Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria

Stian Foss; Siri A Sakya; Leire Aguinagalde; Marta Lustig; Jutamas Shaughnessy; Ana Rita Cruz; Lisette Scheepmaker; Line Mathiesen; Fulgencio Ruso-Julve; Aina Karen Anthi; Torleif Tollefsrud Gjølberg; Simone Mester; Malin Bern; Mitchell Evers; Diane B Bratlie; Terje E Michaelsen; Tilman Schlothauer; Devin Sok; Jayanta Bhattacharya; Jeanette Leusen; Thomas Valerius; Sanjay Ram; Suzan H M Rooijakkers; Inger Sandlie; Jan Terje Andersen

doi:10.1038/s41467-024-46321-9

Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria

Stian Foss, Siri A Sakya, Leire Aguinagalde, Marta Lustig, Jutamas Shaughnessy, Ana Rita Cruz, Lisette Scheepmaker, Line Mathiesen, Fulgencio Ruso-Julve, Aina Karen Anthi, Torleif Tollefsrud Gjølberg, Simone Mester, Malin Bern, Mitchell Evers, Diane B Bratlie, Terje E Michaelsen, Tilman Schlothauer, Devin Sok, Jayanta Bhattacharya, Jeanette LeusenThomas Valerius, Sanjay Ram, Suzan H M Rooijakkers, Inger Sandlie, Jan Terje Andersen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.

Original language	English
Article number	2007
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-46321-9
Publication status	Published - Dec 2024

Keywords

Animals
Anti-Bacterial Agents/therapeutic use
Antibodies, Monoclonal
Gram-Negative Bacteria/metabolism
Gram-Positive Bacteria/metabolism
Half-Life
Histocompatibility Antigens Class I/metabolism
Humans
Immunoglobulin G
Mice
Mice, Transgenic
Neoplasms/therapy
Receptors, Fc

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Foss, S., Sakya, S. A., Aguinagalde, L., Lustig, M., Shaughnessy, J., Cruz, A. R., Scheepmaker, L., Mathiesen, L., Ruso-Julve, F., Anthi, A. K., Gjølberg, T. T., Mester, S., Bern, M., Evers, M., Bratlie, D. B., Michaelsen, T. E., Schlothauer, T., Sok, D., Bhattacharya, J., ... Andersen, J. T. (2024). Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria. Nature Communications, 15(1), Article 2007. https://doi.org/10.1038/s41467-024-46321-9

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abstract = "Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.",

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doi = "10.1038/s41467-024-46321-9",

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Foss, S, Sakya, SA, Aguinagalde, L, Lustig, M, Shaughnessy, J, Cruz, AR, Scheepmaker, L, Mathiesen, L, Ruso-Julve, F, Anthi, AK, Gjølberg, TT, Mester, S, Bern, M, Evers, M, Bratlie, DB, Michaelsen, TE, Schlothauer, T, Sok, D, Bhattacharya, J, Leusen, J, Valerius, T, Ram, S, Rooijakkers, SHM, Sandlie, I & Andersen, JT 2024, 'Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria', Nature Communications, vol. 15, no. 1, 2007. https://doi.org/10.1038/s41467-024-46321-9

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AU - Foss, Stian

AU - Sakya, Siri A

AU - Aguinagalde, Leire

AU - Lustig, Marta

AU - Shaughnessy, Jutamas

AU - Cruz, Ana Rita

AU - Scheepmaker, Lisette

AU - Mathiesen, Line

AU - Ruso-Julve, Fulgencio

AU - Anthi, Aina Karen

AU - Gjølberg, Torleif Tollefsrud

AU - Mester, Simone

AU - Bern, Malin

AU - Evers, Mitchell

AU - Bratlie, Diane B

AU - Michaelsen, Terje E

AU - Schlothauer, Tilman

AU - Sok, Devin

AU - Bhattacharya, Jayanta

AU - Leusen, Jeanette

AU - Valerius, Thomas

AU - Ram, Sanjay

AU - Rooijakkers, Suzan H M

AU - Sandlie, Inger

AU - Andersen, Jan Terje

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/12

Y1 - 2024/12

N2 - Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.

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KW - Anti-Bacterial Agents/therapeutic use

KW - Antibodies, Monoclonal

KW - Gram-Negative Bacteria/metabolism

KW - Gram-Positive Bacteria/metabolism

KW - Half-Life

KW - Histocompatibility Antigens Class I/metabolism

KW - Humans

KW - Immunoglobulin G

KW - Mice

KW - Mice, Transgenic

KW - Neoplasms/therapy

KW - Receptors, Fc

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U2 - 10.1038/s41467-024-46321-9

DO - 10.1038/s41467-024-46321-9

M3 - Article

C2 - 38453922

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2007

ER -

Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria

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