Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn<i>in vitro</i>and<i>in vivo</i>

Mester, Simone; Evers, Mitchell; Meyer, Saskia; Nilsen, Jeannette; Greiff, Victor; Sandlie, Inger; Leusen, Jeanette H.W.; Andersen, Jan Terje

doi:10.1080/19420862.2021.1893888

Cited by 22 publications

(12 citation statements)

References 90 publications

(145 reference statements)

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“…The development of therapeutic antibodies has utilized this information to design novel immunoglobulins with modified FcRn binding properties to improve effectiveness ( 292 , 293 ). The recognition that albumin-FcRn affinity can also be impacted by species differences and thus utilized to extend or reduce half-life of bound albumins has more recently been investigated ( 155 , 254 , 294 ). Of critical importance for understanding albumin dynamics may be how modified albumins, i.e., glycated, carbamylated, oxidized, and albumin bound to molecules such as drugs or fluorophores, affect the albumin-FcRn pH-dependent binding interaction ( TABLE 4 ).…”

Section: Transcytosis By Proximal Tubule Cellmentioning

confidence: 99%

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Molitoris

Sandoval

Yadav

et al. 2022

Physiological Reviews

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For nearly fifty years the proximal tubule has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes, and several genetic diseases, nonselective proximal tubule cell (PTC) defects, chronic kidney disease and acute PTC injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PTC injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism and transcytosis are being reexamined utilizing techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multi-receptor complex that mediates albumin binding, uptake and directs proteins for lysosomal degradation following endocytosis. The neonatal Fc receptor mediates albumin transcytosis by its pH-dependent binding affinity in endosomal compartments. This transcytotic, reclamation, pathway minimizes urinary losses and cellular catabolism of albumin thus prolonging its serum half-life. It also serves as a PTC molecular sorting mechanism to preserve and reclaim physiologic albumin while allowing "altered" albumin that does not bind to FcRn to enter the lysosomal pathway. The clinical importance of PTC albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussing genetic disorders and therapeutic considerations.

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Section: Transcytosis By Proximal Tubule Cellmentioning

confidence: 99%

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Molitoris

Sandoval

Yadav

et al. 2022

Physiological Reviews

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“…Nbs have a short half-life in serum due to the lack of the Fc region of traditional antibodies. To overcome this deficiency, some studies have conjugated target molecules to albumin-targeting Nbs, thereby increasing the half-life of the target molecules [ 31 – 33 ]. This is because albumin prevents lysosomal degradation by binding to FcRn, which is highly expressed by many cells, resulting in a half-life of 17–19 days in humans [ 34 – 36 ].…”

Section: Discussionmentioning

confidence: 99%

Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma

Zhu²,

Li³

et al. 2022

Respir Res

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Background Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. Results We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. Conclusions These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma. Graphical Abstract

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“…One major hurdle to the translation of IgA-based therapeutics to the clinic is its relatively short half-life of ~6 days compared to ~23 days for IgG. 35 , 36 One of the mechanisms that equips IgG with its relatively long half-life is its ability to bind FcRn and get recycled to the cell surface from the endosomal pathway. 37 IgA does not natively bind to FcRn and, therefore, chimeric engineering strategies have been employed to combine FcαRI binding native to IgA and FcRn binding native to IgG.…”

Section: Discussionmentioning

confidence: 99%

Engineering a pure and stable heterodimeric IgA for the development of multispecific therapeutics

Heinkel

Verstraete

Cao

et al. 2022

mAbs

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Immunoglobulin G (IgG) has served as a traditional framework for antibody-based biology, and engineering approaches for creating multispecific therapeutics have greatly expanded its applicability. Despite these developments, there are limits to the functionality of IgG with respect to effector cells that can be activated and paratope valency that can be obtained. Other Ig isotypes have distinct functions that can engage and activate different effector cells, and some can be found naturally in higher-order assemblies. In an effort to expand the repertoire of multispecific designs for other antibody isotypes, we present here engineering of the first heterodimeric IgA Fc that can be produced at high purity with native IgA-like thermal stability. The crystal structure confirmed the accuracy of the in silico model used for engineering and that the mutations introduced at the CH3 interface do not perturb the overall IgA Fc structure. Affinity measurements and on-cell neutrophil binding demonstrated that the heterodimeric IgA Fc retains the ability to bind FcαRI, an important prerequisite for IgA-based therapeutics designed to interact with effector cells, such as neutrophils. Given the ability of IgA antibodies to multimerize via interaction with the J-chain, the designs presented here could also be used to generate multispecific, multimeric scaffolds that leverage valency to increase clustering and specificity via avidity. Taken together, the newly developed heterodimeric IgA Fc platform allows for the development of novel, multifunctional, and multimeric molecules that have the potential to transform the next generation of antibody therapeutics. Abbreviations CE-SDS: capillary electrophoresis sodium dodecyl sulfate; DSC: differential scanning calorimetry; FACS: fluorescence-activated cell sorting; FSA: full-sized antibody; Her2: human epidermal growth factor receptor 2; MFI: mean fluorescent intensity; OAA: one-armed antibody; PBS: phosphate-buffered saline; PDB: Protein Data Bank; SEC: size-exclusion chromatography; prepSEC (preparative SEC); RMSD: root-mean-square deviation; RU: resonance units; SPR: surface plasmon resonance; TAA: tumor-associated antigen; WT: wild-type.

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Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRnin vitroandin vivo

Abstract: Andersen (2021) Extended plasma half-life of albuminbinding domain fused human IgA upon pH-dependent albumin engagement of human FcRn invitro

Cited by 22 publications

References 90 publications

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications

Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma

Engineering a pure and stable heterodimeric IgA for the development of multispecific therapeutics

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