The effects of affinity and valency of an albumin-binding domain (ABD) on the half-life of a single-chain diabody-ABD fusion protein

Hopp, Jonas; Hornig, Nora; Zettlitz, Kirstin A.; Schwarz, Aline; Fuss, Nadine; Müller, Dafne; Kontermann, Roland E.

doi:10.1093/protein/gzq058

Cited by 85 publications

(52 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The three Z FcRn -ABD-Z Taq fusion proteins and the control were injected into mice, and serum concentrations were measured at different time points. ABD fusion proteins have been shown to have a long circulation half-life caused by ABD binding to SA, followed by FcRn-mediated rescue from lysosomal degradation (25,26). In agreement with the previous results, the terminal half-life of Z Taq -ABD was ∼33 h. This half-life is also comparable to the half-life of MSA (35 h).…”

Section: Serum Circulation Half-life Extension By the Affibody Molecusupporting

confidence: 89%

An engineered affibody molecule with pH-dependent binding to FcRn mediates extended circulatory half-life of a fusion protein

Seijsing

Lindborg

Höidén-Guthenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance One of the central questions in biopharmaceutical development is how to extend circulation residence times of protein-based drugs to improve efficacy and patient comfort. Immunoglobulin G and serum albumin are rescued from lysosomal degradation by the pH-dependent binding to the neonatal Fc receptor and consequently have naturally long circulation half-lives. Here we describe the development and characterization of small affinity proteins (affibody molecules) that can hitchhike on the neonatal Fc receptor rescue system. We find that addition of the affibody molecules to an already half-life–extended recombinant protein leads to a nearly threefold longer circulation residence time in mice. Such affibody molecules may have a general use as fusion partners with biopharmaceuticals to extend their circulation residence times.

show abstract

Section: Serum Circulation Half-life Extension By the Affibody Molecusupporting

confidence: 89%

An engineered affibody molecule with pH-dependent binding to FcRn mediates extended circulatory half-life of a fusion protein

Seijsing

Lindborg

Höidén-Guthenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…One of these would be to couple the agent to polyethylene-glycol (PEG), a method used for half-life extension of other common drugs [91]. Another option would be to fuse the agent to fragments of human serum albumin (HSA) or albumin binding ab-fragments, and thereby improve the plasma half-life [92]. Finally, the BiTE format can be extended by adding a third ab-derived scFv binding site, thus generating a tandem single-chain triplebody.…”

Section: Recruiting T-cells Via Cd3mentioning

confidence: 99%

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

2012

View full text Add to dashboard Cite

Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK)-and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM) and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

show abstract

“…9 Nevertheless, several studies demonstrated that Fc fusion proteins have a shorter plasma half-life in mice than IgG molecules. 3,10,11 While differences in affinity for FcRn was proposed as a possible mechanism responsible for the shorter half-lives of Fc fusion proteins in humans, 3,12 others failed to find a correlation between affinity for FcRn and the serum half-life for a family of antibodies investigated in mice and humans. 13 Here, we generated various carcinoembryonic antigen (CEA)-targeted IgG-like fusion proteins and compared their biochemical and pharmacokinetic properties to a chimeric IgG1 molecule.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic properties of IgG and various Fc fusion proteins in mice

Unverdorben

Richter

Hutt

et al. 2015

mAbs

View full text Add to dashboard Cite

Fusion to an IgG Fc region is an established strategy to extend the half-life of therapeutic proteins. Most Fc fusion proteins, however, do not achieve the long half-life of IgGs. Based on findings that scFv-Fc fusion proteins exhibit a shorter half-life than the corresponding IgG molecules, we performed a comparative study of different antibodyderived Fc fusion proteins. We could confirm that fusion of single-chain Fv (scFv) and single-chain diabody (scDb) molecules to an Fc region yields in fusion proteins with substantially extended half-lives compared with the singlechain versions. However, even fusion proteins with a size similar to that of IgG, e.g., scDb-Fc, did not have a half-life as long as an IgG molecule. Binding to the neonatal Fc receptor (FcRn) under acidic and neutral conditions was similar for IgG and all Fc fusion proteins. However, we observed differences between IgG and the Fc fusion proteins for dissociation of FcRn-bound proteins induced by shifting from acidic to neutral pH, reflecting the physiological release mechanism, further supporting a contribution of the kinetics of pH-dependent release from FcRn to the pharmacokinetic properties of IgG and Fc fusion proteins.

show abstract

The effects of affinity and valency of an albumin-binding domain (ABD) on the half-life of a single-chain diabody-ABD fusion protein

Cited by 85 publications

References 30 publications

An engineered affibody molecule with pH-dependent binding to FcRn mediates extended circulatory half-life of a fusion protein

An engineered affibody molecule with pH-dependent binding to FcRn mediates extended circulatory half-life of a fusion protein

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

Pharmacokinetic properties of IgG and various Fc fusion proteins in mice

Contact Info

Product

Resources

About