There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction ca...There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or Fc.fusion protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer half.life. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and off.target binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.展开更多
Myasthenia gravis is an acquired,humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction.The intervention-mediated...Myasthenia gravis is an acquired,humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction.The intervention-mediated clearance of immunoglobulin G(IgG)was shown to be effective in controlling the progression of the disease.The neonatal Fc receptor(FcRn)plays a key role in prolonging the serum half-life of IgG.Antagonizing FcRn to prevent its binding to IgG can accelerate the catabolism of the latter,resulting in decreased levels of IgG,including pathogenic autoantibodies,thereby achieving a therapeutic effect.In this review,we detail the substantial research progress,both basic and clinical,relating to the use of FcRn inhibitors in the treatment of myasthenia gravis.展开更多
新生儿Fc受体(neonatal Fc receptor,FcRn)广泛地表达在呼吸道、生殖道及消化道黏膜上皮细胞,通过介导IgG跨黏膜上皮细胞双向胞转作用,对黏膜起到重要的保护作用。除此之外,FcRn在胎盘、乳腺、肾脏、肺脏、血管内皮、血脑屏障及一些免...新生儿Fc受体(neonatal Fc receptor,FcRn)广泛地表达在呼吸道、生殖道及消化道黏膜上皮细胞,通过介导IgG跨黏膜上皮细胞双向胞转作用,对黏膜起到重要的保护作用。除此之外,FcRn在胎盘、乳腺、肾脏、肺脏、血管内皮、血脑屏障及一些免疫细胞上均有表达。根据近几年有关FcRn研究的相关进展,对FcRn蛋白的分子结构及分布、与IgG相互作用位点及条件、在不同组织中的功能及作用以及未来的应用前景等进行综述。展开更多
重症肌无力(myasthenia gravis,MG)是一种由神经肌肉连接处特异性的自身抗体引起的慢性自身免疫病。虽然静脉注射免疫球蛋白、血浆置换等传统治疗方法具有一定的临床效果,但因传统治疗方法对MG的选择性问题而存在一系列的不良反应。随着...重症肌无力(myasthenia gravis,MG)是一种由神经肌肉连接处特异性的自身抗体引起的慢性自身免疫病。虽然静脉注射免疫球蛋白、血浆置换等传统治疗方法具有一定的临床效果,但因传统治疗方法对MG的选择性问题而存在一系列的不良反应。随着对MG疾病机理研究的深入及生物技术药物的发展,特别是抗体类药物的出现,如新生儿Fc受体(neonatal Fc receptor,FcRn)靶点抗体类药物、抗补体5单克隆抗体药物等,为MG患者带来了许多潜在的治疗选择。现就目前临床研究用于治疗MG的抗体类药物作一概述。展开更多
The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier.There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor(FcR...The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier.There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor(FcRn)for the absorption and secretion of IgGs in infant and adult intestine.We had previously described the FnAb-8 protein that could bind to h FcRn tightly at pH 6.0 but barely at pH 7.4.In this study,we examined its uptake,biodistribution and pharmacokinetics after peroral administration in both wild-type and human FcRn transgenic(Tg)mice.FnAb-8 was modified to contain trans-cyclooctene(TCO)which could interact with18 F labeled tetrazine in situ via the bioorthogonal inverseelectron-demand Diels-Alder reaction.We showed that FnAb-8 had a tendency to distribute and persist in the Tg mice intestine for an extended duration of time.It could also be absorbed into the circulation and distributed systemically over a long period of time up to 172 h.The improvement in oral uptake and concentration in the intestine tissue may be valuable for designing oral delivery of biopharmaceuticals,especially for diseases involving the gastric intestinal tissue.展开更多
Oral insulin delivery could change the life of millions of diabetic patients as an effective,safe,easy-to-use,and affordable alternative to insulin injections,known by an inherently thwarted patient compliance.Here,we...Oral insulin delivery could change the life of millions of diabetic patients as an effective,safe,easy-to-use,and affordable alternative to insulin injections,known by an inherently thwarted patient compliance.Here,we designed a multistage nanoparticle(NP)system capable of circumventing the biological barriers that lead to poor drug absorption and bioavailability after oral administration.The nanosystem consists of an insulin-loaded porous silicon NP encapsulated into a pH-responsive lignin matrix,and surface-functionalized with the Fc fragment of immunoglobulin G,which acts as a targeting ligand for the neonatal Fc receptor(FcRn).The developed NPs presented small size(211±1 nm)and narrow size distribution.The NPs remained intact in stomach and intestinal pH conditions,releasing the drug exclusively at pH 7.4,which mimics blood circulation.This formulation showed to be highly cytocompatible,and surface plasmon resonance studies demonstrated that FcRn-targeted NPs present higher capacity to interact and being internalized by the Caco-2 cells,which express FcRn,as demonstrated by Western blot.Ultimately,in vitro permeability studies showed that Fc-functionalized NPs induced an increase in the amount of insulin that permeated across a Caco-2/HT29-MTX co-culture model,showing apparent permeability coefficients(Papp)of 2.37×106 cm/s,over the 1.66×106 cm/s observed for their non-functionalized counterparts.Overall,these results demonstrate the potential of these NPs for oral delivery of anti-diabetic drugs.展开更多
文摘There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or Fc.fusion protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer half.life. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and off.target binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.
基金supported by the National Natural Science Foundation of China,No.U1604181the Joint Project of Medical Science and Technology Research Program of Henon Province,No.LHGJ20190078+1 种基金Henan Medical Education Research Project,No.Wjlx2020531Henan Province Key R&D and Promotion Special Project(Science and Technology Tackle),No.212102310834(all to JW)。
文摘Myasthenia gravis is an acquired,humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction.The intervention-mediated clearance of immunoglobulin G(IgG)was shown to be effective in controlling the progression of the disease.The neonatal Fc receptor(FcRn)plays a key role in prolonging the serum half-life of IgG.Antagonizing FcRn to prevent its binding to IgG can accelerate the catabolism of the latter,resulting in decreased levels of IgG,including pathogenic autoantibodies,thereby achieving a therapeutic effect.In this review,we detail the substantial research progress,both basic and clinical,relating to the use of FcRn inhibitors in the treatment of myasthenia gravis.
文摘新生儿Fc受体(neonatal Fc receptor,FcRn)广泛地表达在呼吸道、生殖道及消化道黏膜上皮细胞,通过介导IgG跨黏膜上皮细胞双向胞转作用,对黏膜起到重要的保护作用。除此之外,FcRn在胎盘、乳腺、肾脏、肺脏、血管内皮、血脑屏障及一些免疫细胞上均有表达。根据近几年有关FcRn研究的相关进展,对FcRn蛋白的分子结构及分布、与IgG相互作用位点及条件、在不同组织中的功能及作用以及未来的应用前景等进行综述。
文摘重症肌无力(myasthenia gravis,MG)是一种由神经肌肉连接处特异性的自身抗体引起的慢性自身免疫病。虽然静脉注射免疫球蛋白、血浆置换等传统治疗方法具有一定的临床效果,但因传统治疗方法对MG的选择性问题而存在一系列的不良反应。随着对MG疾病机理研究的深入及生物技术药物的发展,特别是抗体类药物的出现,如新生儿Fc受体(neonatal Fc receptor,FcRn)靶点抗体类药物、抗补体5单克隆抗体药物等,为MG患者带来了许多潜在的治疗选择。现就目前临床研究用于治疗MG的抗体类药物作一概述。
基金funded by the Natural Science Foundation of China(Grant no.81690262)。
文摘The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier.There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor(FcRn)for the absorption and secretion of IgGs in infant and adult intestine.We had previously described the FnAb-8 protein that could bind to h FcRn tightly at pH 6.0 but barely at pH 7.4.In this study,we examined its uptake,biodistribution and pharmacokinetics after peroral administration in both wild-type and human FcRn transgenic(Tg)mice.FnAb-8 was modified to contain trans-cyclooctene(TCO)which could interact with18 F labeled tetrazine in situ via the bioorthogonal inverseelectron-demand Diels-Alder reaction.We showed that FnAb-8 had a tendency to distribute and persist in the Tg mice intestine for an extended duration of time.It could also be absorbed into the circulation and distributed systemically over a long period of time up to 172 h.The improvement in oral uptake and concentration in the intestine tissue may be valuable for designing oral delivery of biopharmaceuticals,especially for diseases involving the gastric intestinal tissue.
基金Dr.Shiqi Wang acknowledges financial support from Academy of Finland(decision no.331106)Prof.H´elder A.Santos acknowledges financial support from the HiLIFE Research Funds,the Sigrid Jus´elius Foundation(decision no.4704580)+1 种基金the Academy of Finland(grant no.317042 and 331151)The authors acknowledge the following core facilities funded by Biocenter Finland:Electron Microscopy Unity of the University of Helsinki,Finland for providing the facilities for TEM imaging.The authors acknowledge the use of ALD center Finland research infrastructure for EDX measurements.The authors acknowledge Tomas Bauleth-Ramos for technical support with the cell viability assays.
文摘Oral insulin delivery could change the life of millions of diabetic patients as an effective,safe,easy-to-use,and affordable alternative to insulin injections,known by an inherently thwarted patient compliance.Here,we designed a multistage nanoparticle(NP)system capable of circumventing the biological barriers that lead to poor drug absorption and bioavailability after oral administration.The nanosystem consists of an insulin-loaded porous silicon NP encapsulated into a pH-responsive lignin matrix,and surface-functionalized with the Fc fragment of immunoglobulin G,which acts as a targeting ligand for the neonatal Fc receptor(FcRn).The developed NPs presented small size(211±1 nm)and narrow size distribution.The NPs remained intact in stomach and intestinal pH conditions,releasing the drug exclusively at pH 7.4,which mimics blood circulation.This formulation showed to be highly cytocompatible,and surface plasmon resonance studies demonstrated that FcRn-targeted NPs present higher capacity to interact and being internalized by the Caco-2 cells,which express FcRn,as demonstrated by Western blot.Ultimately,in vitro permeability studies showed that Fc-functionalized NPs induced an increase in the amount of insulin that permeated across a Caco-2/HT29-MTX co-culture model,showing apparent permeability coefficients(Papp)of 2.37×106 cm/s,over the 1.66×106 cm/s observed for their non-functionalized counterparts.Overall,these results demonstrate the potential of these NPs for oral delivery of anti-diabetic drugs.
