Anti-SERPINA1 monoclonal antibody, clone FQS0101-82

Alpha-1-antitrypsin (AAT), an acute phase protein, is the principal circulatory anti-protease. This multifunctional protein is encoded by the SERPINA1 gene. Although AAT was recognised as a potential tumour marker, its role in cancer biology remains unknown. Given that it has been demonstrated that AAT has an anti-apoptotic property against non-malignant cells, we aimed to investigate whether AAT affects apoptosis in a colon cancer cell line (HCT116). The presence of AAT in the HCT116 cell culture antagonized cytotoxicity of blockers of MEK1/2, PI3K/Akt pathways as well as NF-kappa B. The dominantly recovered cell viability was observed in the co-treatment with MEK1/2 inhibitor U0126. In addition, it was revealed that AAT almost completely abolished U0126-induced apoptosis through maintenance of the autophagy process. Our study revealed for the first time that the observed cyto-protection triggered by AAT was accompanied by sustained autophagy which opposed apoptosis. These results may contribute to understanding of the role of AAT in cancer development and evaluation of efficacy of cancer therapy.

We performed a series of studies in baboons to evaluate the safety of intramuscular administration of rAAV vector expressing the alpha-1 antitrypsin (AAT) gene (SERPINA1) in a nonhuman primate model. Initial experiments performed with an rAAV vector expressing the human SERPINA1 gene (at doses of up to 5 X 10(12) vector genomes/kg) resulted in the generation of anti-human AAT antibodies, which correlated with a loss of detectable transgene expression. Subsequent studies made use of the baboon SERPINA1 gene tagged with a short (10-amino-acid) c-myc tag. When animals were sacrificed, 4 months after vector injection, transduced myofibers showed efficient transgene expression without detectable humoral immune responses. Mild inflammation was observed in and near the sites of injection in some vector- and saline-injected animals, but serum creatine kinase (CK) values were normal in nearly every case. Real-time PCR was also performed 4 months after injection on gonadal tissue to evaluate the risk of germline transmission. No vector sequences were detected in the gonadal tissues from these animals. These studies indicate that the risks of immune reaction and germline transmission after intramuscular injection of rAAV-SERPINA1 in nonhuman primates are relatively low within the range of vector doses studied.