Persistent expression of biologically active anti-HER2 antibody by AAVrh.10-mediated gene transfer

Abstract

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.

Recombinant AAV-mediated in vivo long-term expression and antitumour activity of an anti-ganglioside GM3(Neu5Gc) antibody

“…Antibody processing and expression were found to be just as effective in vivo, as functional recombinant antibody 14F7 was detected in animal circulation just a week after rAAV injection. This is in line with previous works reporting the in vivo expression of recombinant antibodies by rAAV-mediated gene transfer in several preclinical models of viral and parasitic diseases[37][38][39] , cancer40,43 and neurological conditions41,42 .…”

“…The in vivo expression of recombinant antibodies by rAAV-mediated gene transfer in several disease models has also been reported [37][38][39][40][41][42][43] .…”

Engineering humoral immunity as prophylaxis or therapy

“…Clinical trials of trastuzumab, an mAb that targets an extracellular region of HER2, have been successful at steady state serum concentrations of greater than 10μg/mL [53] . The murine precursor to trastuzumab was encoded in an AAV rh.10 vector [54] and administered to C57BL/6 mice, resulting in serum concentrations near 35μg/mL within twelve weeks that were sustained for at least 56 weeks post injection. A single injection of this vector increased the survival of Balb/c nu/nu mice injected subcutaneously with Calu-3 tumor cells over-expressing HER2, demonstrating its efficacy at inhibiting cancer in vivo [54].…”

Reconstitutable charged polymeric (PLGA)2-b-PEI micelles for gene therapeutics delivery

“…There are several applications for gene therapy including replacing a mutated gene with a healthy copy of gene [1, 2], introducing a new gene to help fight disease [3, 4], or inactivating a mutated gene that is not functioning correctly [5]. This technique has the potential for broad scale application and impact in treating both acquired and inherited diseases.…”