Harnessing mRNA for the expression of monoclonal IgG and IgA in non-human primates.

Abstract

Monoclonal antibodies (mAbs) are an increasingly essential class of medicines across many disease areas (1). In the human body, there are five antibody isotypes, each with potential prophylactic or therapeutic benefits for different disease indications. However, 97% of all clinically approved mAbs are produced as the IgG isotype, partly due to differences in half-life, but largely due to challenges associated with recombinantly producing non-IgG isotypes like IgM or IgA, which have additional N-linked glycan sites and can present as multivalent oligomers. One potential solution to this challenge is to express mAbs in situ using mRNA encapsulated in lipid nanoparticles (LNP), bypassing the need for recombinant protein production (2). Here, we demonstrate the feasibility of expressing a mAb as both IgG and IgA in non-human primates (NHPs) using mRNA-LNPs. We express ePGDM1400v9, a broadly neutralizing mAb targeting human immunodeficiency virus (HIV), in both IgG1 and IgA2 formats by infusing NHPs with LNPs containing the appropriate mRNA. Though IgG1 expression levels were higher than those of IgA2, both formats were detectable in serum within one day of LNP infusion in all NHPs, and both were detectable in mucosal secretions of most animals. Importantly, serum mRNA-produced IgG1 and IgA2 retained HIV-neutralizing function. Furthermore, mass spectrometry analysis confirmed that mAbs of either isotype produced in situ exhibited glycosylation patterns highly similar to that of native antibody, which is likely to confer therapeutic advantages. Altogether, this work demonstrates the feasibility of using mRNA-LNPs to express native-like mAbs of non-IgG isotypes in primates and enables further development of non-IgG mAb constructs. SignificanceMonoclonal antibodies (mAbs) are a rapidly growing class of essential medicines across diverse disease areas and applications. However, the impact potential of mAbs is limited by challenges in production and purification, which favors the use of the IgG antibody isotype despite the disease-specific advantages that other isotypes might offer. One way to overcome this challenge is to express mAbs in situ using messenger ribonucleic acid delivered by lipid nanoparticles (mRNA-LNPs). Here, we show that an anti-human immunodeficiency virus (HIV) mAb, ePGDM1400v9, can be expressed as two different antibody isotypes, IgG and IgA, in nonhuman primates (NHPs) by mRNA-LNP delivery. We demonstrate that both mAb isotypes retain function and exhibit native-like glycosylation patterns that are not achievable with conventional recombinant mAbs.