In Vitro and In Vivo Secretion of Cloned Antibodies by Genetically Modified Myogenic Cells

Abstract

In vivo production of recombinant antibodies by engineered cells may have applications for gene therapy of certain cancers and of certain severe viral diseases. It would also permit the development of new animal models of autoimmune diseases and new approaches for in vivo ablation of specific cell types for fundamental purposes. Using gene transfer of an anti-human thyroglobulin monoclonal antibody, we show here that several cell types permitting autologous grafting of genetically engineered cells are efficiently able to secrete antibodies in vitro. Those cells include skin fibroblasts, hepatocytes, and myogenic cells. We also show that the secreted antibodies display an affinity for the antigen close to that of the parental antibody, with, however, slight differences varying according to the cell type. This indicates that the foldings of antigen combining sites of antibodies produced in B cell- and non-B cell contexts are very similar. Finally, we report that, when implanted in the forelimb of a mouse, genetically modified myogenic cells are able to secrete antibodies for at least 4 months. Taken together, our observations point to the notion that genetic modification of patient cells may be used for long-term antibody-based gene therapies.

Overview summary

Expression of cloned antibodies by genetically modified cells of patients may be used for developing surveillance treatments after primary anticancer therapies such as surgery, chemotherapies, or radiotherapies to avoid relapse or for inhibiting virus proliferation in the case of severe viral diseases. Because of their short life span and because of the fact that they already produce an antibody, plasmocytes from patients cannot be used for such a purpose. It is shown here that several cell types amenable to genetic modification and grafting to patients and which include skin fibroblasts, myogenic cells, and hepatocytes can produce cloned antibodies retaining the specificity and the affinity of the parental antibody. Grafting of engineered myogenic cells to mice also showed that delivery of recombinant antibodies in the blood stream was possible in vivo. This work casts the cellular basis for new antibody-based gene therapies and also more fundamental applications such as specific cell ablation and the study of certain aspects of autoimmunity.