Transgenic mice as a model to test the immunogenicity of proteins altered by site-specific mutagenesis.
Second generation therapeutic proteins are now being produced by in vitro mutagenesis of the relevant genes. Of some concern, however, is the possibility that these altered proteins will be immunogenic and the antibodies raised will also recognize the endogenous protein with undesirable consequences. We have designed a biological system to test these possibilities. In this model, transgenic mice produce and secrete human tissue plasminogen activator (h.tPA) to which these mice are immunologically tolerant. However, when challenged with a form in which a single amino acid has been substituted these mice will produce antibodies capable of recognizing h.tPA. These results indicate that there are immunological consequences connected with the design and administration of second generation therapeutic proteins.
Stewart
T A
TA
Department of Developmental Biology, Genetech, Inc., South San Francisco, CA 94080.
Hollingshead
P G
PG
Pitts
S L
SL
Chang
R
R
Martin
L E
LE
Oakley
H
H
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions; D004247:DNA / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D010957:Plasmids; D012313:RNA / Q000032:analysis; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D012313:RNA; D004247:DNA; D010959:Tissue Plasminogen Activator