Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery

Zhou, Li; Wang, Hsuan-Yao; Tong, Shanshan; Okamoto, Curtis T.; Shen, Wei‐Chiang; Zaro, Jennica L.

doi:10.1016/j.biomaterials.2016.11.051

Cited by 8 publications

(4 citation statements)

References 35 publications

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“…In order to overcome above limitations, Zhou et al. 64 developed a novel kind of Fc fusion strategy ( Fig. 4 C) based on a long and flexible glycine–serine (GS) linker between two Fc chains, and removed the hinge sequence to form a single chain Fc-dimer represented as sc(Fc) 2 .…”

Section: Existing Strategies To Manipulate the Drug In Vivo Clearancementioning

confidence: 99%

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

Shi

Wang

et al. 2021

Acta Pharmaceutica Sinica B

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The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.

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Section: Existing Strategies To Manipulate the Drug In Vivo Clearancementioning

confidence: 99%

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

Shi

Wang

et al. 2021

Acta Pharmaceutica Sinica B

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“…Importantly, we retained the hinge region preceding the CH2 domain, as it plays an important role in IgG binding to Fc γ Rs. 14,15 To facilitate the integration of functional modules in the scFc protein without chemical alterations, we genetically fused a SNAPtag at the C-terminus and a SpyTag at the N-terminus (Fig 1a) . These tags covalently bind to benzylguanine (BG) and SpyCatcher modified moieties, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…15, 0.44, and 1.3 µM). Black lines represent the measured curves and red lines represent the bivalent analyte binding model curve fits.…”

mentioning

confidence: 94%

Engineering multivalent Fc display for FcγR blockade

Petrova,

Kiriako,

Rebetz

et al. 2024

Preprint

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Autoimmune diseases, driven by Fcγ receptor (FcγR) activation through autoantibody immune complexes (IC), present a complex therapeutic challenge of achieving pharmacological blockade of FcγR without triggering receptor activation. The assembly of ICs into polydisperse, higher-order structures is required for FcγR activation. However, engineered multimeric, monodisperse Fc assemblies have been reported to prevent FcγR activation, suggesting that Fc spatial organization determines FcγR activation. In this study, we engineered a functional single-chain Fc domain protein (scFc) for unidirectional, multivalent presentation by virus-like particles (VLPs), used as a display platform. We found that the multivalent display of scFc on the VLPs elicited distinct cellular responses compared with monovalent scFc, highlighting the importance of the structural context of scFc on its function. scFc-VLPs had minimal impact on the nanoscale spatial organization of FcγR at the cell membrane and caused limited receptor activation and internalization. In contrast, the monovalent scFc acted as an FcγR agonist, inducing receptor clustering, activation, and internalization. Increasing scFc valency in scFc-VLPs was associated with increased binding to monocytes, reaching a plateau at high valencies. Notably, the ability of scFc-VLPs to block IC-mediated phagocytosis in vitro increased with scFc valency. In a murine model of passive immune thrombocytopenia (ITP), a high valency scFc-VLP variant with a desirable immunogenicity profile induced attenuation of thrombocytopenia. Here we show that multivalent presentation of an engineered scFc on a display platform can be tailored to promote suppression of IC-mediated phagocytosis while preventing FcγR activation. This work introduces a new paradigm that can contribute to the development of therapies for autoimmune diseases.

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“…The successful generation of a conformationally stable, monomeric Fc antibody fragment with a "tunable" serum half-life could open new possibilities for antibody and Fc fusion therapeutics. Of the more than 180 therapeutic proteins that have received approval from the U.S. Food and Drug Administration, many have the potential to be fitted into active, longer-lasting fusion proteins [14][15][16][17][18] . Immune-cell engagers, antibody-drug conjugates, immunocytokine fusions, and other therapeutic proteins could be tailor-designed to provide monovalent targeting in both monospecific and multispecific formats for enhanced activity and reduced toxicity.…”

mentioning

confidence: 99%

In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance

et al. 2021

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In a biologic therapeutic landscape that requires versatility in targeting specificity, valency and half-life modulation, the monomeric Fc fusion platform holds exciting potential for the creation of a class of monovalent protein therapeutics that includes fusion proteins and bispecific targeting molecules. Here we report a structure-guided approach to engineer monomeric Fc molecules to adapt multiple versions of half-life extension modifications. Co-crystal structures of these monomeric Fc variants with Fc neonatal receptor (FcRn) shed light into the binding interactions that could serve as a guide for engineering the half-life of antibody Fc fragments. These engineered monomeric Fc molecules also enabled the generation of a novel monovalent bispecific molecular design, which translated the FcRn binding enhancement to improvement of in vivo serum half-life.

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Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery

Cited by 8 publications

References 35 publications

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

Engineering multivalent Fc display for FcγR blockade

In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance

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