Insertion of constant region domains of human IgG, into CD4-PE40 increases its plasma half-life

作者: Janendra K. Batra , Sanjeevaiah Kasturi , Maria G. Gallo , Richard L. Voorman , Stephen M. Maio

DOI: 10.1016/0161-5890(93)90067-L

关键词:

摘要: Abstract CD4-PE40 is a recombinant toxin containing the binding domain of CD4 and mutant form Pseudomonas exotoxin A from which cell has been removed. To increase serum half-life CD4-PE40, we have inserted various portions constant human IgG, into CD4-PE40. The constructs made include CD4-C H 2-PE40, 3-PE40, 1-C 2-PE40 2-C 3-PE40. fusion proteins were expressed purified E. coli. Insertion domains region IgG 1 did not alter cytotoxic activity CD4-PE40; all these molecules equally to cells expressing gp120 on their surface. However, there was marked in mean residence time CD4-Cn2-PE40 115min as compared 47 min for other also increased however, found longest circulation. One possible explanation plasma diminished susceptibility proteolysis. It that much more resistant proteolysis by trypsin than We proposed insertion C 2 covers up protease sensitive sites molecule, thereby making molecule less susceptible degradation. size reduced sensitivity proteases could both be responsible 2-PE40.

参考文章(20)
Janendra K Batra, David J Fitzgerald, Vijay K Chaudhary, Ira Pastan, Single-chain immunotoxins directed at the human transferrin receptor containing Pseudomonas exotoxin A or diphtheria toxin: anti-TFR(Fv)-PE40 and DT388-anti-TFR(Fv). Molecular and Cellular Biology. ,vol. 11, pp. 2200- 2205 ,(1991) , 10.1128/MCB.11.4.2200
Vijay K. Chaudhary, Tamio Mizukami, Thomas R. Fuerst, David J. FitzGerald, Bernard Moss, Ira Pastan, Edward A. Berger, Selective killing of HIV-infected cells by recombinant human CD4- Pseudomonas exotoxin hybrid protein Nature. ,vol. 335, pp. 369- 372 ,(1988) , 10.1038/335369A0
Per Ashorn, Bernard Moss, John N Weinstein, Vijay K Chaudhary, David J FitzGerald, Ira Pastan, Edward A Berger, Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors. Proceedings of the National Academy of Sciences. ,vol. 87, pp. 8889- 8893 ,(1990) , 10.1073/PNAS.87.22.8889
U. Brinkmann, L. H. Pai, D. J. FitzGerald, I. Pastan, Alteration of a protease-sensitive region of Pseudomonas exotoxin prolongs its survival in the circulation of mice. Proceedings of the National Academy of Sciences of the United States of America. ,vol. 89, pp. 3065- 3069 ,(1992) , 10.1073/PNAS.89.7.3065
Edward J. Wawrzynczak, Alan J. Cumber, Geoffrey D. Parnell, Peter T. Jones, Greg Winter, Blood clearance in the rat of a recombinant mouse monoclonal antibody lacking the N-linked oligosaccharide side chains of the CH2 domains. Molecular Immunology. ,vol. 29, pp. 213- 220 ,(1992) , 10.1016/0161-5890(92)90102-4
E. Vitetta, R. Fulton, R. May, M Till, J. Uhr, Redesigning nature's poisons to create anti-tumor reagents. Science. ,vol. 238, pp. 1098- 1104 ,(1987) , 10.1126/SCIENCE.3317828
Roberta R. Pollock, Deborah L. French, Joshua P. Metlay, Barbara K. Birshtein, Matthew D. Scharff, Intravascular metabolism of normal and mutant mouse immunoglobulin molecules European Journal of Immunology. ,vol. 20, pp. 2021- 2027 ,(1990) , 10.1002/EJI.1830200921
Vijay K. Chaudhary, Gary Queen, Richard P. Junghans, Thomas A. Waldmann, David J. FitzGerald, Ira Pastan, A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin Nature. ,vol. 339, pp. 394- 397 ,(1989) , 10.1038/339394A0
Jay W. Ellison, Bennett J. Berson, Leroy E. Hood, The nucleotide sequence of a human immunoglobulin C gamma1 gene. Nucleic Acids Research. ,vol. 10, pp. 4071- 4079 ,(1982) , 10.1093/NAR/10.13.4071
Daniel J. Capon, Steven M. Chamow, Joyce Mordenti, Scot A. Marsters, Timothy Gregory, Hiroaki Mitsuya, Randal A. Byrn, Catherine Lucas, Florian M. Wurm, Jerome E. Groopman, Samuel Broder, Douglas H. Smith, Designing CD4 immunoadhesins for AIDS therapy Nature. ,vol. 337, pp. 525- 531 ,(1989) , 10.1038/337525A0