title: A triple-transgenic immunotolerant mouse model.
abstract: Avoiding unwanted immunogenicity is of key importance in the development of therapeutic drug proteins. Animal models are of less predictive value because most of the drug proteins are recognized as foreign proteins. However, different methods have been developed to obtain immunotolerant animal models. So far, the immunotolerant animal models have been developed to assess one protein at a time and are not suitable for the assessment of combination products. Our aim was to develop an animal model for evaluating the impact of manufacturing and formulation changes on immunogenicity, suitable for both single protein and combination products. We constructed two lines of transgenic mice expressing the three human coagulation factors, II, VII, and X, by inserting a single vector containing the three coagulation factors encoding sequences separated by insulator sequences derived from the chicken beta-globin locus into the mouse genome. Immunization of transgenic mice from the two lines and their wild-type littermates showed that transgenic mice from both lines were immunotolerant to the expressed human coagulation factors. We conclude that transgenic mice immunotolerant to multiple proteins can be obtained, and that these mice are potentially useful as animal models in the assessment of immunogenicity in response to manufacturing changes.
authors: AstraZeneca, Safety Assessment, Södertälje, Sweden.
authors: Nina
authors: N
authors: Brenden
authors: Katja
authors: K
authors: Madeyski-Bengtson
authors: Klara
authors: K
authors: Martinsson
authors: Rebecka
authors: R
authors: Svärd
authors: Sara
authors: S
authors: Albery-Larsdotter
authors: Britta
authors: B
authors: Granath
authors: Hanna
authors: H
authors: Lundgren
authors: Ann
authors: A
authors: Lövgren
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D002645:Chickens; D005167:Factor VII / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D005170:Factor X / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007114:Immunization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D011516:Prothrombin / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019076:Transgenes; D055544:beta-Globins / Q000235:genetics
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D055544:beta-Globins; D005167:Factor VII; D011516:Prothrombin; D005170:Factor X