Monoclonal antibodies (mAb) have been successfully applied to the treatment of chronic diseases, such as cancer, inflammation and immune diseases. With the technical advances in antibody engineering, development of small recombinant antibody fragments as high affinity therapeutics with reduced immunogenicity has become under the spotlight. A popular format of the engineered recombinant antibody fragments is the single-chain fixed-variable (scFv) molecules, in which the VH and VL regions of the parental antibody are jointed together by a polypeptide linker. The scFv fragment retains the target specificity and antigen-binding affinity of the intact antibody, and can be genetically designed and produced in large quantity by ectopically expressing both VH and VL regions from a single cDNA in cells. Due to its smaller size, the scFv molecule shows improved pharmacokinetics in tumor penetration and is better tolerated by the host immune system. Despite these potential advantages of using scFv molecules for immunotherapy, especially for chronic diseases such as cancers, the treatment efficacy, however, is often compromised by the rapid blood clearance and insufficient concentration of the infused scFv fragments at the target site. To achieve high local concentrations in the target tissues, large amount of the recombinant scFv proteins (hundreds milligrams or more/a period of treatment) have to be administrated in the conventional antibody therapy. Thus, broad application of recombinant scFv antibody is limited by manufacturing difficulty and the high cost of production. To overcome these bottle-necks, Shi et al. 1 developed a promising therapeutic strategy by expressing in vivo scFv fragments of a mouse monoclonal antibody (AD5-10) that is directed against the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptor DR5 (death receptor 5, also known as TRAIL receptor 2) 2, via recombinant adeno-associated virus (rAAV) vector-mediated antibody gene therapy.

The great shortcoming of using mouse monoclonal antibody (mAb) in human, however, is the associated human anti-mouse antibody (HAMA) reaction, which makes long-term use of the mouse mAb therapy infeasible in patients with chronic progressive conditions such as cancers. The immunogenicity of rodent mAbs sometimes can be successfully reduced, but in a laborious and time-consuming way, by antibody chimerization and humanization using gene-engineering technologies. In addition, due to their large size, it is difficult for intact antibodies to penetrate into solid tumors, further limiting their applications in cancer therapy 4. Since AAV-mediated gene therapy enables long-term transgene expression in vivo and shows low immunogenicity, Shi et al. 1 adopted this system to express scFv fragments of AD5-10 in mouse models and achieved a significant therapeutic efficacy against tumor xenografts.

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