Persistent Expression of Biologically Active Anti-HER2 Antibody by AAVrh.10-mediated Gene Transfer

Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against an extracellular region of the HER2 protein. We hypothesized that a single adeno-associated virus mediated genetic delivery of an anti-HER2 antibody should be effective in mediating long term production of anti-HER2 and in suppressing the growth of human tumors in a xenograft model in nude mice. The adeno-associated virus gene transfer vector AAVrh.10αHER2 was constructed based on non-human primate AAV serotype rh.10 to express the cDNAs for the heavy and light chains of monoclonal antibody 4D5, the murine precursor to trastuzumab. The data demonstrates that genetically transferred anti-HER2 selectively bound human HER2 protein and suppressed proliferation of HER2 positive tumor cell lines. A single administration of AAVrh.10αHER2 provided long term therapeutic levels of anti-HER2 antibody expression without inducing anti-idiotype response, suppressed the growth of HER2 positive tumors and increased survival of the tumor-bearing mice. In the context that trastuzumab therapy requires frequent, repeated administration, this strategy might be developed as an alternate platform for delivery anti-HER2 therapy.