CoChat
Sign Up
Cited by 108Renal Transplantation Outcomes and TreatmentsMonoclonal and Polyclonal Antibodies ResearchComplement system in diseases

The DOI matches its Crossref record; 22 of the 23 references it cites were found in a registry or an index.

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

Open access
Lorant, Tomas, Bengtsson, Mats, Eich, Torsten, Eriksson, Britt-Marie, Winstedt, Lena, Järnum, Sofia, Stenberg, Yvonne, Robertson, Anna-Karin, Mosén, Kristina, Björck, Lars, Bäckman, Lars, Larsson, Erik, Wood, Kathryn, Tufveson, Gunnar, Kjellman, Christian·2018·American Journal of Transplantation
DOI 10.1111/ajt.14733PMC PMC6221156
Open this paper in CoChat — free accountOpen PDF

Abstract

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. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19 + memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7 + ) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/ajt.14733

Cites

22 of 22 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 IdeS plasma concentration. Logarithm of mean IdeS plasma concentrations in patients given 2 doses of 0.12 mg/kg (n = 3), patients given a single dose of 0.25 mg/kg (n = 2), and patients given 2 doses of 0.25 mg/kg (n = 2). IdeS concentration measured using a validated assay after antibody dissociation (LLOQ: 0.1 μg/mL). Pharmacokinetics was evaluated using an open 2‐compartment model. Arithmetic mean values were reported for all parameters except for α and β half‐lives, where harmonic means were calculated. Cmax and Tmax were obtained directly from the experimental data. Nominal time is given on the x‐axis. Error bars = SD
Figure 1 IdeS plasma concentration. Logarithm of mean IdeS plasma concentrations in patients given 2 doses of 0.12 mg/kg (n = 3), patients given a single dose of 0.25 mg/kg (n = 2), and patients given 2 doses of 0.25 mg/kg (n = 2). IdeS concentration measured using a validated assay after antibody dissociation (LLOQ: 0.1 μg/mL). Pharmacokinetics was evaluated using an open 2‐compartment model. Arithmetic mean values were reported for all parameters except for α and β half‐lives, where harmonic means were calculated. Cmax and Tmax were obtained directly from the experimental data. Nominal time is given on the x‐axis. Error bars = SDCC BY-NC · PubMed Central
Figure 2 IdeS effectively cleaves IgG. A, B. IgG in serum samples collected before and at consecutive time‐points after IdeS treatment. C. Nonreducing SDS‐PAGE analysis of serum from patient 205 who received 2 doses of 0.25 mg/kg BW IdeS showing protein banding patterns at the indicated time‐points. Right. IgG, scIgG, F(ab')2, and Fc bands are indicated
Figure 2 IdeS effectively cleaves IgG. A, B. IgG in serum samples collected before and at consecutive time‐points after IdeS treatment. C. Nonreducing SDS‐PAGE analysis of serum from patient 205 who received 2 doses of 0.25 mg/kg BW IdeS showing protein banding patterns at the indicated time‐points. Right. IgG, scIgG, F(ab')2, and Fc bands are indicatedCC BY-NC · PubMed Central
Figure 3 IdeS reduces CDC antibody reactivity. A. T‐cell non‐amplified CDC‐PRA 6‐24 hours after first treatment for patients dosed with 0.12 (patients 101, 102, and 103) or 0.25 (patients 201, 203, 204, and 205) mg/kg IdeS. B. B‐cell non‐amplified CDC‐PRA 6‐24 hours after first treatment. Paired t‐test
Figure 3 IdeS reduces CDC antibody reactivity. A. T‐cell non‐amplified CDC‐PRA 6‐24 hours after first treatment for patients dosed with 0.12 (patients 101, 102, and 103) or 0.25 (patients 201, 203, 204, and 205) mg/kg IdeS. B. B‐cell non‐amplified CDC‐PRA 6‐24 hours after first treatment. Paired t‐testCC BY-NC · PubMed Central
Figure 4 IdeS effectively cleaves anti‐HLA antibodies and eliminates C1q‐binding. Box‐plot of anti‐HLA antibodies having a pre‐dose MFI >1100 (cutoff in study) before and at consecutive time‐points following first and second IdeS treatment (0.12 or 0.25 mg/kg BW). A. Patient 205 LABScreen MFI. B. Patient 205 C1q‐Screen MFI. C. Patient 101 LABScreen MFI. D. Patient 101 C1q‐Screen MFI. Horizontal lines represent median MFI, boxes represent 25th and 75th percentile and vertical lines represent 10th and 90th percentile MFI. Dots are MFI of individual HLAs above or below the percentiles. The P‐values denote first significant difference between pre and post dose. N.S. is the time‐point when there is no longer any significance between pre and post dose. Statistics: Friedman test with Dunn multiple comparison test. The number (n) of HLAs having an MFI above the cutoff at 1100 is given in graph
Figure 4 IdeS effectively cleaves anti‐HLA antibodies and eliminates C1q‐binding. Box‐plot of anti‐HLA antibodies having a pre‐dose MFI >1100 (cutoff in study) before and at consecutive time‐points following first and second IdeS treatment (0.12 or 0.25 mg/kg BW). A. Patient 205 LABScreen MFI. B. Patient 205 C1q‐Screen MFI. C. Patient 101 LABScreen MFI. D. Patient 101 C1q‐Screen MFI. Horizontal lines represent median MFI, boxes represent 25th and 75th percentile and vertical lines represent 10th and 90th percentile MFI. Dots are MFI of individual HLAs above or below the percentiles. The P‐values denote first significant difference between pre and post dose. N.S. is the time‐point when there is no longer any significance between pre and post dose. Statistics: Friedman test with Dunn multiple comparison test. The number (n) of HLAs having an MFI above the cutoff at 1100 is given in graphCC BY-NC · PubMed Central
Figure 5 IdeS effectively cleaves anti‐HLA and C1q‐binding antibodies. A, B. Average (+SD) anti‐HLA antibodies (LABScreen) before and at consecutive time‐points after IdeS treatment in patients treated with 2 doses of 0.12 mg/kg IdeS (patients 101, 102, and 103), 1 dose of 0.25 mg/kg IdeS (patients 201 and 204), or 2 doses of 0.25 mg/kg IdeS (patients 203 and 205). C, D. Average (+SD) C1q‐binding antibodies (C1qScreen) before and at consecutive time‐points after IdeS treatment. Antigens having a predose MFI >1100 were selected for analyses
Figure 5 IdeS effectively cleaves anti‐HLA and C1q‐binding antibodies. A, B. Average (+SD) anti‐HLA antibodies (LABScreen) before and at consecutive time‐points after IdeS treatment in patients treated with 2 doses of 0.12 mg/kg IdeS (patients 101, 102, and 103), 1 dose of 0.25 mg/kg IdeS (patients 201 and 204), or 2 doses of 0.25 mg/kg IdeS (patients 203 and 205). C, D. Average (+SD) C1q‐binding antibodies (C1qScreen) before and at consecutive time‐points after IdeS treatment. Antigens having a predose MFI >1100 were selected for analysesCC BY-NC · PubMed Central
Figure 6 IdeS degrades B cell receptor expressed by circulating CD19+ B cells. Flow cytometry analysis of CD19+/IgG+ cells at different time‐points after IdeS treatment as a mean of 6 patients. A. The patients showed a significant reduction in percentage of Fab‐positive CD19+ cells. B. The patients showed no significant reduction in percentage of Fc‐positive CD19+ cells. Data presented as mean (±SEM). The x‐axis shows time post first dosing. Data from patient 102 were not included due to too few CD19+ cells in the majority of the sampling points, and samples from patient 202 were not collected for BCR evaluation as this patient did not receive a full dose of IdeS
Figure 6 IdeS degrades B cell receptor expressed by circulating CD19+ B cells. Flow cytometry analysis of CD19+/IgG+ cells at different time‐points after IdeS treatment as a mean of 6 patients. A. The patients showed a significant reduction in percentage of Fab‐positive CD19+ cells. B. The patients showed no significant reduction in percentage of Fc‐positive CD19+ cells. Data presented as mean (±SEM). The x‐axis shows time post first dosing. Data from patient 102 were not included due to too few CD19+ cells in the majority of the sampling points, and samples from patient 202 were not collected for BCR evaluation as this patient did not receive a full dose of IdeSCC BY-NC · PubMed Central
Figure 7 Anti‐IdeS IgG concentration in serum from all patients before and after IdeS treatment. The green lines represent group 1 (patients 101, 102, and 103) who received 2× 0.12 mg/kg BW IdeS, the red lines represent group 2 (patients 203 and 205) who received 2× 0.25 mg/kg BW IdeS, and the blue lines represent group 3 (patients 201 and 204) who received 1× 0.25 mg/kg BW IdeS. The dotted line is patient 202 who had dosing interrupted. Serum samples were analyzed using the IdeS‐ImmunoCAP (Thermo Fisher Scientific) on a Phadia 250 instrument. The cutoff (LLOQ) for IgG was 2 mg/L
Figure 7 Anti‐IdeS IgG concentration in serum from all patients before and after IdeS treatment. The green lines represent group 1 (patients 101, 102, and 103) who received 2× 0.12 mg/kg BW IdeS, the red lines represent group 2 (patients 203 and 205) who received 2× 0.25 mg/kg BW IdeS, and the blue lines represent group 3 (patients 201 and 204) who received 1× 0.25 mg/kg BW IdeS. The dotted line is patient 202 who had dosing interrupted. Serum samples were analyzed using the IdeS‐ImmunoCAP (Thermo Fisher Scientific) on a Phadia 250 instrument. The cutoff (LLOQ) for IgG was 2 mg/LCC BY-NC · PubMed Central
Figure 8 Normal creatinine levels in patient 102 after transplant. Plasma creatinine levels at different time‐points in an IdeS‐treated recipient transplanted with an HLA‐incompatible kidney from a deceased donor
Figure 8 Normal creatinine levels in patient 102 after transplant. Plasma creatinine levels at different time‐points in an IdeS‐treated recipient transplanted with an HLA‐incompatible kidney from a deceased donorCC BY-NC · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 23 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Lorant, T., Bengtsson, M., Eich, T., Eriksson, B.-M., Winstedt, L., Järnum, S., Stenberg, Y., Robertson, A.-K., Mosén, K., Björck, L., Bäckman, L., Larsson, E., Wood, K., Tufveson, G., & Kjellman, C.
Affiliations
  • Uppsala University (SE)
  • Hansa Biopharma (Sweden) (SE)
  • Lund University (SE)
  • University of Oxford (GB)
Corresponding author
Kjellman, Christian
ORCID
Venue
American Journal of Transplantation
Publisher
Elsevier BV
Published
2018-11
Volume
18
Issue
11
Pages
2752-2762
ISSN
1600-6135 (ISSN-L)
DOI
10.1111/ajt.14733
PMC
PMC6221156
OpenAlex
W2789946756
Cited by
108
References
23
Citations by year
2026: 11 · 2025: 11 · 2024: 18 · 2023: 14 · 2022: 18 · 2021: 12 · 2020: 12 · 2019: 11 · 2018: 1
FWCI
7.69
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Transplantation (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • Lund University Publications (Lund University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Keywords
ide, imlifidase, HLA antibodies, chronic kidney disease, HLA sensitization, IgG degradation, complement-dependent cytotoxicity, HLA crossmatch, kidney transplantation, immunogenicity, pharmacokinetics
MeSH terms
Adult, Aged, Bacterial Proteins, Desensitization, Immunologic, Female, Follow-Up Studies, Graft Rejection, Graft Survival, Histocompatibility, HLA Antigens, Humans, Immunoglobulin G, Infusions, Intravenous, Isoantibodies, Male, Middle Aged, Prognosis, Risk Factors, Streptococcus pyogenes, Complement C1q, Kidney Transplantation, Renal Insufficiency, Chronic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review