soluble antibody, and that of sLex-liposomes by 7 orders of magnitude. Directed to immobilized E-selectin the inhibition activity was enhanced only 3-fold for (sLex)2-peptides, 10-fold for (sLex)3-peptides but 5 orders of magnitude for sLex-liposomes, respectively. Further decrease of the inhibition efficiencies of glycoligands prepared was observed for cell binding to activated HUVECs. Compared to monovalent sLexwe measured relative efficiencies of 1 for (sLex)2-peptides, of 2 for (sLex)3-peptides but about 20,000 for sLex-liposomes. We concluded that the multivalency of the sLex-ligands prepared is an essential but not sufficient precondition for a high inhibition potency. Additionally, structural properties of the inhibitors determine their binding behavior, which must be considered for the design of potential therapeutic probes.
Liposomes from octadecyl-(1,1-dimethyl-4-piperidino-4-yl)-phosphate (OPP), a new alkylphospholipid derivative with an improved cancerostatic activity, were prepared for the first time and the activity in vitro and in vivo was characterised. The formation of liposomes (MLV, SUV and LUVET) differing in cholesterol content, charge, and sterical stabilisation is possible without serious problems, despite the lysolipid-like structure of the OPP. Liposomes with a low amount of cholesterol and with PEG2000DSPE-coating were the most stable OPP liposomes, both in buffer and in serum. The cytotoxicity of micellar or liposomal OPP against breast cancer cell lines in vitro was in the range of 20-60 microM. The cytotoxicity of the liposomal formulation was inversely related to the content of cholesterol, whereas the sterical stabilisation and/or the incorporation of a positive charge had only a very moderate modulating effect on the inhibition of cell proliferation. The strongest antitumour effect on the xenotransplanted breast cancer MT-3 in vivo was obtained with sterically stabilised OPP liposomes with low CH content. The beneficial therapeutic effect of these liposomes was accompanied by better tolerance and a significant inhibition of haemolysis compared to micellar OPP.
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