In situ production of therapeutic monoclonal antibodies

Abstract

The use of antibodies as a treatment for disease has it origins in experiments performed in the 1890s, and since these initial experiments, monoclonal antibodies (mAbs) have become one of the fastest growing therapeutic classes for the treatment of cancer, autoimmune disease, and infectious diseases. However, treatment with therapeutic mAbs often requires high doses given via long infusions or multiple injections, which, coupled with the prohibitively high cost associated with the production of clinical-grade proteins and the transient serum half-lives that necessitate multiple administrations to gain therapeutic benefits, makes large-scale treatment of patients, especially patients in the developing world, difficult. Due to their low-cost and rapid scalability, nucleic acid-based approaches to deliver antibody gene sequences for in situ mAb production have gained substantial traction. In this review, we discuss new approaches to produce therapeutic mAbs in situ to overcome the need for the passive infusion of purified protein.

Keywords:

• adeno-associated virus
• adenovirus
• ex vivo gene transfer
• gene therapy
• in situ production
• monoclonal antibody
• non-vectored gene delivery

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Monoclonal antibody (mAb)-based therapeutics are one of the fastest growing classes of therapeutics, with over 300 currently in various stages of clinical development. However, the large doses required, coupled with the high cost of production and long-administration times, limits the use of mAb-based therapeutics as a widespread prophylactic or therapeutic treatment in resource-poor settings.

• Three main approaches have been used for the in situ production of therapeutic mAbs: ex vivo cell manipulation, vectored gene delivery and non-vectored gene delivery.

• Multiple cell types have been successfully modified ex vivo to produce mAbs with demonstrable therapeutic effects, and advancements in tissue engineering will likely increase the titer of antibodies obtainable. However, the therapeutic usefulness of this approach is limited by the cost and labor required to collect, engineer and implant the modified cells as well as the mutagenic risk associated with ex vivo manipulation of cells.

• Vectored gene delivery has demonstrated the greatest success for in situ mAb production due to its ability to generate high titers of mAbs. These antibodies have shown significant therapeutic benefits, particularly as a prophylaxis against infectious diseases, and the first clinical trials using this approach have begun. However, the therapeutic usefulness of this approach is limited by the development of or pre-existing immunity against the vector, the relatively low coding capacity of the commonly used vectors and manufacturing difficulties.

• Non-vectored gene delivery utilizing plasmid DNA has shown limited success for the in situ production of mAbs, while RNA has been successfully used to express therapeutic secreted proteins in situ, but not antibodies. While this approach still struggles to achieve clinically effective titers, recent advances in in vivo nucleic acid delivery approaches may drastically improve this therapeutic approach.