Grandits, Melanie;
Gruenwald-Gruber, Clemens;
Gastine, Silke;
Standing, Joseph F;
Reljic, Rajko;
Teh, Audrey Y-H;
Ma, Julian K-C;
(2023)
Improving the efficacy of plant-made anti-HIV monoclonal antibodies for clinical use.
Frontiers in Plant Science
, 14
, Article 1126470. 10.3389/fpls.2023.1126470.
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Abstract
Introduction: Broadly neutralising antibodies are promising candidates for preventing and treating Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), as an alternative to or in combination with antiretroviral therapy (ART). These mAbs bind to sites on the virus essential for virus attachment and entry, thereby inhibiting entry into the host cell. However, the cost and availability of monoclonal antibodies, especially combinations of antibodies, hampers implementation of anti-HIV bNAb therapies in low- to middle- income countries (LMICs) where HIV-1 prevalence is highest. Methods: We have produced three HIV broadly neutralizing antibodies (bNAbs), 10-1074, VRC01 and 3BNC117 in the Nicotiana benthamiana transient expression system. The impact of specific modifications to enhance potency and efficacy were assessed. To prolong half-life and increase bioavailability, a M252Y/S254T/T256E (YTE) or M428L/N434S (LS) mutation was introduced. To increase antibody dependent cellular cytotoxicity (ADCC), we expressed an afucosylated version of each antibody using a glycoengineered plant line. Results: The majority of bNAbs and their variants could be expressed at yields of up to 47 mg/kg. Neither the expression system nor the modifications impacted the neutralization potential of the bNAbs. Afucosylated bNAbs exhibit enhanced ability to bind to FcγRIIIa and trigger ADCC, regardless of the presence of Fc amino acid mutations. Lastly, we demonstrated that Fc-modified variants expressed in plants show enhanced binding to FcRn, which results in a favourable in vivo pharmacokinetic profile compared to their unmodified counterparts. Conclusion: Tobacco plants are suitable expression hosts for anti-HIV bNAbs with increased efficacy and an improved pharmacokinetic profile.
| Type: | Article |
|---|---|
| Title: | Improving the efficacy of plant-made anti-HIV monoclonal antibodies for clinical use |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fpls.2023.1126470 |
| Publisher version: | https://doi.org/10.3389/fpls.2023.1126470 |
| Language: | English |
| Additional information: | Copyright © 2023 Grandits, Grünwald-Gruber, Gastine, Standing, Reljic, Teh and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Plant Sciences, bNAb, HIV, Half-Life, glycosylation, pharmacokinetics, antibody engineering, ADCC, plant molecular biopharming, NEONATAL FC-RECEPTOR, HUMAN IGG1, VARIABLE DOMAIN, MOUSE MODEL, GAMMA-RIII, HALF-LIFE, BINDING, PHARMACOKINETICS, AFFINITY, PROTECTION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10168604 |
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