Detail of "331731-18-1"

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Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation

Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation. Yang, Karen; Basu, Amartya; Wang, Maoliang; Chintala, Ramesh; Hsieh, Ming-Ching; Liu, Sam; Hua, Jack; Zhang, Zhenfan; Zhou, John; Li, Mark; Phyu, Hnin; Petti, Gerald; Mendez, Magda; Janjua, Haleema; Peng, Ping; Longley, Clifford; Borowski, Virna; Mehlig, Mary; Filpula, David (Enzon Pharmaceuticals, Piscataway, NJ 08854 3969, USA). Protein Engineering, 16(10), 761-770 (English) 2003 Oxford University Press. CODEN: PRENE9. ISSN: 0269-2139. DOCUMENT TYPE: Journal CA Section: 15 (Immunochemistry) The utility of single-chain Fv proteins as therapeutic agents would be realized if the circulating lives of these minimal antigen-binding polypeptides could be both prolonged and adjustable. We have developed a general strategy for creating tailored monoPEGylated single-chain antibodies. Free cysteine residues were engineered in an anti-TNF-a scFv at the C-terminus or within the linker segments of both scFv orientations, VL-linker-VH and VH-linker-VL. High-level expression of 10 designed variant scFv proteins in Pichia pastoris allowed rapid purifn. Optimization of site-specific conjugate prepn. 331731-18-1 and 25322-68-3 which are cas registry numbers are also used here. with 5, 20 and 40 kDa maleimide-PEG polymers was achieved and a comparison of the structural and functional properties of the scFv proteins and their PEGylated counterparts was performed. Peptide mapping and MALDI-TOF mass spectrometric anal. confirmed the unique attachment site for each PEG polymer. Independent biochem. and bioactivity analyses, including binding affinities and kinetics, antigenicity, flow cytometric profiling and cell cytotoxicity rescue, demonstrated that the functional activities of the 10 designed scFv conjugates are maintained, while scFv activity variations between these alternative assays can be correlated with conjugate and anal. designs. Pharmacokinetic studies of the PEGylated scFv in mice demonstrated up to 100-fold prolongation of circulating lives, in a range comparable to clin. antibodies. .

Comparison of the efficacy of the tumour necrosis factor a blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis

Comparison of the efficacy of the tumour necrosis factor a blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis. Hochberg, M. C.; Tracy, J. K.; Hawkins-Holt, M.; Flores, R. H. (Division of Rheumatology and Clinical Immunology, Department of Medicine, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA). Annals of the Rheumatic Diseases, 62(Suppl. 11), ii13-ii16 (English) 2003 BMJ Publishing Group. CODEN: ARDIAO. ISSN: 0003-4967. 331731-18-1 and 185243-69-0 which are cas registry numbers are also used here. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 15 Objective: To det., using the method of adjusted indirect comparisons, whether there are differences in efficacy of tumor necrosis factor (TNFa) blocking agents, as measured by the rate ratios for American College of Rheumatol. (ACR) 20, 50, and 70 responses, in patients with rheumatoid arthritis with an incomplete response to methotrexate. Methods: A systematic review was performed to identify placebo controlled trials of 24-30 wk' duration of combination therapy that used a step-up approach with the addn. of TNFa blocking agents to methotrexate. The method of "adjusted indirect comparisons" was used to compare results across trials to det. the relative risk for an ACR20 or 50 response. Results: Placebo controlled trials for adalimumab, etanercept, and infliximab provided data on ACR20 and 50 responses. Both the similarity of demog. and disease characteristics of patients at entry, and the homogeneity of response rates in the placebo groups across trials, suggested that comparing results across trials was valid. The relative risk for obtaining an ACR20 and 50 response derived from the adjusted indirect comparisons of the TNFa blocking agents did not significantly differ from unity. Conclusion: The anal. showed that the three currently marketed TNFa blocking agents have similarly efficacy when added to methotrexate in the treatment of patients with rheumatoid arthritis with active disease. .