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Antibody-drug conjugates (also known as "immunoconjugates") have only recently entered the arsenal of anticancer drugs, but the number of undergoing clinical trials including them is ever increasing and most therapeutic antibodies are now patented including their potential immunoconjugate derivatives. They typically consist of three components: antibody, linker, and cytotoxin. An antibody or antibody fragment targeted to a tumor-associated antigen acts as a carrier for drug delivery and can be conjugated by cleavable or uncleavable linkers to a variety of effector molecules, either a drug, toxin, radioisotope, enzyme (the latter also used in Antibody-Directed Enzyme Prodrug Therapy), or to drug-containing liposomes or nanoparticles. In this review, we propose a general outline of the field, starting from the diagnostic and clinical applications of this class of molecules. Special attention will be devoted to the principles and issues in molecular design (choice of tumor-associated antigen, critical milestones in antibody development, available alternatives for linkers and effector molecule, and strategies for fusion proteins building) to the importance of antibody affinity modulation to optimize therapeutic effect and the potential of emerging alternative scaffolds. Most of the power of these molecules is to reach high concentrations in the tumor, relatively unaffecting normal cells, although one drawback lies in their short half-life. In this respect, modifications of immunoconjugates, which have shown to strongly influence pharmacokinetics, like glycosylation and PEGylation, will be discussed. Undergoing clinical trials and active patents will be analyzed and problems present in clinical use will be reported.

Objective: To estimate the relationship between structural changes in the heart and in the carotid arteries in hypertensives and to analyze the correlations between these structural changes and cardiovascular risk factors., Methods: We studied 76 subjects (39 men and 27 women, mean age 45+/-7 years) with mild-to-moderate untreated and uncomplicated hypertension. All of the subjects underwent ambulatory blood pressure monitoring, M-mode echocardiography for evaluation of their left ventricular mass and B-mode high-resolution ultrasonography to determine their carotid arterial wall thickness., Results: The mean intimal plus medial thickness of the common carotid artery was found to be related significantly and independently to the left ventricular mass indexed by the body surface area. In multivariate analysis, age and the high-density lipoprotein cholesterol level were related strongly to the intimal plus medial thickness, whereas the clinic systolic blood pressure, average night-time systolic blood pressure and glycemia were the most important determinants of the left ventricular mass index. Logistic regression analysis suggested that the thickness of the posterior left ventricular wall was a stronger predictor of the carotid intima-medial thickness than were age and the high-density lipoprotein cholesterol level., Conclusion: The carotid wall thickness and left ventricular mass of hypertensives are related independently; nevertheless the main determinants of structural cardiac and vascular changes are probably different.

Low density lipoprotein (LDL) oxidation plays a crucial role in the development and progression of atherosclerosis and is enhanced in patients with essential hypertension. This finding has stimulated a search for antihypertensive drugs with high intrinsic antioxidant properties. We investigated the antihypertensive and antioxidant effects of carvedilol, a new vasodilating beta-adrenoceptor blocking agent in a group of patients with mild to moderate essential hypertension after 4-month treatment. Carvedilol administration markedly increased the resistance to oxidation of LDL isolated from treated patients to values comparable to those of control, nonhypertensive subjects. This effect was achieved despite a significant loss in LDL-associated vitamin E. The increased resistance of LDL to oxidation promoted by carvedilol was not related to the normalization of previously increased blood pressure (BP). Indeed, the administration of other conventional antihypertensive drugs, capable of decreasing arterial BP but without high intrinsic antioxidant properties, to a control group of matched hypertensive patients failed to ameliorate LDL oxidation parameters. Carvedilol treatment also reduced the extent of in vivo LDL oxidation, as reflected by the decrease in antioxidized LDL autoantibody titer. This effect as well was detected only in the group of carvedilol-treated hypertensive patients and not after the simple reduction in BP obtained with antihypertensive drugs different from carvedilol.