Python, C.; Kissling, C.J.; Pandya, P.; Marissen, W.E.; Brink, M.F.; Lagerwerf, F.; Worst, S.; van Corven, E.; Kostense, S.; Hartmann, K.; Weverling, G.J.; Uytdehaag, F.; Herzog, C.; Briggs, D.J.; Rupprecht, C.E.; Grimaldi, R.; and Goudsmit, J., "First Administration to Humans of a Monoclonal Antibody Cocktail Against Rabies Virus: Safety, Tolerability, and Neutralizing Activity" (2008 a b s t r a c tImmediate passive immune prophylaxis as part of rabies post-exposure prophylaxis (PEP) often cannot be provided due to limited availability of human or equine rabies immunoglobulin (HRIG and ERIG, respectively). We report first clinical data from two phase I studies evaluating a monoclonal antibody cocktail CL184 against rabies. The studies included healthy adult subjects in the USA and India and involved two parts. First, subjects received a single intramuscular dose of CL184 or placebo in a double blind, randomized, dose-escalation trial. Second, open-label CL184 (20 IU/kg) was co-administered with rabies vaccine. Safety was the primary objective and rabies virus neutralizing activity (RVNA) was investigated as efficacy parameter.Pain at the CL184 injection site was reported by less than 40% of subjects; no fever or local induration, redness or swelling was observed. RVNA was detectable from day 1 to day 21 after a single dose of CL184 20 or 40 IU/kg. All subjects had adequate (>0.5 IU/mL) RVNA levels from day 14 onwards when combined with rabies vaccine. CL184 appears promising as an alternative to RIG in PEP.

Binding and metabolism of low density lipoprotein (LDL) and acetylated LDL were examined in endothelial cells from human umbilical cord arteries and veins. Both high and low affinity LDL interactions were observed. High affinity LDL binding and catabolism were increased five-to sevenfold after preincubation for 18 hours in LPDS containing medium. Subconfluent cells degraded, endocytosed, and bound 1.5 to 2.7 times more LDL by high affinity interaction than confluent cells, when endothelial cell growth supplement (ECGS) was present in the culture system. In the absence of ECGS, these ratios were somewhat less. Low affinity LDL metabolism was less affected by the state of confluency. Binding of LDL and acetylated LDL by venous endothelial cells was more than two-and threefold, respectively, than that by comparable arterial cells. However, the difference in LDL binding was not reflected in an altered LDL catabolism. There apparently is a population of low affinity binding sites not involved in LDL catabolism.LDL metabolism was identical in cells, which were cultured in medium supplemented with 20% to 100% serum or hirudin-or heparin-treated platelet-poor plasma. Without preincubation in LPDS, high affinity adsorptive endocytosis mediated the main part of LDL uptake only at low LDL concentrations (5 to 20 /ng protein/ml). However, at physiological LDL concentrations (550 ixg/m\), we estimated that this process mediated only 17% of the LDL uptake. We calculated that fluid endocytosis and low affinity adsorptive endocytosis of LDL accounted for the remaining 12% and 70%, respectively, of the LDL uptake at physiological LDL concentrations. (Arteriosclerosis 3:547-559, November/December 1983) L ow density lipoprotein (LDL) is a risk factor for atherosclerosis.1 The plasma level of LDL depends on the balance between its formation and its catabolism. To become catabolized, LDL has to enter or pass through the endothelium that lines the blood vessels. Only in the liver, bone marrow, and spleen does blood plasma have direct access to the tissue parenchymal cells via open fenestrations. 2Clearing by the liver accounts for 35% to 67% of the LDL removal in pigs, rabbits, and rats.3 " 6 Possibly, LDL also passes through the fenestrations of other visceral capillaries, e.g., those in the gut and the adrenal glands. However, the fenestrations in these tissues, which account for 10% to 15% of the LDL

Type III hyperlipoproteinaemia (HLP) is, amongst others, characterized by the E2/2 phenotype as determined by isoelectric focusing of apolipoprotein E. However, one of our clinically symptomatic type III HLP patients showed a E3/3 phenotype. After complexation with phospholipid vesicles, apo E from this patient was, in contrast with apo E from a type IV HLP patient (E3/4 phenotype), unable to compete with low density lipoprotein (LDL) for binding to the specific LDL receptors on cultured human fibroblasts. This defect in binding to the LDL receptor was not due to an impaired lipid binding capability. The clinical symptomatic type III hyperlipoproteinaemia of our patient is probably due to a functionally inactive apo E3.

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