Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex–mediated immune responses

Blumberg, Laurence J.; Humphries, James E.; Jones, Susan Dana; Pearce, L. Bruce; Holgate, Robert; Hearn, Arron; Cheung, Jonah; Mahmood, Arshad; Tito, B Del; Graydon, James S.; Stolz, Leonie; Bitonti, Alan J.; Purohit, Shalaka; Graaf, Dirk C. de; Kacena, Katherine; Andersen, Jan Terje; Christianson, Gregory J.; Roopenian, Derry C.; Hubbard, Jonathan J.; Gandhi, Amit; Lasseter, Kenneth C.; Pyzik, Michał; Blumberg, Richard S.

doi:10.1126/sciadv.aax9586

Cited by 75 publications

(124 citation statements)

References 63 publications

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“…Thus, a clinical precedent for applying enzymatic IgG degradation to promote rapid and transient antibody clearance already exists. Further, it is noteworthy to mention that other orthogonal methods to facilitate IgG clearance using soluble antibody binding bacterial proteins (e.g., Protein M(40)), FcRn (neonatal Fc receptor) domains(41), anti-FcRn antibodies such as Rozanolixizumab(42), SYNT001(43, 44) etc have shown promise in the clinic as well.…”

Section: Discussionmentioning

confidence: 99%

Rescuing AAV gene transfer from antibody neutralization with an IgG-degrading enzyme

Elmore

Simon

et al. 2020

Preprint

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20Pre-existing humoral immunity to recombinant adeno-associated viral (AAV) vectors 21 restricts the treatable patient population and efficacy of human gene therapies. Approaches to 22 clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression are either 23 ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to 24 rapidly and transiently degrade NAbs prior to AAV administration using an IgG degrading 25 enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaves IgG in dog, monkey 26 and human antisera. Prophylactically administered IdeZ cleaves circulating, human IgG in mice 27 and prevents AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescues 28 AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaves 29 NAbs and rescues AAV transduction in mice passively immunized with individual human donor 30 sera representing a diverse population. Our antibody clearance approach presents a new 31 paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene 32 therapy. 34Human gene therapy using recombinant AAV vectors continues to advance steadily as a 37 treatment paradigm for rare, monogenic disorders. This is highlighted by the recent FDA approval 38 and clinical success of Zolgensma®, an intravenously dosed AAV vector delivering a functional 39 copy of the SMN1 gene in children with Spinal Muscular Atrophy (SMA)(1). Further, the list of 40 systemically dosed AAV-based gene therapies for rare disorders such as Hemophilia A & B, 41 Duchenne Muscular Dystrophy (DMD), X-linked myotubularin myopathy (XLMTM) and Pompe 42 disease amongst others continues to grow(2, 3). These promising clinical examples have 43 concurrently highlighted important challenges that include manufacturing needs, patient 44 recruitment, and the potential for toxicity at high AAV doses. One such challenge that limits the 45 recruitment of patients for gene therapy clinical trials and adversely affects the efficacy of AAV 46 gene therapy is the prevalence of pre-existing neutralizing antibodies (NAbs) to AAV capsids in 47 the human population. Such NAbs arise due to natural infection or cross-reactivity between 48 different AAV serotypes(4-7). NAbs can mitigate AAV infection through multiple mechanisms 49 by (a) binding to AAV capsids and blocking critical steps in transduction such as cell surface 50 attachment and uptake, endosomal escape, productive trafficking to the nucleus or uncoating and 51 (b) promoting AAV opsonization by phagocytic cells, thereby mediating their rapid clearance from 52 the circulation. Multiple preclinical studies in different animal models have demonstrated that pre-53 existing NAbs impede systemic gene transfer by AAV vectors(8-11). 54In humans, serological studies reveal a high prevalence of NAbs in the worldwide 55 population, with about 67% of people having antibodies against AAV1, 72% against AAV2, and 56 ~ 40% against AAV serotypes 5 thr...

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Section: Discussionmentioning

confidence: 99%

Rescuing AAV gene transfer from antibody neutralization with an IgG-degrading enzyme

Elmore

Simon

et al. 2020

Preprint

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“…Single TEAE reports considered possibly related to efgartigimod and temporally associated with its administration included decreases in total lymphocyte counts, T lymphocytes and B lymphocytes, and monocytes, and an increase in neutrophil counts (Table I). [18][19][20][21][22][23][24][25] Hematologic changes (ie, abnormal differential WBC counts) observed in 3 patients following treatment with efgartigimod were mild and asymptomatic, and most likely explained by concomitant use of immunosuppressants. However, the first-in-human (FIH) study of efgartigimod 23 also reported abnormal differential WBC counts (mild decrease in CD8, CD3, CD56, CD4, and CD19 lymphocyte counts) after receipt of the drug (3 of 4 healthy volunteers who received 25 mg/kg and 4 of 4 who received 50 mg/kg).…”

Section: Lysosomal Degradationmentioning

confidence: 99%

“…Dose-dependent decreases in serum IgG concentration were observed by day 8, with the 20 mg/kg (n 5 12) single-dose group achieving its nadir of a 60% mean change from baseline in total serum IgG at this time point, whereas the 5 3 4 mg/kg (n 5 15) group achieved its nadir of 43.6% change from baseline on day 29. Nipocalimab (M281), a high-affinity, fully human monoclonal IgG 1 anti-FcRn antibody engineered to have no Fc effector potential (no C1q binding, and no binding to activating FcgR), and orilanolimab (SYNT001), a humanized IgG 4 k mAb, are 2 additional FcRn inhibitors with published FIH data 18,25 ( Table I). Nipocalimab is currently in phase 2 trials for autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, and MG.…”

Section: Lysosomal Degradationmentioning

confidence: 99%

“…Using this targeted mechanism to reduce tissue and serum concentrations of IgG has the potential to provide significant therapeutic benefit for patients with both monomeric and IC IgG autoantibody-mediated diseases. [18][19][20][21] Should these therapies prove successful, they will provide an alternative to high-dose IVIg and PLEX, reducing treatment burden on health care systems and patients. FcRn inhibitors currently in clinical trials include efgartigimod, 20,22,23 rozanolixizumab, 19,21,24 nipocalimab (M281), 25 and orilanolimab (SYNT001) 18 ; additional FcRn inhibitors in development include IMVT-1401/RVT-1401, CSL730/M230, and ABY-039 (see Patel and Bussel 17 for further details).…”

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confidence: 99%

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Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations

Peter

Ochs

Cunningham‐Rundles

et al. 2020

Journal of Allergy and Clinical Immunology

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The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.

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“…Novel molecules, referred to as "antibodies that enhance IgG degradation" or "Abdegs" (210), that bind to the FcRn with a higher affinity than IgG and in a pH-independent manner, have recently been generated. Moreover, FcRn-blocking monoclonal antibodies, such as Rozanolixizumab (211), SYNT001 (212), M281 (213) and Efgartigimod (214) are currently in phase 2 or 3 clinical trials (NCT04200456, NCT03075878, NCT04119050, NCT04225156). These molecules hold promise for the treatment of IgG-mediated diseases such as systemic lupus erythematosus, myasthenia gravis or immune thrombocytopenic purpura (210,215).…”

Section: Saturation Of the Igg Recycling Pathwaymentioning

confidence: 99%

Relevance of the Materno-Fetal Interface for the Induction of Antigen-Specific Immune Tolerance

et al. 2020

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In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. IgGs present in the maternal milk are also transferred to the newborn through the digestive epithelium upon binding to the FcRn. Importantly, the binding of IgGs to the FcRn is also responsible for the recycling of circulating IgGs that confers them with a long half-life. Maternally delivered IgG provides passive immunity to the newborn, for instance by conferring protective anti-flu or anti-pertussis toxin IgGs. It may, however, lead to the development of autoimmune manifestations when pathological autoantibodies from the mother cross the placenta and reach the circulation of the fetus. In recent years, strategies that exploit the transplacental delivery of antigen/IgG complexes or of Fc-fused proteins have been validated in mouse models of human diseases to impose antigen-specific tolerance, particularly in the case of Fc-fused factor VIII (FVIII) domains in hemophilia A mice or pre-pro-insulin (PPI) in the case of preclinical models of type 1 diabetes (T1D). The present review summarizes the mechanisms underlying the FcRn-mediated transcytosis of IgGs, the physiopathological relevance of this phenomenon, and the repercussion for drug delivery and shaping of the immune system during its ontogeny.

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Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex–mediated immune responses

Cited by 75 publications

References 63 publications

Rescuing AAV gene transfer from antibody neutralization with an IgG-degrading enzyme

Rescuing AAV gene transfer from antibody neutralization with an IgG-degrading enzyme

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations

Relevance of the Materno-Fetal Interface for the Induction of Antigen-Specific Immune Tolerance

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