Harnessing mRNA for the expression of monoclonal IgG and IgA in non-human primates
Harnessing mRNA for the expression of monoclonal IgG and IgA in non-human primates
Background: monoclonal antibodies (mAbs) are an increasingly essential class of medicines across many disease areas. In the human body, there are five antibody isotypes, each with potential therapeutic benefits for different disease indications. However, 97% of all clinically approved mAbs are produced as the IgG isotype, 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 way to circumvent this challenge is to express mAbs in situ using mRNA encapsulated in lipid nanoparticles (LNP), bypassing the need for recombinant protein production.
Objective: here, we demonstrate the feasibility of expressing a mAb as both IgG and IgA in non-human primates (NHPs) using mRNA-LNPs.
Methods: 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 mRNAs.
Results: though IgA2 expression levels were low, 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.
Conclusion: altogether, this work demonstrates that mRNA-LNPs can be used to express native like mAbs of non-IgG isotypes in primates at detectable levels and enables further development and optimization of non-IgG mAb constructs.
Animals, Antibodies, Monoclonal/genetics, Antibodies, Neutralizing/genetics, HIV Antibodies/genetics, Humans, Immunoglobulin A/genetics, Immunoglobulin G/genetics, Liposomes, Nanoparticles/chemistry, RNA, Messenger/genetics
Rouzeau, Romy
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Schmidt, Hayden R.
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Deal, Cailin E.
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Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
Dudley, Dawn M.
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Burton, Iszac
56c156b2-6772-4fc9-b852-12620458457e
Rakasz, Eva G.
65a5bd96-1a33-48a2-b951-8a035991c580
Plante, Obadiah
42fd1f42-8dff-4b81-a58f-3d6cec655ea7
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Carfi, Andrea
4d5bc7c3-ab52-4c93-838e-0ada7621393f
Sok, Devin
036d5259-d0a2-45ea-8436-f4c5a7deafe0
16 January 2026
Rouzeau, Romy
29dd3ae5-0100-4c14-8981-efa4574f3745
Schmidt, Hayden R.
8ad30161-fe16-4bc3-99f6-4f2e893cfa2e
Deal, Cailin E.
5af02f99-d535-4d3c-af64-c83d6d66027d
Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
Dudley, Dawn M.
95b87b81-762a-4ad4-afa4-3181e92bd64d
Burton, Iszac
56c156b2-6772-4fc9-b852-12620458457e
Rakasz, Eva G.
65a5bd96-1a33-48a2-b951-8a035991c580
Plante, Obadiah
42fd1f42-8dff-4b81-a58f-3d6cec655ea7
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Carfi, Andrea
4d5bc7c3-ab52-4c93-838e-0ada7621393f
Sok, Devin
036d5259-d0a2-45ea-8436-f4c5a7deafe0
Rouzeau, Romy, Schmidt, Hayden R., Deal, Cailin E., Allen, Joel D., Dudley, Dawn M., Burton, Iszac, Rakasz, Eva G., Plante, Obadiah, Crispin, Max, Carfi, Andrea and Sok, Devin
(2026)
Harnessing mRNA for the expression of monoclonal IgG and IgA in non-human primates.
Frontiers in Immunology, 16, [1700041].
(doi:10.3389/fimmu.2025.1700041).
Abstract
Background: monoclonal antibodies (mAbs) are an increasingly essential class of medicines across many disease areas. In the human body, there are five antibody isotypes, each with potential therapeutic benefits for different disease indications. However, 97% of all clinically approved mAbs are produced as the IgG isotype, 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 way to circumvent this challenge is to express mAbs in situ using mRNA encapsulated in lipid nanoparticles (LNP), bypassing the need for recombinant protein production.
Objective: here, we demonstrate the feasibility of expressing a mAb as both IgG and IgA in non-human primates (NHPs) using mRNA-LNPs.
Methods: 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 mRNAs.
Results: though IgA2 expression levels were low, 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.
Conclusion: altogether, this work demonstrates that mRNA-LNPs can be used to express native like mAbs of non-IgG isotypes in primates at detectable levels and enables further development and optimization of non-IgG mAb constructs.
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fimmu-16-1700041
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Accepted/In Press date: 19 December 2025
e-pub ahead of print date: 16 January 2026
Published date: 16 January 2026
Keywords:
Animals, Antibodies, Monoclonal/genetics, Antibodies, Neutralizing/genetics, HIV Antibodies/genetics, Humans, Immunoglobulin A/genetics, Immunoglobulin G/genetics, Liposomes, Nanoparticles/chemistry, RNA, Messenger/genetics
Identifiers
Local EPrints ID: 510977
URI: http://eprints.soton.ac.uk/id/eprint/510977
ISSN: 1664-3224
PURE UUID: 853f5e04-c5ef-46c8-a7ac-5f87065599ee
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Date deposited: 28 Apr 2026 16:45
Last modified: 29 Apr 2026 02:05
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Contributors
Author:
Romy Rouzeau
Author:
Hayden R. Schmidt
Author:
Cailin E. Deal
Author:
Dawn M. Dudley
Author:
Iszac Burton
Author:
Eva G. Rakasz
Author:
Obadiah Plante
Author:
Andrea Carfi
Author:
Devin Sok
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