Delivery platforms for broadly neutralizing antibodies

Abstract

Purpose of reviewPassive administration of broadly neutralizing antibodies (bNAbs) is being evaluated as a therapeutic approach to prevent or treat HIV infections. However, a number of challenges face the widespread implementation of passive transfer for HIV. To reduce the need of recurrent administrations of bNAbs, gene-based delivery approaches have been developed which overcome the limitations of passive transfer.Recent findingsThe use of DNA and mRNA for the delivery of bNAbs has made significant progress. DNA-encoded monoclonal antibodies (DMAbs) have shown great promise in animal models of disease and the underlying DNA-based technology is now being tested in vaccine trials for a variety of indications. The COVID-19 pandemic greatly accelerated the development of mRNA-based technology to induce protective immunity. These advances are now being successfully applied to the delivery of monoclonal antibodies using mRNA in animal models. Delivery of bNAbs using viral vectors, primarily adeno-associated virus (AAV), has shown great promise in preclinical animal models and more recently in human studies. Most recently, advances in genome editing techniques have led to engineering of monoclonal antibody expression from B cells. These efforts aim to turn B cells into a source of evolving antibodies that can improve through repeated exposure to the respective antigen.SummaryThe use of these different platforms for antibody delivery has been demonstrated across a wide range of animal models and disease indications, including HIV. Although each approach has unique strengths and weaknesses, additional advances in efficiency of gene delivery and reduced immunogenicity will be necessary to drive widespread implementation of these technologies. Considering the mounting clinical evidence of the potential of bNAbs for HIV treatment and prevention, overcoming the remaining technical challenges for gene-based bNAb delivery represents a relatively straightforward path towards practical interventions against HIV infection.

Pharmacokinetic Analyses of a Lipid Nanoparticle-Encapsulated mRNA-Encoded Antibody against Rift Valley Fever Virus

“…The antibodies encoded by nucleic acids can be produced rapidly and are likely to be produced commercially at a much lower cost than equivalent protein therapies . Researchers are already exploring the possibility of using antibodies encoded by nucleic acids to treat and prevent infectious diseases. , For decades, with the development of lipid nanoparticle (LNP) delivery systems, mRNA platforms have evolved from a theoretical idea to a clinical reality . Encapsulation of nucleoside-modified mRNA in LNP has also proven to be an effective tool for producing target proteins .…”

Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies

“…One promising method for sustained delivery of bNAbs is through AAV-mediated delivery of antibody expression cassettes, known as vectored immunoprophylaxis. [20][21][22][23][24][25] Trials in mice, macaques, and recently humans have demonstrated the potential of this strategy for sustained secretion of therapeutic anti-HIV-1 antibodies. However, pre-existing immunity against AAV vectors, low levels of antibody secretion, uncertainty regarding long-term expression, and seroconversion preventing re-dosing remain challenges limiting this approach.…”