[Varicella infection in patients with acute lymphocytic leukemia].
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Acyclovir↗
Biomedical subjects
K L Law
Publications and source records attributed to K L Law.
III6NeuAcLc4Cer in human SW1116 colorectal carcinoma cells: a possible oncofetal antigen that is not dependent on Lewis gene expression.
Monospecific rabbit antibodies directed against the human milk sialyloligosaccharides III6NeuAcLcOse4 (sialyltetrasaccharide b), IV3NeuAcLcOse4 (sialyltetrasaccharide a), and IV6NeuAcnLc4Ose (sialyltetrasaccharide c) were used to detect their homologous haptens as gangliosides or ganglioside-derived sialyloligosaccharides from the human colorectal carcinoma cell line SW1116. III6NeuAcLc4Cer was first detected in human meconium [P. A. Prieto and D. F. Smith (1985) Arch. Biochem. Biophys. 241, 281-289], and its presence in a total ganglioside fraction of SW1116 cells together with its absence from a total lipid extract of normal human intestinal mucosa are consistent with III6NeuAcLc4Cer being a tumor-associated oncofetal antigen. IV3NeuAcLc4Cer, a ganglioside in human meconium [P. A. Prieto and D. F. Smith (1986) Arch. Biochem. Biophys. 249, 243-253], was also detected in SW1116 cells; an observation that is consistent with its being the immediate precursor to the sialyl-Lea ganglioside in SW1116 cells. Specific antisera against sialylated type 1 oligosaccharide chains whose expression is independent of the Lewis gene fucosyltransferase may be useful diagnostic reagents for oncofetal, carbohydrate antigens.
Antibodies↗
High yield, site-specific coupling of N-terminally modified beta-lactamase to a proteolytically derived single-sulfhydryl murine Fab'.
The preparation of bispecific protein conjugates capable of performing diverse biological functions is an area of active investigation. Such conjugates are routinely prepared using techniques which employ random derivatization of lysine residues, but the overall utility of these methods is limited due to poor yields and heterogeneous conjugates. In this report we describe the development of site-specific linkage methodology for the chemical synthesis of a homogeneous enzyme-antibody Fab' conjugate with coupling efficiencies of at least 72%. The N-terminal threonine residue of beta-lactamase from the P99 strain of Enterobacter cloacae was oxidized to an aldehyde functional group under mild conditions with a 5-fold molar excess of sodium periodate. The murine Fab' with a single sulfhydryl at the hinge region was generated by further digestion of the peptic Fab' fragment with lysyl endopeptidase to remove a decapeptide containing two of the three cysteine residues. Coupling of the two modified proteins was accomplished through a bifunctional coupling reagent containing meleimide and aminooxy functional groups. Synthesis of the linker is described. Yields of 1:1 enzyme-Fab' were at least three times higher than for comparable random derivatization methods. Immunoreactivity and enzymatic activity were unaffected. Biodistribution studies showed a more favorable tumor to blood ratio with the site-specifically linked conjugate.
Amino Acid Sequence↗
Site-specific prodrug activation by antibody-beta-lactamase conjugates: preclinical investigation of the efficacy and toxicity of doxorubicin delivered by antibody directed catalysis.
Antibody directed catalysis (ADC), the catalytic conversion of prodrugs to drugs by enzymes localized at disease targets by appropriate monoclonal antibodies, has shown promise in the treatment of cancer in nude mouse xenograft models. We investigated this concept using antibody enzyme conjugates constructed from beta-lactamase and Fab's reactive with carcinoembryonic antigen, CEA, and tumor associated glycoprotein, TAG-72, to convert prodrugs that are cephalosporin sulfoxide derivatives into oncolytic drugs. Previous work focused on ADC delivery of the potent vinca alkaloid derivative desacetylvinblastine carboxhydrazide (DAVLBHYD). In the current study the ability of the system to deliver doxorubicin was tested in MCF7 breast carcinoma xenografts and OVCAR3 ovarian carcinoma xenografts, and in T380 and LS174T colon tumor xenografts for comparison with previous DAVLBHYD results. ADC enhanced the delivery of doxorubicin in the model systems investigated. Tumor growth suppression was equivalent to or greater than that observed with free doxorubicin at its maximum tolerated dose (MTD). In contrast to the DAVLBHYD results, ADC delivery of doxorubicin did not regress tumors, but did result in a substantial increase in the MTD.
Animals↗
Dextran modification of a Fab'--beta-lactamase conjugate modulated by variable pretreatment of Fab' with amine-blocking reagents.
The physical and pharmacological properties of proteins can be altered by chemical modification with polymers. Preliminary studies showed that attachment of oxidized dextran to the bacterial protein, beta-lactamase (beta L) effectively reduced in vivo immunogenicity in mice with no loss of enzymatic activity. This report describes a general method for differentially dextran modifying the Fab' component of a Fab'--beta-lactamase conjugate by the use of amine-blocking reagents. Methyl acetimidate (MeAcm) and the N-succinimidyl derivative of (methylsulfonyl)ethyl carbonate (NHS-Msc), reagents which can reversibly block primary amines, were used in model studies to modulate the level of available reactive amines on the F(ab')2 fragments of both the anti-carcinoembryonic antigen antibody, ZCE025, and the antitumor-associated glycoprotein-72 antibody, CC49. MeAcm had little or no effect on immunoreactivity and was maximally effective in modulating dextran attachment, while NHS-Msc was much less effective. A comparison of NHS-Msc and MeAcm is described. Treatment of F(ab')2 with 5-300 mM MeAcm prior to dextran treatment showed a proportional decline in the level of dextran attachment as well as intramolecular cross-linking of the protein by the dextran polymers (6 kDa or 33-mer). A conjugate of beta L coupled to MeAcm-treated ZCE025 Fab' [reduced F(ab')2] was constructed under standard conditions using sulfosuccinimidyl N-[(4-carboxycyclohexyl)methyl]maleimide. After dextran modification, this conjugate maintained good immunoreactivity and enzymatic activity. Biodistribution studies in tumor-bearing nude mice of dextranated and nondextranated conjugate showed comparable overall distribution profiles except that the clearance of the dextranated conjugate from both blood and tumor was delayed about 48-72 h.
Animals↗
Novel acid labile COL1 trityl-linked difluoronucleoside immunoconjugates: synthesis, characterization, and biological activity.
LY207702 (1) is a difluorinated purine nucleoside that exhibits impressive antitumor activity in preclinical models. This agent, however, also possesses cardiotoxicity which limits the potential clinical utility of this novel drug candidate. We therefore developed linker chemistry whereby regioselective N6-tritylation of LY207702 (1) allowed this drug to be coupled to epsilon-lysine amino groups of mAb's reactive with human tumor-associated antigens. The resulting immunoconjugates 3 possessed conjugation ratios ranging from 5 to 7 mol of LY207702/mol of mAb, minimal aggregate content (5-10%), and good immunoreactivity. The electronic nature of substituents on the aromatic rings of the trityl group dictated the degree of acid lability of the trityl linker. Increased electronic stabilization of the transient trityl carbocation led to increase in the release rate of free drug, i.e., m-DMT 10a = p-DMT 10b > p-MMT 10d > p-T 10f. Consequently, the more acid labile DMT conjugates 3a and 3b proved to be the most potent cytotoxic agents, and the most stable p-T conjugate 3f exhibited the least antitumor activity when evaluated in vitro and in vivo. p-MeT-linked conjugate 3e, the most stable construct that retained excellent in vivo antitumor activity, was selected for more extensive evaluation. No detectable free drug or metabolite was observed in mouse plasma at a single intravenous dose of p-MeT conjugate 3e, which was consistent with its predicted stability under physiological conditions. This construct did, however, exhibit significant antigen-mediated antitumor activity in vivo. No cardiotoxicity was detected in mice dosed with conjugate 3e (6 mg/kg free drug content per day for 21 days) equivalent to approximately 8 times the total dose required for complete regression of well-established (approximately 1 g) HC1 human colon tumor xenografts in nude mice. Cardiotoxicity was induced in 20% of free drug 1 treated group at the equivalent dose. Cardiomyopathy was, however, observed when the dose of conjugate 3e was increased to 8 mg/kg per day for 21 days. These data suggest that antitumor activity of LY207702 (1) was maintained and its cardiotoxic potential reduced when this agent was administered to human tumor xenograft bearing nude mice as COL1-N6-p-MeT-207702 conjugate 3e.
Animals↗
Daunorubicin coupled to monoclonal antibodies via a cis-aconitic anhydride linker: biochemical and cytotoxic properties revisited.
Daunorubicin (DNR) was coupled to monoclonal antibodies (Mab) reactive to breast tumor cells using the acid-labile linking agents cis-asonitic anhydride and two other non acid-labile analogs, glutaric anhydride and citraconic anhydride. The acid derivatives of DNR formed by reaction with the anhydrides were converted to their N-hydroxysuccinimide (NHS) active esters for coupling to MAb. The molar input of drug NHS ester to MAb ranged from 1:1 to 100:1. The resulting MAb-DNR conjugates were purified by gel filtration and analyzed by high performance liquid chromatography. Monomeric conjugates contained 0.2 to 11.0 moles of DNR/mole of MAb. No evidence of cell killing was observed up to a concentration of 10 micrograms/ml DNR bound to MAb, while DNR exhibited 50% killing of the breast tumor cell line MCF-7 at a concentration of 1 microgram/ml.
Aconitic Acid↗
Tumor reactive cis-aconitylated monoclonal antibodies coupled to daunorubicin through a peptide spacer are unable to kill tumor cells.
Antibody-drug conjugates containing a linkage susceptible to lysosomal hydrolases were constructed by coupling peptide-daunorubicin (DNR) derivatives to MAb. Using a modification in the method of Trouet et al, peptide derivatives of DNR containing the sequences Ala-Leu and Ala-Leu-Ala-Leu linked to drug via their carboxy terminus were prepared. Cleavage of these derivatives by lysosomal enzymes resulting in the release of free DNR was demonstrated. Human antitumor MAb were derivatized with either succinic anhydride or cis-aconitic anhydride to introduce spacer arms for coupling. Binding studies showed that MAb with a decrease of 12-20 amino groups retained greater than 70% of their immunoreactivity, a level deemed acceptable for constructing conjugates. Derivatized and native MAb were conjugated to peptide-DNR via a carbodiimide mediated reaction. None of the conjugates displayed cytotoxicity toward target tumor cell lines in vitro.
Aconitic Acid↗
Childhood non-Hodgkin's lymphoma--results of treatment with ALL high-risk protocol.
Between August 1984 and September 1990, 13 children with non-Hodgkin's lymphoma (NHL) were treated with ALL high-risk protocol (5 with TCLSG 842 regimen and 8 with TPOG 882B protocol) at Taichung Veterans General Hospital. Diagnosis of NHL was confirmed by histology. Nine had lymphoblastic lymphoma, three had histiocytic lymphoma and one had small non-cleaved cell lymphoma, according to the Rappaport classification. After thorough clinical evaluation eight children were NHL stage IV; four were stage III; and one was stage II. All these children had received chemotherapy as acute lymphocytic leukemia (ALL) high-risk protocol for a total of three years, including central nervous system (CNS) prophylaxis. Of the 13 patients, 9 (69.2%) gained complete remission. Over-all survival rate was 46.2%, with a median interval of 36 months. The complete remission rate and survival rate for the nine children with lymphoblastic lymphoma was better at 77.7% & 66.6% respectively. Within the nonresponsive group, two failed to remit because of early withdrawal from the protocol; the other two patients were refractory to treatment. Relapse was noted in one patient. As to the side effects, neutropenic fever was the most common problem encountered (9 occurrences in 13 patients). Other major complications included severe mucositis, massive GI bleeding, intracranial thrombosis induced by l-asparaginase and tumor lysis syndrome. Childhood NHL is often of diffuse types in pathology, and most affected children have advanced diseases at diagnosis. Choosing an optimal treatment protocol is important for good treatment results.
Adolescent↗