An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo

• Published in: Molecular therapy Vol. 15; no. 6; pp. 1153 - 1159
• Main Authors: Fang, Jianmin, Yi, Saili, Simmons, Andrew, Tu, Guang Huan, Nguyen, Minh, Harding, Thomas C, VanRoey, Melinda, Jooss, Karin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2007; Elsevier Limited
• Subjects: Amino Acid Sequence; Amino acids; Animals; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - metabolism; Binding Sites; Blotting, Western; Cell Line; CHO Cells; Cricetinae; Cricetulus; Cytomegalovirus; Dependovirus - genetics; Dose-Response Relationship, Drug; Drug Delivery Systems - methods; Enzyme-Linked Immunosorbent Assay; Female; Furin - metabolism; Gene Expression - drug effects; Gene therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humans; Immunoglobulin Heavy Chains - chemistry; Immunoglobulin Heavy Chains - genetics; Immunology; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Nude; Molecular Sequence Data; Monoclonal antibodies; Oncology; Proteins; Scientific imaging; Sirolimus - pharmacology; Vectors (Biology); United States > US; South San Francisco California; California
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/sj.mt.6300142

Monoclonal antibody (mAb) delivery by gene transfer in vivo may be an attractive alternative to current mAb therapies for applications that require long-term therapy. This article describes a transfer system that allows inducible high-level expression of unmodified mAbs in vivo. A recombinant adeno-associated viral (rAAV) vector is used that comprises an expression cassette consisting of a dimerizer-regulated promoter that drives expression of the antibody heavy and light chains linked by a 2A self-processing peptide and a furin cleavage site. Following intravenous injection of the rAAV vector, serum mAb levels >1 mg/ml were attained by administration of the inducer, rapamycin. Antibody expression could be rapidly shut off by discontinuing treatment with rapamycin. By optimizing the furin cleavage sequence, this system generated native antibody in vivo, decreasing the likelihood of a host immune response to foreign sequences. In summary, this optimized mAb expression system allows regulated high-level expression of native full-length mAbs in vivo and may offer a new opportunity for delivery of therapeutic mAbs in the clinic.