Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule

Kim, Jin Kyoo; Tsen, May F.; Gheţie, Victor

doi:10.1016/0161-5890(95)00019-b

Cited by 33 publications

(12 citation statements)

References 33 publications

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“…Lack of inter heavy-chain disulfide linkage has been shown to influence antibody serum half-life 29 . Furthermore, as half-molecules contain only one instead of two binding sites for the neonatal Fc receptor (FcRn) 30 , their rescue from the IgG degradation pathway is likely to be impaired 31 .…”

Section: Resultsmentioning

confidence: 99%

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

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Labrijn

Kranen-Mastenbroek

et al. 2017

Sci Rep

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Autoantibodies against ion channels are the cause of numerous neurologic autoimmune disorders. Frequently, such pathogenic autoantibodies have a restricted epitope-specificity. In such cases, competing antibody formats devoid of pathogenic effector functions (blocker antibodies) have the potential to treat disease by displacing autoantibodies from their target. Here, we have used a model of the neuromuscular autoimmune disease myasthenia gravis in rhesus monkeys (Macaca mulatta) to test the therapeutic potential of a new blocker antibody: MG was induced by passive transfer of pathogenic acetylcholine receptor-specific monoclonal antibody IgG1-637. The effect of the blocker antibody (IgG4Δhinge-637, the hinge-deleted IgG4 version of IgG1-637) was assessed using decrement measurements and single-fiber electromyography. Three daily doses of 1.7 mg/kg IgG1-637 (cumulative dose 5 mg/kg) induced impairment of neuromuscular transmission, as demonstrated by significantly increased jitter, synaptic transmission failures (blockings) and a decrease in the amplitude of the compound muscle action potentials during repeated stimulations (decrement), without showing overt symptoms of muscle weakness. Treatment with three daily doses of 10 mg/kg IgG4Δhinge-637 significantly reduced the IgG1-637-induced increase in jitter, blockings and decrement. Together, these results represent proof-of principle data for therapy of acetylcholine receptor-myasthenia gravis with a monovalent antibody format that blocks binding of pathogenic autoantibodies.

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Section: Resultsmentioning

confidence: 99%

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Losen

Labrijn

Kranen-Mastenbroek

et al. 2017

Sci Rep

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“…Whether this asymmetry is due to steric effects and/or some longer range conformational changes at the CH2–CH3 domain junction is currently unknown. However, the segmental flexibility of the IgG molecule (Nezlin, 1990; Oi et al ., 1978), together with the observation that a hinge-less Fc has lower activity in FcRn-mediated functions (Kim et al ., 1995), would be consistent with conformational alterations.…”

Section: The Molecular Nature Of Fcrn–igg Interactionsmentioning

confidence: 99%

Chapter 4 Multitasking by Exploitation of Intracellular Transport Functions

Ward

Ober

2009

Advances in Immunology

142

169

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The MHC Class I-related receptor, FcRn, transports antibodies of the immunoglobulin G (IgG) class within and across a diverse array of different cell types. Through this transport, FcRn serves multiple roles throughout adult life that extend well beyond its earlier defined function of transcytosing IgGs from mother to offspring. These roles include the maintenance of IgG levels and the delivery of antigen in the form of immune complexes to degradative compartments within cells. Recent studies have led to significant advances in knowledge of the intracellular trafficking of FcRn and (engineered) IgGs at both the molecular and cellular levels. The engineering of FcRn–IgG (or Fc) interactions to generate antibodies of increased longevity represents an area of active interest, particularly in the light of the expanding use of antibodies in therapy. The strict pH dependence of FcRn–IgG interactions, with binding at pH 6 that becomes essentially undetectable as near neutral pH is approached, is essential for efficient transport. The requirement for retention of low affinity at near neutral pH increases the complexity of engineering antibodies for increased half-life. Conversely, engineered IgGs that have gained significant binding for FcRn at this pH can be potent inhibitors of FcRn that lower endogenous IgG levels and have multiple potential uses as therapeutics. In addition, molecular studies of FcRn–IgG interactions indicate that mice have limitations as preclinical models for FcRn function, primarily due to cross-species differences in FcRn-binding specificity.

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“…Limited pepsin digestion was carried out essentially as described previously [33]. In brief, radiolabeled WT Fc-hinge or Fc-papain (10 5 cpm/mg) were incubated at 500 ?…”

Section: Limited Proteolysis Of Fc Fragmentsmentioning

confidence: 99%

Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn

et al. 1999

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The analysis of the pharmacokinetics of wild‐type and mutated Fc fragments derived from human IgG1 indicates that Ile253, His310 and His435 play a central role in regulating serum half‐life in mice. Reduced serum half‐life of the recombinant, mutated fragments correlates with decreased binding to the MHC class I‐related neonatal Fc receptor, FcRn. In addition, the analysis of an Fc fragment in which His435 is mutated to Arg435 demonstrates that the sequence difference at this position between human IgG1 (His435) and IgG3 (Arg435) most likely accounts for the shorter serum half‐life of IgG3 relative to IgG1. In contrast to His310 and His435, the data indicate that His433 does not play a role in regulating the serum half‐life of human IgG1. Thus, the interaction site of mouse FcRn on human and mouse IgG1 involves the same conserved amino acids located at the CH2‐CH3 domain interface of the IgG molecule. The sequence similarities between mouse and human FcRn suggest that these studies have direct relevance to understanding the factors that govern the pharmacokinetics of therapeutic IgG.

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Evidence that the hinge region plays a role in maintaining serum levels of the murine IgG1 molecule

Cited by 33 publications

References 33 publications

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Chapter 4 Multitasking by Exploitation of Intracellular Transport Functions

Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn

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