Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients

Lorant, Tomas; Bengtsson, Mats; Eich, Torsten; Eriksson, Björn; Winstedt, Lena; Järnum, Sofia; Stenberg, Yvonne; Robertson, Anna‐Karin; Mosén, Kristina; Björck, Lars; Bäckman, Lars; Larsson, Erik; Wood, Kathryn J.; Tufveson, Gunnar; Kjellman, Christian

doi:10.1111/ajt.14733

Cited by 74 publications

(89 citation statements)

References 21 publications

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“…The IgG-degrading enzyme, IdeS, also known as Imlifidase® has shown promise in a clinical trial (ClinicalTrials.gov Identifier: NCT02224820) permitting successful kidney transplantation in patients harboring donor-specific antibodies(37–39). Briefly, the latter study assessed the safety, immunogenicity, pharmacokinetics, and efficacy of Imlifidase in an open-label, dose escalation study in highly sensitized patients with anti-HLA antibodies and chronic kidney disease.…”

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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“…IdeS also cleaves B cell receptors from circulating B cells, with the resultant inhibition of antigen specific B cell IgG responses in vitro [63]. Within minutes after dosing, plasma IgG was converted into scIgG, and within a few hours after IdeS treatment, plasma IgG was cleaved into F(ab') 2 and Fc fragments with no intact IgG [64]. reactive antibody level of 95% (range, 22-100).…”

Section: Complication From Igg Endopeptidase (Ides)mentioning

confidence: 99%

“…IdeS originates from Streptococcus pyogenes and is consequently expected to be recognized as foreign to the human immune system. The fact that all patients had detectable anti-IdeS IgG before dosing implies that the patients had been preexposed to IdeS, undoubtedly [64].…”

Section: Immunogenicity Of Idesmentioning

confidence: 99%

“…A phase 2 clinical study on the safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease [64]. Section of Transplant Surgery at Uppsala University Hospital, were eligible for the study if they had ≥2 identified HLA antibodies of which ≥1 was >3,000 MFI in single antigen bead analysis on ≥2 separate occasions.…”

Section: Infectionmentioning

confidence: 99%

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Complication from Desensitization

Han

2019

Kidney Transplantation in Sensitized Patients

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“…Imlifidase, previously known as IgG degrading enzyme of Streptococcus pyogenes (IdeS), enables kidney transplantation in human leukocyte antigen (HLA)‐incompatible highly sensitized recipients through cleavage of donor‐specific IgG into Fc‐ and F(ab′) 2 fragments, abrogating complement activation and Fcγ receptor (FcγR)‐mediated mechanisms 8 . Imlifidase is a highly interesting candidate for desensitization to enable bone marrow engraftment and chimerism induction in sensitized hosts 9 .…”

Section: Introductionmentioning

confidence: 99%

Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

Lin

Boon

Bockermann

et al. 2020

American Journal of Transplantation

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Mixed hematopoietic chimerism induction as a way to foster tolerance to donor organs in recipients who have been sensitized to donor antigens is challenging. Donor‐specific antibodies (DSA) are a dominant barrier toward successful donor bone marrow engraftment. Although desensitization methods are routinely used in recipients with allosensitization for allogeneic bone marrow transplantation, engraftment is frequently unsuccessful. To overcome the barrier of prior sensitization we tested enzymatic desensitization of donor‐specific IgG using imlifidase and endoglycosidase of Streptococcus pyogenes (EndoS), which both partially block the function of DSA in mice, as a novel approach to improve murine bone marrow engraftment in primed hosts. We found that EndoS was capable of inhibiting antibody‐mediated killing of donor cells in vivo. Furthermore, the effect of EndoS depended on the titer of DSA and the genetic background of the recipients. In combination with imlifidase, EndoS improved the survival of donor bone marrow cells. Together with cyclophosphamide, bortezomib, T cell depletion, and nonlethal irradiation, imlifidase in combination with EndoS allowed allogeneic bone marrow engraftment in sensitized recipients. We conclude that enzymatic inactivation of DSA, using the combination of imlifidase and EndoS, can be used for inducing donor hematopoietic chimerism in allosensitized recipient mice in combination with other desensitization strategies.

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Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients

Cited by 74 publications

References 21 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

Complication from Desensitization

Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

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