Author:
Loos Andreas,Gach Johannes S.,Hackl Thomas,Maresch Daniel,Henkel Theresa,Porodko Andreas,Bui-Minh Duc,Sommeregger Wolfgang,Wozniak-Knopp Gordana,Forthal Donald N.,Altmann Friedrich,Steinkellner Herta,Mach Lukas
Abstract
Broadly neutralizing anti–HIV-1 monoclonal antibodies, such as PG9, and its derivative RSH hold great promise in AIDS therapy and prevention. An important feature related to the exceptional efficacy of PG9 and RSH is the presence of sulfated tyrosine residues in their antigen-binding regions. To maximize antibody functionalities, we have now produced glycan-optimized, fucose-free versions of PG9 and RSH in Nicotiana benthamiana. Both antibodies were efficiently sulfated in planta on coexpression of an engineered human tyrosylprotein sulfotransferase, resulting in antigen-binding and virus neutralization activities equivalent to PG9 synthesized by mammalian cells (CHOPG9). Based on the controlled production of both sulfated and nonsulfated variants in plants, we could unequivocally prove that tyrosine sulfation is critical for the potency of PG9 and RSH. Moreover, the fucose-free antibodies generated in N. benthamiana are capable of inducing antibody-dependent cellular cytotoxicity, an activity not observed for CHOPG9. Thus, tailoring of the antigen-binding site combined with glycan modulation and sulfoengineering yielded plant-produced anti–HIV-1 antibodies with effector functions superior to PG9 made in CHO cells.
Funder
Österreichische Forschungsförderungsgesellschaft
Austrian Science Fund
Publisher
Proceedings of the National Academy of Sciences
Cited by
42 articles.
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