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At least 19 recordsLinked to original sources
PubMed1978

Immunogenicity and antigenicity of soluble cross-linked enzyme/albumin polymers: Advantages for enzyme therapy.

Soluble cross-linked polymers of hog-liver uricase and an excess of either rabbit or dog albumin were injected repeatedly into rabbits in order to determine their antigenicity and immunogenicity. Whereas the enzyme in its free form induces antibody production, homologous albumin polymerised with the enzyme renders the complex non-immunogenic and non-antigenic. Dog-albumin/uricase polymers injected into rabbits induce antibody formation against the dog albumin but not against the uricase. The results suggest an important advantage of these soluble enzyme polymers in enzyme-replacement therapy.

Albumins↗
PubMed1977

Enzyme therapy. VI: Comparative in vivo fates and effects on lysosomal integrity of enzyme entrapped in negatively and positively charged liposomes.

Entrapment of enzyme in liposomes, biodegradable lipid vesicles, offers an intriguing strategy for the intracellular delivery of these macromolecules to the lysosomal apparatus for enzyme replacement endeavors in selected lysosomal storage diseases. Therefore, the in vivo tissue and subcellular fate and effect on the subcellular distribution of endogenous lysosomal hydrolases was determined following intravenous administration of beta-glucuronidase entrapped in positively and negatively charged liposomes into C3H/HeJ beta-glucuronidase-deficient mice. Enzyme entrapped in negatively charged liposomes was rapidly cleared from the circulation (t1/2 approximately 4 min); maximal tissue recovery, 75% of dose, was detedtec in the liver at 1 h, was maintained fro 48 h and then gradually declined to non-detectable levels by 8 days. A similar circulatory clearance and reciprocal hepatic uptake was observed fro positively charged liposomes; however, the beta-glucuronidase was retained in murine liver for 11 days. Significant activity, 15% of dose, was found in the kidneys up to 1 and 4 days post-injection of positively and negatively charged liposomes, respectively. No activity was recovered in neural or other visceral tissues except in spleen and lungs (less than 5% of the dose). Exogenous beta-glucuronidase activity administered in negatively charged liposomes was primarily localized in the lysosomally-enriched hepatic subcellular fraction, compared to the predominantly soluble localization of exogenous activity entrapped in positively charged liposomes. Administration of negatively charged liposomes caused no detectable change in the subcellular localization of several endogenous lysosomal hydrolase activities compared to their distribution in untreated mice. In contrast, a marked but temporary translocation of these hydrolase activities into the soluble fraction was observed following the administration of positively charged liposomes, identifying possible deleterious effects on cellular physiology.

Animals↗
PubMed1992

Metabolism of NAD(P)H by blood components. Relevance to bioreductively activated prodrugs in a targeted enzyme therapy system.

NADH was metabolized both by serum components and at the cell surface. The metabolism by serum was either oxidation to NAD+, or hydrolysis of the pyrophosphate to yield nicotinamide mononucleotide (reduced) (NMNH) and AMP. NMNH was further hydrolysed to yield nicotinamide riboside (reduced) (NRH), which was stable. NAD+ was hydrolysed (although at a slower rate than was NADH), but was also reduced to yield NADH. The reduction of NAD+ was catalysed by the enzyme serum L(+)lactate dehydrogenase (EC 1.1.1.27) and was dependent on the concentration of L(+)lactate in the serum. NADPH was hydrolysed in a similar manner to NADH but not oxidized by serum. NADH generated from NAD+ by serum derived from human, foetal calf and horse sources was capable of driving the bioreductive activation of CB 1954 by the enzyme DT diaphorase. Cell surfaces oxidized NADH to NAD+, but did not oxidize NADPH or NRH. These observations suggest that NAD(P)H would be unsuitable as a source of reducing equivalents for the bioreductive activation of prodrugs by a reductase enzyme in Antibody Directed Enzyme Prodrug Therapy (ADEPT). In contrast, NAD+ (which could act as a source of NADH) and NRH could avoid the shortcomings of NAD(P)H, and act as suitable cofactors for an enzyme in an ADEPT system.

Animals↗
PubMed1975

Enzyme therapy. V. In vivo fate of erythrocyte-entrapped beta-glucuronidase in beta-glucuronidase-deficient mice.

The use of erythrocyte entrapment as a strategy to deliver and protect exogenously administered enzymes for replacement therapy in selected genetic diseases has been evaluated in a mammalian model system. The uptake, tissue distribution, intracellular localization, and in vivo lifetime of erythrocyte-entrapped bovine beta-glucuronidase were determined by a selective thermal inactivation assay after intravenous administration into beta-glucuronidase-deficient mice. The exogenous activity was cleared from the circulation with a half-life of about 20 min and was no longer detectable at 2 hr. A concomitant uptake of the injected enzyme was observed in murine tissues, primarily the liver; approximately 30% of the bovine activity was recovered at 30 min and maximal hepatic uptake, 71% of dose, was detected at 2 hr. Hepatic recovery of the bovine activity was observed to decrease in a biphasic pattern to nondetectable levels by 5 days. The recovery of the entrapped activity was characterized by a latency of detection in hepatic tissue up to 13 hr postinjection. At each time point more than 80% (84-100%) of the recovered bovine activity was detected in the lysosomally enriched hepatic subcellular fraction. Maximal recoveries of 10% and 15% of administered dose were observed in splenic and renal tissues, respectively, soon after enzyme administration. In comparison to results obtained after intravenous administration of unentrapped bovine beta-glucuronidase, erythrocyte-entrapped activity was retained fourfold longer in the circulation, fivefold longer in hepatic tissue, and was more efficiently delivered to a variety of tissues.

Animals↗
PubMed1979

Enzyme therapy in Fabry disease: differential in vivo plasma clearance and metabolic effectiveness of plasma and splenic alpha-galactosidase A isozymes.

A pilot trial of enzyme replacement with splenic and plasma alpha-galactosidase A (alpha-D-galactosidase; alpha-D-galactoside galactohydrolase, EC 3.2.1.22) isozymes was undertaken in two brothers with Fabry disease, an X-linked glycosphingolipid storage disease. Six unentrapped doses (2000 units/kg) of each isozyme were administered intravenously to the respective recipients during a 117-day period. The circulating half-life of the splenic isozyme was about 10 min, whereas that for the plasma isozyme was approximately 70 min. No immune response was detected by skin and immunodiffusion tests or by alterations in the maximal activity or clearance kinetics for either isozyme after successive administrations. After each dose of the splenic isozyme, the concentration of the accumulated circulating substrate, trihexosylceramide (globotriaosylceramide), decreased maximally (approximately 50% of initial values) in 15 min and returned to preinfusion levels by 2-3 hr. In marked contrast, injection of the plasma isozyme decreased the circulating substrate levels 50-70% by 2-6 hr; the concentrations gradually returned to preinfusion values by 36-72 hr.

Adult↗
PubMed1977

Preliminary studies with L-asparaginase bound to implantable bovine collagen heterografts: a potential long-term, sustained dosage, antitumor enzyme therapy system.

In this study, L-Asparaginase has been bound to collagen heterografts derived from carotid bovine arteries. The immobilization procedure utilizes both non-covalent and covalent interactions to fix the enzyme. Binding of the enzyme to the graft material was shown to the pH dependent, with optimum binding occurring at pH 6.0 and pH 8.5. Amidohydrolysis by the bound enzyme exhibited zero-order kinetic behavior at substrate saturating conditions. Total apparent asparaginase activity expressed by the grafts as a function of the number of repeated in vitro assay trials demonstrated that over a span of 3 months of intermittent storage and use, the enzyme-grafts retained as much as 62% of their initial activities. Implantation of 4 asparaginase-collagen grafts in various locations of the thoracic and abdominal aorta resulting in prolonged reductions of plasma asparagine levels in 3 of the 4 implants. Presence of plasma asparaginase was checked in one of the four implants and determined to be less than 2 X 10(-4) I.U./ml. Removal of grafts from 3 of the 4 animal subjects showed reductions in the apparent asparaginase activity expressed by the grafts of 7 to 70 percent after in vivo contact times which varied from 6 to 15 days.

Animals↗
PubMed1979

A new extracorporeal reactor-dialyzer for enzyme therapy using immobilized L-asparaginase.

Depletion of circulating L-asparagine has proved beneficial in the treatment of some acute lymphoyctic leukemias. To avoid the immunologic sequelae of administering L-asparaginase parenterally, we have covalently attached the enzyme to the outside of the fibers of a conventional hollow fiber hemodialyzer. This provides ready access of the substrate to the enzyme, while simultaneously isolating the foreign protein from the immune system. Such reactor-dialyzers perform well, both in vitro and in vivo. Circulating L-asparagine in the healthy dog is reduced from about 50 micrometer to less than 2 micrometer within 30 min of connecting the reactor-dialyzer and the reduction persists for at least 4 hr after cessation of treatment.

Animals↗
PubMed1991

Targeted enzyme therapy of experimental glomerulonephritis in rats.

We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin, and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A, which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria, rats given untargeted protease (biotin-conjugated without avidin, or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats, targeted protease was again more effective than untargeted protease at reducing proteinuria, and also decreased the size of electron-dense glomerular deposits, hypercholesterolemia, and creatininemia. Inactivated targeted proteases had no effect on proteinuria, hypercholesterolemia, or azotemia. Finally, active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits, proteinuria, hyperlipidemia, and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis, and that targeted protease is more effective than untargeted protease.

Albuminuria↗