In vivo depletion of serum IgG by an affibody molecule binding the neonatal Fc receptor

Seijsing, Johan; Yu, Shengze; Frejd, Fredrik Y.; Höidén-Guthenberg, Ingmarie; Gräslund, Torbjörn

doi:10.1038/s41598-018-23481-5

Cited by 36 publications

(25 citation statements)

References 31 publications

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“…IgG antibodies are the most abundant Ig-class in the circulation, especially in the fetus through placental transfer mediated by the FcRn receptors ( 82 ). Placentally transferred IgG provide protection in the first weeks of life due to the relatively long in vivo half-life of IgG (~3 weeks) ( 83 ). Of the four IgG subclasses, IgG1 can primarily be induced by soluble protein antigens and membrane proteins, IgG2 by bacterial capsular polysaccharides, IgG3 by viral antigens (like IgG1) and induce pro-inflammatory effects, and IgG4 by repeated exposure to a non-infectious antigen ( 84 ).…”

Section: Resultsmentioning

confidence: 99%

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life

et al. 2020

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Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn’s immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.

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Section: Resultsmentioning

confidence: 99%

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life

et al. 2020

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“…A possible explanation for this lack of additional efficacy could be the diminished half‐life of rituximab resulting from its administration immediately after IVIg dosing 27 . Recent data have shown that rapid FcRn blockade by affibodies reduced total circulating IgG levels by up to 40%‐70% within 5‐10 days in 2 distinct preclinical models 28,29 …”

Section: Discussionmentioning

confidence: 99%

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti-C5 monoclonal antibody tesidolumab

Jordan

Kucher

Bagger

et al. 2020

American Journal of Transplantation

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Awareness of drug‐drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high‐dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti‐C5 monoclonal antibody tesidolumab (LFG316) in end‐stage renal disease patients awaiting kidney transplant. In this single‐center, phase 1, open‐label, parallel‐group study, 8 patients were assigned to receive either single‐dose tesidolumab + IVIg or tesidolumab alone, with 56‐day follow‐up. Within‐group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half‐life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.

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“…79,80 Administration of immunomodulatory doses of IVIG (1-2 g/kg), often used for desensitization and treatment of AMR, can reduce endogenous total IgG concentrations due to FcRn saturation. [81][82][83][84][85] Although FcRn saturation by IVIG is likely important in accelerating the clearance of pathogenic antibodies, it could also result in the rapid clearance of therapeutic antibodies as reported previously. It is therefore critical to avoid dosing therapeutic mAbs in temporal proximity to high-dose IVIG because high-dose IVIG could diminish the therapeutic benefits.…”

Section: Fc Recep Tor Neonatal (Fcrn) Manipul Ati On S For Tre Atmementioning

confidence: 74%

The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection

Jordan

Ammerman

Choi

et al. 2020

American Journal of Transplantation

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Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell-directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody-mediated rejection (AMR) treatment by targeting CD20 found on B-lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR. K E Y W O R D S clinical research/practice, immunosuppression/immune modulation, kidney transplantation/ nephrology, rejection: antibody-mediated (ABMR), sensitization | 43 JORDAN et Al.

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In vivo depletion of serum IgG by an affibody molecule binding the neonatal Fc receptor

Cited by 36 publications

References 31 publications

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti-C5 monoclonal antibody tesidolumab

The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection

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