title: Improved in vivo anti-tumor effects of IgA-Her2 antibodies through half-life extension and serum exposure enhancement by FcRn targeting.
abstract: Antibody therapy is a validated treatment approach for several malignancies. All currently clinically applied therapeutic antibodies (Abs) are of the IgG isotype. However, not all patients respond to this therapy and relapses can occur. IgA represents an alternative isotype for antibody therapy that engages FcαRI expressing myeloid effector cells, such as neutrophils and monocytes. IgA Abs have been shown to effectively kill tumor cells both in vitro and in vivo. However, due to the short half-life of IgA Abs in mice, daily injections are required to reach an effect comparable to IgG Abs. The relatively long half-life of IgG Abs and serum albumin arises from their capability of interacting with the neonatal Fc receptor (FcRn). As IgA Abs lack a binding site for FcRn, we generated IgA Abs with the variable regions of the Her2-specific Ab trastuzumab and attached an albumin-binding domain (ABD) to the heavy or light chain (HCABD/LCABD) to extend their serum half-life. These modified Abs were able to bind albumin from different species in vitro. Furthermore, tumor cell lysis of IgA-Her2-LCABD Abs in vitro was similar to unmodified IgA-Her2 Abs. Pharmacokinetic studies in mice revealed that the serum exposure and half-life of the modified IgA-Her2 Abs was extended. In a xenograft mouse model, the modified IgA1 Abs exhibited a slightly, but significantly, improved anti-tumor response compared to the unmodified Ab. In conclusion, empowering IgA Abs with albumin-binding capacity results in in vitro and in vivo functional Abs with an enhanced exposure and prolonged half-life.
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Meyer
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Nederend
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: J H Marco
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: b Center for Proteomics and Metabolomics; Leiden University Medical Center ; Leiden , The Netherlands.
authors.forename: Karli R
authors.initials: KR
authors.lastname: Reiding
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Shamir R
authors.initials: SR
authors.lastname: Jacobino
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Meeldijk
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.|c Department of Pathology ; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.affiliation: b Center for Proteomics and Metabolomics; Leiden University Medical Center ; Leiden , The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
authors.affiliation: d Division of Stem Cell Transplantation and Immunotherapy ; Department of Internal Medicine II; Christian-Albrechts-University ; Kiel , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
authors.affiliation: e Synthon Biopharmaceuticals BV ; Nijmegen , The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Ubink
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
authors.affiliation: e Synthon Biopharmaceuticals BV ; Nijmegen , The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Rouwendal
authors.affiliation: a Laboratory of Translational Immunology; UMC Utrecht ; Utrecht , The Netherlands.
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
mesh_terms: D000818:Animals; D005260:Female; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy*; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D015395:Histocompatibility Antigens Class I; D007070:Immunoglobulin A; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C100688:Fc receptor, neonatal
keywords: Fc a receptor (FcaRI); IgA; albumin-binding domain (ABD); antibody therapy; glycosylation; half-life extension; neonatal Fc receptor (FcRn); serum exposure