State of play and clinical prospects of antibody gene transfer

Abstract

Recombinant monoclonal antibodies (mAbs) are one of today’s most successful therapeutic classes in inflammatory diseases and oncology. A wider accessibility and implementation, however, is hampered by the high product cost and prolonged need for frequent administration. The surge in more effective mAb combination therapies further adds to the costs and risk of toxicity. To address these issues, antibody gene transfer seeks to administer to patients the mAb-encoding nucleotide sequence, rather than the mAb protein. This allows the body to produce its own medicine in a cost- and labor-effective manner, for a prolonged period of time. Expressed mAbs can be secreted systemically or locally, depending on the production site. The current review outlines the state of play and clinical prospects of antibody gene transfer, thereby highlighting recent innovations, opportunities and remaining hurdles. Different expression platforms and a multitude of administration sites have been pursued. Viral vector-mediated mAb expression thereby made the most significant strides. Therapeutic proof of concept has been demonstrated in mice and non-human primates, and intramuscular vectored mAb therapy is under clinical evaluation. However, viral vectors face limitations, particularly in terms of immunogenicity. In recent years, naked DNA has gained ground as an alternative. Attained serum mAb titers in mice, however, remain far below those obtained with viral vectors, and robust pharmacokinetic data in larger animals is limited. The broad translatability of DNA-based antibody therapy remains uncertain, despite ongoing evaluation in patients. RNA presents another emerging platform for antibody gene transfer. Early reports in mice show that mRNA may be able to rival with viral vectors in terms of generated serum mAb titers, although expression appears more short-lived. Overall, substantial progress has been made in the clinical translation of antibody gene transfer. While challenges persist, clinical prospects are amplified by ongoing innovations and the versatility of antibody gene transfer. Clinical introduction can be expedited by selecting the platform approach currently best suited for the mAb or disease of interest. Innovations in expression platform, administration and antibody technology are expected to further improve overall safety and efficacy, and unlock the vast clinical potential of antibody gene transfer.

mRNA vaccines — a new era in vaccinology

“…Antibody-gene transfer technologies could potentially overcome these difficulties, as they administer nucleotide sequences encoding monoclonal antibodies to patients, enabling in vivo production of properly folded and modified protein therapeutics 193 . Multiple gene therapy vectors have been investigated (for example, viral vectors and plasmid DNA) that bear limitations such as pre-existing host immunity, acquired anti-vector immunity, high innate immunogenicity, difficulties with in vivo regulation of antibody production and toxic effects 193,194 . mRNA therapeutics combine safety with exquisite dose control and the potential for multiple administrations with no pre-existing or anti-vector immunity.…”

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

“…Importantly, the use of AAV voids the need for repeated administrations of purified antibody to maintain therapeutic levels in circulation. Due to its simplicity and ease of deployment, the approach is ideal for global use (26).…”

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

“…In vivo viral vectors encoding antibody genes have been reported to be administered either locally [via intramuscular (IM), intranasal (IN), intraocular (IO), or intracranial (IC) routes] or systemically via IV or intrathecal (IT) routes, leading to viral infection with production of the virus-encoded antibody predominately from liver and lung and perhaps other tissues (reviewed in Ref. [19]). Interestingly, AAV vectors take several weeks to reach their peak expression; therefore, to accelerate expression, De et al evaluated a combination of both an Ad vectorencoded antibody followed by an AAV-encoded mAb targeting anthrax and demonstrated successful rapid and long-lasting expression [20].…”