An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions.

Colonization of the gut and airways by pathogenic bacteria can lead to local tissue destruction and life-threatening systemic infections, especially in immunologically compromised individuals. Here, we describe an mRNA-based platform enabling delivery of pathogen-specific immunoglobulin A (IgA) monoclonal antibodies into mucosal secretions. The platform consists of synthetic mRNA encoding IgA heavy, light, and joining (J) chains, packaged in lipid nanoparticles (LNPs) that express glycosylated, dimeric IgA with functional activity in vitro and in vivo. Importantly, mRNA-derived IgA had a significantly greater serum half-life and a more native glycosylation profile in mice than did a recombinantly produced IgA. Expression of an mRNA encoded Salmonella-specific IgA in mice resulted in intestinal localization and limited Peyer's patch invasion. The same mRNA-LNP technology was used to express a Pseudomonas-specific IgA that protected from a lung challenge. Leveraging the mRNA antibody technology as a means to intercept bacterial pathogens at mucosal surfaces opens up avenues for prophylactic and therapeutic interventions.

Antibody-mediated prevention of vaginal HIV transmission is dictated by IgG subclass in humanized mice.

HIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and driving innate immune responses against HIV-infected cells through their Fc region. Vaccination or productive infection results in a polyclonal mixture of class-switched immunoglobulin G (IgG) antibodies composed of four subclasses, each encoding distinct Fc regions that differentially engage innate immune functions. Despite evidence that innate immunity contributes to protection, the relative contribution of individual IgG subclasses is unknown. Here, we used vectored immunoprophylaxis in humanized mice to interrogate the efficacy of individual IgG subclasses during prevention of vaginal HIV transmission by VRC07, a potent CD4-binding site-directed bNAb. We find that VRC07 IgG2, which lacks Fc-mediated functionality, exhibited substantially reduced protection in vivo relative to other subclasses. Low concentrations of highly functional VRC07 IgG1 yielded substantial protection against vaginal challenge, suggesting that interventions capable of eliciting modest titers of functional IgG subclasses may provide meaningful benefit against infection.

Advancements in mRNA Encoded Antibodies for Passive Immunotherapy.

Monoclonal antibodies are the fastest growing therapeutic class in medicine today. They hold great promise for a myriad of indications, including cancer, allergy, autoimmune and infectious diseases. However, the wide accessibility of these therapeutics is hindered by manufacturing and purification challenges that result in high costs and long lead times. Efforts are being made to find alternative ways to produce and deliver antibodies in more expedient and cost-effective platforms. The field of mRNA has made significant progress in the last ten years and has emerged as a highly attractive means of encoding and producing any protein of interest in vivo. Through the natural role of mRNA as a transient carrier of genetic information for translation into proteins, in vivo expression of mRNA-encoded antibodies offer many advantages over recombinantly produced antibodies. In this review, we examine both preclinical and clinical studies that demonstrate the feasibility of mRNA-encoded antibodies and discuss the remaining challenges ahead.

Engineering humoral immunity as prophylaxis or therapy.

PURPOSE OF THE REVIEW: In this review, we will discuss the field of engineered humoral immunity with an emphasis on recent work using viral vectors to produce antibodies in vivo. As an alternative to passive transfer of monoclonal antibody protein, a transgene encoding an antibody is delivered to cells via vector transduction, resulting in expression and secretion by the host cell. This review will summarize the evidence in support of this strategy as an alternative to traditional vaccines against infection and as novel therapeutics for a variety of diseases. RECENT FINDINGS: Historically, humoral immunity has been engineered through vaccination and passive transfer of monoclonal antibodies. However, recent work suggests that vectors can be used to deliver transgenes encoding broadly neutralizing antibodies to non-hematopoietic tissues and can mediate long-term expression that is capable of preventing or treating infectious diseases. The production of engineered monoclonal antibodies allows for precise targeting and elimination of aberrant self-proteins that are characteristic of certain neurodegenerative disease. This approach has also been successfully used to combat cancer and addiction in several animal models. Despite the wide array of expression platforms that have been described, adeno-associated virus vectors have emerged as the frontrunner for rapid clinical translation. SUMMARY: Recent advances in vector-mediated antibody expression have demonstrated the potential for such interventions to prevent infection and treat disease. As such, it offers an alternative to immunogen-based vaccine design and a novel therapeutic intervention by enabling precise manipulation of humoral immunity. Success translating these approaches to patients may enable the development of effective prevention against previously intractable pathogens that evade immunity such as HIV, influenza, malaria or HCV and may also enable new treatment options for neurodegenerative diseases such as Alzheimer's disease.

Vectored antibody gene delivery for the prevention or treatment of HIV infection.

PURPOSE OF REVIEW: To discuss recent progress in the use of vectors to produce antibodies in vivo as an alternative form of HIV prophylaxis or therapy. Instead of passive transfer of monoclonal antibody proteins, a transgene encoding an antibody is delivered to cells by the vector, resulting in expression and secretion by the host cell. This review will emphasize adeno-associated virus (AAV)-based strategies and summarize the evidence in support of this strategy as an alternative to traditional vaccines. We will highlight the major findings in the field and discuss the impact that this approach could have on the prevention, treatment and possibly eradication of HIV in patients. RECENT FINDINGS: In this emerging field, the emphasis has been on the use of vectors delivering antibodies as an alternative to the development of an HIV vaccine. However, recent findings suggest that AAV-delivered broadly neutralizing antibodies can suppress HIV replication. As such, a single injection of AAV could mediate long-term antibody expression to act as a long-lived therapeutic in the absence of antiretroviral drugs. SUMMARY: Vector-mediated antibody expression can both prevent transmission and inhibit the replication of established HIV infections. As such, it offers an alternative to immunogen-based vaccine design and a novel therapeutic intervention by enabling precise manipulation of humoral immunity. Success may enable not only the development of effective prevention against HIV but may also provide an alternative to a lifetime of antiretroviral drugs taken by those who are already infected.