Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

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An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability

Optimization of the Steam Explosion Pretreatment Effect on Total Flavonoids Content and Antioxidative Activity of Seabuckthom Pomace by Response Surface Methodology

Steam explosion pretreatment was conducted on seabuckthom pomace. Response surface methodology was used to optimize the treatment conditions of steam explosion, including steam pressure, duration and particle size. After this, the content of total flavonoids and the antioxidant capacity of total flavonoids were investigated. Results showed that when the steam pressure was 2.0 MPa, duration was 88 s and a sieving mesh size was 60, the total flavonoids content in seabuckthorm reached a maximum of 24.74 ± 0.71 mg CAE/g, an increase of 246% compared with that without steam explosion treatment (7.14 ± 0.42 mg CAE/g). Also, DPPH and ·OH free radical scavenging ability showed significant improvement, with an IC50 decrease to 13.53 μg/mL and 4.32 μg/mL, respectively, far lower than that in original samples. Through the scanning electron microscope, the surface of seabuckthom pomace after steam explosion was crinkled, curly, and holey. Our study showed that the content of total flavonoids in seabuckthom pomace could be obviously promoted and the antioxidant capacity of total flavonoids also improved significantly, after applying steam explosion pretreatment to seabuckthom pomace, making this approach meaningful for the reuse of seabuckthom pomace resources

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice

International audienceBACKGROUND:Anaphylaxis can proceed through distinct IgE- or IgG-dependent pathways, which have been investigated in various mouse models. We developed a novel mouse strain in which the human low-affinity IgG receptor locus, comprising both activating (hFcγRIIA, hFcγRIIIA, and hFcγRIIIB) and inhibitory (hFcγRIIB) hFcγR genes, has been inserted into the equivalent murine locus, corresponding to a locus swap.OBJECTIVE:We sought to determine the capabilities of hFcγRs to induce systemic anaphylaxis and identify the cell types and mediators involved.METHODS:hFcγR expression on mouse and human cells was compared to validate the model. Passive systemic anaphylaxis was induced by injection of heat-aggregated human intravenous immunoglobulin and active systemic anaphylaxis after immunization and challenge. Anaphylaxis severity was evaluated based on hypothermia and mortality. The contribution of receptors, mediators, or cell types was assessed based on receptor blockade or depletion.RESULTS:The human-to-mouse low-affinity FcγR locus swap engendered hFcγRIIA/IIB/IIIA/IIIB expression in mice comparable with that seen in human subjects. Knock-in mice were susceptible to passive and active anaphylaxis, accompanied by downregulation of both activating and inhibitory hFcγR expression on specific myeloid cells. The contribution of hFcγRIIA was predominant. Depletion of neutrophils protected against hypothermia and mortality. Basophils contributed to a lesser extent. Anaphylaxis was inhibited by platelet-activating factor receptor or histamine receptor 1 blockade.CONCLUSION:Low-affinity FcγR locus-switched mice represent an unprecedented model of cognate hFcγR expression. Importantly, IgG-related anaphylaxis proceeds within a native context of activating and inhibitory hFcγRs, indicating that, despite robust hFcγRIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFc gamma Rs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.Y