Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model.

Miriam Manook,Walter J Flores,Sallie Permar,Janghoon Yoon,Alton B Farris,Jean Kwun,Allan Kirk,Stuart Knechtle,Robin Schmitz,Melissa Harnois,Zachary Fitch,Diogo M Magnani,Yeeun Bae,Brian Shaw

doi:10.3389/fimmu.2021.660900

Abstract

BackgroundIn transplantation, plasmapheresis and IVIg provide the mainstay of treatment directed at reducing or removing circulating donor-specific antibody (DSA), yet both have limitations. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA.MethodsSix (6) rhesus macaque monkeys, previously sensitized by skin transplantation, received a single dose of 30mg/kg anti-RhFcRn IV, and effects on total IgG, as well as DSA IgG, were measured, in addition to IgM and protective immunity. Subsequently, 60mg/kg IV was given in the setting of kidney transplantation from skin graft donors. Kidney transplant recipients received RhATG, and tacrolimus, MMF, and steroid for maintenance immunosuppression.ResultsCirculating total IgG was reduced from a baseline 100% on D0 to 32.0% (mean, SD ± 10.6) on d4 post infusion (p<0.05), while using a DSA assay. T-cell flow cross match (TFXM) was reduced to 40.6±12.5% of baseline, and B-cell FXCM to 52.2±19.3%. Circulating total IgM and DSA IgM were unaffected by treatment. Pathogen-specific antibodies (anti-gB and anti-tetanus toxin IgG) were significantly reduced for 14d post infusion. Post-transplant, circulating IgG responded to anti-FcRn mAb treatment, but DSA increased rapidly.ConclusionTargeting the FcRn-mediated recycling of IgG is an effective means of lowering circulating donor-specific IgG in the sensitized recipient, although in the setting of organ transplantation mechanisms of rapid antibody rise post-transplant remains unaffected.

Highlights

In transplantation, plasmapheresis has been one of the mainstays of many protocols aiming to remove circulating donor-specific antibody (DSA)
Further evidence suggests that IdeS is effective in cleaving IgG when cell bound to the IgG subtype B-cell Receptor (BCR) (B cell receptor) complex, resulting in an inhibitory effect on antibody-secreting cells (ASCs) [9]
One month following skin transplantation, once serum DSA had declined from a peak, 6 animals were given a single dose of 30mg/kg of anti-Rh Neonatal Fc Receptor (FcRn) monoclonal antibodies (mAbs) IV

Summary

Introduction

Plasmapheresis (plasma exchange, PEX, or double filtration plasmapheresis, DFPP) has been one of the mainstays of many protocols aiming to remove circulating donor-specific antibody (DSA). Indications for therapy are prophylactic removal of DSA perioperatively to facilitate transplantation [1, 2], or as treatment for antibody-mediated rejection (AMR) [3] Despite wide utility, this treatment is limited by efficacy [4], and major complications are rare, the therapy is non-specific and risks off-target effects, such as removal of circulating soluble coagulation factors increasing bleeding risk [5], as well as concurrent pharmacological therapies [6], necessitating additional treatment. Further evidence suggests that IdeS is effective in cleaving IgG when cell bound to the IgG subtype BCR (B cell receptor) complex, resulting in an inhibitory effect on antibody-secreting cells (ASCs) [9] Despite this success, the utility of this treatment may be limited by the emergence of anti-drug antibodies (ADA), which would reduce efficacy and prevent repeated use of IdeS [10]. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA

Methods

Results

Conclusion