Development and optimization of an mRNA-vectored single-chain IgA1 isotype monoclonal antibody with potential to treat or prevent dengue virus infection.

Dengue virus (DENV) is a rapidly expanding infectious disease threat that causes an estimated 100 million symptomatic infections every year. A barrier to preventing DENV infections with traditional vaccines or prophylactic monoclonal antibody (mAb) therapies is the phenomenon of Antibody-Dependent Enhancement (ADE), wherein sub-neutralizing levels of DENV-specific IgG antibodies can enhance infection and pathogenesis rather than providing protection from disease. Fortunately, IgG is not the only antibody isotype capable of binding and neutralizing DENV, as DENV-specific IgA1 isotype mAbs can bind and neutralize DENV while without exhibiting any ADE activity. However, the development of IgA1-based mAb therapies is currently hindered by inefficient in vitro expression systems and the lack of saleable purification platforms. Accordingly, alternative delivery modalities are required to realize the therapeutic potential of IgA-based infectious-disease therapies. In this study we describe the development and optimization of a DENV-specific single-chain IgA construct that retains the desirable biological properties of the parental IgA mAb yet is compatible with efficient in vivo delivery with a novel/liver-tropic lipid nanoparticle. We propose that this platform is uniquely and exceptionally well suited for preventing and/or treating DENV infections and may have broad applicability in the greater infectious disease space in situations where the use of IgG isotype mAbs may be counterindicated.