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Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates

Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates
Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates

Protection from immunodeficiency virus challenge in nonhuman primates (NHPs) by a first-generation HIV broadly neutralizing antibody (bnAb) b12 has previously been shown to benefit from interaction between the bnAb and Fcγ receptors (FcγRs) on immune cells. To investigate the mechanism of protection for a more potent second-generation bnAb currently in clinical trials, PGT121, we carried out a series of NHP studies. These studies included treating with PGT121 at a concentration at which only half of the animals were protected to avoid potential masking of FcγR effector function benefits by dominant neutralization and using a new variant that more completely eliminated all rhesus FcγR binding than earlier variants. In contrast to b12, which required FcγR binding for optimal protection, we concluded that PGT121-mediated protection is not augmented by FcγR interaction. Thus, for HIV-passive antibody prophylaxis, these results, together with existing literature, emphasize the importance of neutralization potency for clinical antibodies, with effector function requiring evaluation for individual antibodies.

1946-6234
Hangartner, Lars
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Beauparlant, David
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Rakasz, Eva
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Nedellec, Rebecca
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Hozé, Nathanaël
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McKenney, Katherine
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Martins, Mauricio A.
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Seabright, Gemma E.
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Allen, Joel D.
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Weiler, Andrea M.
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Friedrich, Thomas C.
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Regoes, Roland R.
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Crispin, Max
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Burton, Dennis R.
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Hangartner, Lars
e2c4669a-bc0e-43e4-a5fe-29581dbf10b3
Beauparlant, David
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Rakasz, Eva
66038837-9d68-4017-bb3d-7010242e92c6
Nedellec, Rebecca
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Hozé, Nathanaël
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McKenney, Katherine
db164338-6dc8-4f64-88bd-4a2fe5a0dea5
Martins, Mauricio A.
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Seabright, Gemma E.
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Allen, Joel D.
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Weiler, Andrea M.
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Friedrich, Thomas C.
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Regoes, Roland R.
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Crispin, Max
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Burton, Dennis R.
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Hangartner, Lars, Beauparlant, David, Rakasz, Eva, Nedellec, Rebecca, Hozé, Nathanaël, McKenney, Katherine, Martins, Mauricio A., Seabright, Gemma E., Allen, Joel D., Weiler, Andrea M., Friedrich, Thomas C., Regoes, Roland R., Crispin, Max and Burton, Dennis R. (2021) Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates. Science Translational Medicine, 13 (585), [eabe3349]. (doi:10.1126/scitranslmed.abe3349).

Record type: Article

Abstract

Protection from immunodeficiency virus challenge in nonhuman primates (NHPs) by a first-generation HIV broadly neutralizing antibody (bnAb) b12 has previously been shown to benefit from interaction between the bnAb and Fcγ receptors (FcγRs) on immune cells. To investigate the mechanism of protection for a more potent second-generation bnAb currently in clinical trials, PGT121, we carried out a series of NHP studies. These studies included treating with PGT121 at a concentration at which only half of the animals were protected to avoid potential masking of FcγR effector function benefits by dominant neutralization and using a new variant that more completely eliminated all rhesus FcγR binding than earlier variants. In contrast to b12, which required FcγR binding for optimal protection, we concluded that PGT121-mediated protection is not augmented by FcγR interaction. Thus, for HIV-passive antibody prophylaxis, these results, together with existing literature, emphasize the importance of neutralization potency for clinical antibodies, with effector function requiring evaluation for individual antibodies.

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Accepted/In Press date: 3 February 2021
Published date: 17 March 2021

Identifiers

Local EPrints ID: 448970
URI: http://eprints.soton.ac.uk/id/eprint/448970
ISSN: 1946-6234
PURE UUID: ea0a2512-0291-4091-97d4-517104ef4b74
ORCID for Joel D. Allen: ORCID iD orcid.org/0000-0003-2547-968X
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 12 May 2021 16:31
Last modified: 06 Jun 2024 04:09

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Contributors

Author: Lars Hangartner
Author: David Beauparlant
Author: Eva Rakasz
Author: Rebecca Nedellec
Author: Nathanaël Hozé
Author: Katherine McKenney
Author: Mauricio A. Martins
Author: Gemma E. Seabright
Author: Joel D. Allen ORCID iD
Author: Andrea M. Weiler
Author: Thomas C. Friedrich
Author: Roland R. Regoes
Author: Max Crispin ORCID iD
Author: Dennis R. Burton

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