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.

A replicating adenovirus capsid display recombinant elicits antibodies against Plasmodium falciparum sporozoites in Aotus nancymaae monkeys.

Decades of success with live adenovirus vaccines suggest that replication-competent recombinant adenoviruses (rAds) could serve as effective vectors for immunization against other pathogens. To explore the potential of a live rAd vaccine against malaria, we prepared a viable adenovirus 5 (Ad5) recombinant that displays a B-cell epitope from the circumsporozoite protein (CSP) of Plasmodium falciparum on the virion surface. The recombinant induced P. falciparum sporozoite-neutralizing antibodies in mice. Human adenoviruses do not replicate in mice. Therefore, to examine immunogenicity in a system in which, as in humans, the recombinant replicates, we constructed a similar recombinant in an adenovirus mutant that replicates in monkey cells and immunized four Aotus nancymaae monkeys. The recombinant replicated in the monkeys after intratracheal instillation, the first demonstration of replication of human adenoviruses in New World monkeys. Immunization elicited antibodies both to the Plasmodium epitope and the Ad5 vector. Antibodies from all four monkeys recognized CSP on intact parasites, and plasma from one monkey neutralized sporozoites in vitro and conferred partial protection against P. falciparum sporozoite infection after passive transfer to mice. Prior enteric inoculation of two animals with antigenically wild-type adenovirus primed a response to the subsequent intratracheal inoculation, suggesting a route to optimizing performance. A vaccine is not yet available against P. falciparum, which induces the deadliest form of malaria and kills approximately one million children each year. The live capsid display recombinant described here may constitute an early step in a critically needed novel approach to malaria immunization.

Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice.

Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.

Prospects for oral replicating adenovirus-vectored vaccines.

Orally delivered replicating adenovirus (Ad) vaccines have been used for decades to prevent adenovirus serotype 4 and 7 respiratory illness in military recruits, demonstrating exemplary safety and high efficacy. That experience suggests that oral administration of live recombinant Ads (rAds) holds promise for immunization against other infectious diseases, including those that have been refractory to traditional vaccination methods. Live rAds can express intact antigens from free-standing transgenes during replication in infected cells. Alternatively, antigenic epitopes can be displayed on the rAd capsid itself, allowing presentation of the epitope to the immune system both prior to and during replication of the virus. Such capsid-display rAds offer a novel vaccine approach that could be used either independently of or in combination with transgene expression strategies to provide a new tool in the search for protection from infectious disease.