Deal, C. E. | Search bioRxiv

bioRxiv2023

mRNA delivery of dimeric human IgA protects mucosal tissues from bacterial infection

Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is limited to IgG1 isotypes that have restricted access to mucosal sites. IgA is well-established as the predominant antibody isotype in mucosal secretions but is clinically underutilized. To enable development of IgA-based mAbs, we exploited mRNA platform technology and demonstrated expression of functional, antigen-specific IgA (IgAmRNA) that can limit bacterial invasion in the intestine and prevent colonization in the lung. Moreover, in vivo IgAmRNA had enhanced serum half-life and a greater degree of sialylation than a recombinantly produced IgA. The results underscore the potential of mRNA-based platforms to deliver protective human mAbs to mucosal surfaces and open new avenues to combat infectious diseases in the face of pervasive antibiotic resistance. One Sentence SummarymRNA-encoded human monoclonal IgA traffics to mucosal tissues and provides protection against bacterial challenge

immunology↗

bioRxiv2022

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 recruiting innate immunity to HIV-infected cells through their fragment crystallizable (Fc) region. Vaccination or productive infection results in a polyclonal mixture of class-switched IgG antibodies comprised 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 use vectored immunoprophylaxis (VIP) 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, exhibits significantly reduced protection in vivo relative to other subclasses. However, even low concentrations of highly functional VRC07-IgG1 yields substantial protection against vaginal challenge, suggesting that interventions capable of eliciting modest titers of functional subclasses may provide meaningful benefit against infection.

immunology↗