Biology subjects

Deal, C. E.

Publications and source records attributed to Deal, C. E..

4 recordsLinked to original sources

bioRxiv2025

Maternal transfer of mRNA LNP-derived, pathogen-specific, monoclonal IgG to suckling mice

Breast milk provides a rich source of naturally derived maternal antibodies that confer passive immunity to infants, protecting them from a variety of respiratory and enteric infections. For at-risk newborns in low- and middle-income countries, supplementing breast milk with pathogen-specific neutralizing and bactericidal antibodies could offer significant short- and long-term health benefits. In this study, we explored the use of mRNA and lipid nanoparticle (LNP) technology to deliver a Vibrio cholerae-specific monoclonal IgG antibody ("ZAC-3") into the milk of lactating mice. Swiss Webster mice were intravenously administered ZAC-3 IgG mRNA-LNPs, and we monitored serum and breast milk for the presence of V. cholerae-specific human IgG1. A single injection of mRNA-LNPs led to rapid and sustained expression of ZAC-3 IgG in both the blood and breast milk of lactating dams. ZAC-3 IgG1 in these samples recognized whole V. cholerae cells by ELISA and exhibited potent vibriocidal activity in the presence of human complement. Furthermore, ZAC-3 IgG was detected in the sera of suckling pups at levels proportional to those in the mothers, demonstrating successful transfer of functional antibodies to the newborns. In conclusion, our findings highlight the potential of mRNA-based monoclonal antibody platforms in the maternal-newborn context and address key challenges associated with the direct delivery of recombinant antibodies.

immunology↗

bioRxiv2024

HIV broadly neutralizing antibody escapability drives the therapeutic efficacy of vectored immunotherapy

Broadly neutralizing antibodies (bNAbs) have shown promise for prevention and treatment of HIV. Potency and breadth measured in vitro are often used as predictors of clinical potential; however, human studies demonstrate that clinical efficacy of bNAbs can be undermined by both pre-existing and de novo resistance. Here we find that HIV-infected humanized mice receiving bNAbs delivered via AAV as Vectored ImmunoTherapy (VIT) can be used to identify antibody escape paths, which are largely conserved for each bNAb. Path selection, and consequent therapeutic success, is driven by the fitness cost and resistance benefit of emerging mutations. Applying this framework, we independently modulated bNAb resistance or the fitness cost of escape mutants, resulting in enhanced efficacy of VIT. This escape path analysis successfully explains the therapeutic efficacy of bNAbs, and enables a tractable means of quantifying and comparing the potential for viral escape from therapeutics in vivo. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/603156v4_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@180c86borg.highwire.dtl.DTLVardef@1e6108dorg.highwire.dtl.DTLVardef@148bac7org.highwire.dtl.DTLVardef@1de93ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

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↗