Generation of a recombinant oncolytic Newcastle disease virus and expression of a full IgG antibody from two transgenes.
The most advanced oncolytic Newcastle disease virus (NDV) strains that are used in clinical trials for the treatment of cancer are wild-type mesogenic strains. These virus strains have an inherent, nongenetically engineered, oncolytic activity and selectively replicate in tumor cells but not in normal human cells. To date no investigations have been performed with genetically engineered mesogenic NDV regarding the oncolytic activity. We describe here the generation of recombinant viruses of the mesogenic naturally oncolytic NDV strain MTH68. We show that not only one, but also two additional transgenes coding for amino-acid chains with a molecular weight of 25 and 50 kDa can be inserted into the viral genome without affecting viral growth, oncolytic potency or tumor-selective replication of the virus. Transgenic expression of the heavy and light chains of a monoclonal antibody, as separate additional transcriptional cassettes, leads to the expression of full immunoglobulin G (IgG) monoclonal antibody by recombinant NDV. Infection of tumor cells with antibody-transgenic viruses results in the efficient production and secretion of a functional full size IgG antibody by the tumor cells, that specifically binds to its target-antigen in tumor tissue. This approach will allow to combine the advantages of oncolytic RNA viruses and monoclonal antibodies in a single powerful anticancer agent with improved or even new therapeutic properties.
Pühler
F
F
Therapeutic Research Group Oncology, Bayer Schering Pharma AG, Berlin, Germany.
Willuda
J
J
Puhlmann
J
J
Mumberg
D
D
Römer-Oberdörfer
A
A
Beier
R
R
D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression; D050438:Genes, Immunoglobulin Heavy Chain; D050439:Genes, Immunoglobulin Light Chain; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D007074:Immunoglobulin G / Q000032:analysis / Q000378:metabolism*; D007150:Immunohistochemistry; D009369:Neoplasms / Q000628:therapy*; D009522:Newcastle disease virus / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000379:methods*; D014162:Transfection / Q000379:methods; D019076:Transgenes
D007074:Immunoglobulin G