Engineering of anticancer human immunoglobulin A equipped with albumin for enhanced plasma half-life

Most therapeutic antibodies are based on immunoglobulin G (IgG) due to their potent effector functions and long plasma half-life. However, also monomeric IgA has emerged as an attractive candidate for cancer treatment as, upon specific binding to tumor cells, it can activate myeloid cells, like polymorphonuclear leukocytes and macrophages, to kill the tumor cells by engaging the Fc α receptor I (FcαRI). Despite this favorable property, human IgA has a short plasma half-life in both mice and humans, which is clearly limiting preclinical studies in a translational perspective. Here, we report on albumin-equipped designs of human IgA antibodies that are long acting due to tailored binding to the human form of neonatal Fc receptor (FcRn), which is a natural plasma half-life regulator of albumin. Importantly, this was achieved without compromising the ability of IgA to engage and activate FcαRI-expressing effector cells for tumor cell killing in vitro and in vivo in a new mouse model transgenic for the human forms of FcRn and FcαRI. We further show that the potency of the engineered long-acting human IgA against tumor cells with intermediate target antigen expression levels could be enhanced by myeloid checkpoint inhibitors targeting the signal regulatory protein α-CD47 axis.

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Publication Details

Journal
PNAS Nexus
Published
2025-02-01
DOI
https://doi.org/10.1093/pnasnexus/pgaf042
Citations
3
Primary Topic
Hemoglobin structure and function
Type
article
Field-Weighted Citation Impact
3.45

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article

Engineering of anticancer human immunoglobulin A equipped with albumin for enhanced plasma half-life

Mitchell Evers, Jeanette H.W. Leusen, Jan Terje Andersen, Simone Mester et al.
3 citations
PNAS Nexus
Hemoglobin structure and function
3.45
article

Engineering of anticancer human immunoglobulin A equipped with albumin for enhanced plasma half-life

Mitchell Evers, Jeanette H.W. Leusen, Jan Terje Andersen, Simone Mester, Karli R. Reiding, Bjørn Dalhus, Marta Lustig, Jeannette Nilsen, Inger Sandlie, Chilam Chan, Algirdas Grevys, Thomas Valerius, Stian Foss, Marie Leangen Herigstad, J.H. Marco Jansen, J Damen, Renate Burger
article en
3 citations

Abstract

Most therapeutic antibodies are based on immunoglobulin G (IgG) due to their potent effector functions and long plasma half-life. However, also monomeric IgA has emerged as an attractive candidate for cancer treatment as, upon specific binding to tumor cells, it can activate myeloid cells, like polymorphonuclear leukocytes and macrophages, to kill the tumor cells by engaging the Fc α receptor I (FcαRI). Despite this favorable property, human IgA has a short plasma half-life in both mice and humans, which is clearly limiting preclinical studies in a translational perspective. Here, we report on albumin-equipped designs of human IgA antibodies that are long acting due to tailored binding to the human form of neonatal Fc receptor (FcRn), which is a natural plasma half-life regulator of albumin. Importantly, this was achieved without compromising the ability of IgA to engage and activate FcαRI-expressing effector cells for tumor cell killing in vitro and in vivo in a new mouse model transgenic for the human forms of FcRn and FcαRI. We further show that the potency of the engineered long-acting human IgA against tumor cells with intermediate target antigen expression levels could be enhanced by myeloid checkpoint inhibitors targeting the signal regulatory protein α-CD47 axis.

PNAS NexusVol. 4(2)
Oslo University Hospital (NO), University of Oslo (NO), Utrecht University (NL), University Medical Center (US), University Medical Center Utrecht (NL), Christian-Albrechts-Universität zu Kiel (DE), 657 Oslo (NO), Clinical Research Center Kiel (DE)
Deutsche Forschungsgemeinschaft, Universiteit Utrecht, Universitair Medisch Centrum Utrecht, KWF Kankerbestrijding, Norges Forskningsråd, Harvard Digestive Diseases Center, Harvard University, Helse Sør-Øst RHF
Openalex Percentile: Top 10%
Hemoglobin structure and function
3.45
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