v. IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation
- Summarise the methodology and the conclusion of this study in your own words.
- What is the mechanism of action of this drug?
- What are the side effects of therapy?
- Can you explain the difference in the outcome between the Swedish and the American arms?
Summary:
-It collects data from two separate open-label, single-group, phase 1–2 studies.
It investigates the safety and efficacy of IdeS to reduce or remove preformed DSA.
-It was performed in Los Angeles, and Stockholm.
-All the patients provided written informed consent.
-Eligible criteria: patients were 18 to 70 years of age on hemodialysis, and awaiting kidney transplantation. PRA=95% with significant sensitization
history.
-A total of 25 patients (14 patients in the United States and 11 in Sweden)
met the criteria outlined above and participated in the transplantation studies.
-Donor-specific antibodies were detected with the use of solid-phase assay systems that were currently in use at the HLA laboratory of each hospital.
–Conclusion:
There is a significant reduction in levels of DSA after treatment with IdeS. The reduction of DSA allowed for successful transplantation in 24 of 25 patients. The single allograft loss was due to hyperacute rejection in a patient who likely have a non-HLA antibody.
What is the mechanism of action of this drug?
It cleaves intact IgG.
IdeS hydrolyzes human IgG at Gly236 in the lower the hinge region of the IgG heavy chains. That activity is important, since the Fc region of IgG is critical for interaction with Fc receptors and complement binding. Thus, the proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity,
two processes that are critical for antibody
rejection.
What are the side effects of the therapy?
1.Infections(bacterial and viral)
2. Myalgia
Can you explain the difference in the outcome between the Swedish and the American arms?
-Three patients in the Swedish study had AMR.
While Two patients in the U.S. study had AMR. Renal function
was generally good in the two groups after transplantation.
-The patients with AMR in the Swedish study had higher C4d+ scores than did those in the U.S. study.
-One patient in the U.S. study had hyperacute rejection immediately after revascularization due to non-HLA antibodies.
1. Summarise the methodology and the conclusion of this study in your own
words.
open-label, phase 1–2 trials (conducted in Sweden and the United States) that assessed
the efficacy of IdeS with regard to desensitization and transplantation of a kidney from
an HLA-incompatible donor.
. METHODS :
administered IdeS to 25 highly HLA-sensitized patient (11 patients in Uppsala or
Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from
an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-
specific antibodies done.
ONCLUSIONS:
IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible
transplantation .
What is the mechanism of action of this drug?
The IgG-degrading enzyme derived from Streptococcus pyogenes ,is a recombinant
cysteine protease of S. pyogenes produced in Escherichia coli that cleaves all four
human IGg..
What are the side effects of therapy?
BACTERIAL INFECTION.
VIRAL INFECTION.
FEVER.
MYLAGIA
.
2. Can you explain the difference in the outcome
Small number of patient.
Different protocol used to treat the patient.
the administration of IdeS before
transplantation in highly sensitized patients appeared to be effective as a means of reducing or eliminating donor-specific antibodies, a strategy that may improve transplantation rates among patients with HLA incompatibility.
The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS; GenBank accession number, ADF13949.1. opens in new tab) is a recombinant cysteine protease of S. pyogenes produced in Escherichia coli that cleaves all four human subclasses of IgG with strict specificity. IgG-degrading activity is a common strategy that is used by pathogenic bacteria. IdeS hydrolyzes human IgG at Gly236 in the lower hinge region of the IgG heavy chains.15,16 That activity is important, since the Fc region of IgG is critical for interaction with Fc receptors and complement binding. Thus, the proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for antibody rejection. Here we report on the use of IdeS as a therapy to disable pathogenic IgG donor-specific antibodies as a desensitization strategy in highly sensitized candidates for transplantation..
Jordan et al. [65] administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor.
Patients in the US study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound. Eligible patients were awaiting kidney transplantation on either the United Network for Organ Sharing waiting list (in the United States) or the Scandia transplant waiting list (in Sweden) with panel-reactive antibody level of 95% (range, 22–100). The acceptance criteria for HLA-incompatible organs in recipients in the United States include a negative complement-cytotoxicity crossmatch, a negative flow-cytometric crossmatch, or a positive T cell and B cell flow-cytometric crossmatch with approximately 250 channel shifts or less and usually donor-specific antibody positivity.
In Sweden, patients were eligible if they had at least two anti-HLA antibodies with a mean fluorescence intensity of 3,000 or more.
Patients who underwent transplantation received IdeS at a dose of 0.24 mg per kilogram of body weight (in the United States) or at a dose of 0.25 or 0.50 mg/kg. Horse antithymocyte globulin is not susceptible to digestion by IdeS (unpublished data). Patients in the U.S. cohort received induction with alemtuzumab, at a dose of 30 mg administered subcutaneously 4 days after transplantation. and received IdeS over a period of 15 min approximately 4–6 h before the receipt of a kidney transplant from an incompatible donor. By 6 h after the start of the infusion, all the IgG molecules are completely cleaved into Fc and F(ab′)2 fragments, which probably reduces their pathogenicity. All the IgG molecules are inactivated for approximately 1–2 weeks, when new IgG synthesis is detected. There was a significant reduction in the total IgG level that persisted for 28 days. Briefly, near-complete inhibition of C1q-binding HLA antibodies was seen 1 h after treatment. The levels of all HLA antibodies were significantly reduced at 6 h after treatment. Rebound occurred in Swedish. In contrast, the U.S. cohort had fewer patients with rebound and lower levels of HLA antibodies after treatment with IdeS.
Methodoly of the study:
the study conducted in multiple centres in US and sweden the researchers combined the data of the an open lable phase1,2 trial , the aim of the study to test the effectiveness and safety of the streptococcal IgG endopeptidase IdeS as desensiztasion agent for kidney transplanr recipinet with highly HLA incompatble criteria they including adults with age range of18-70 years with confirmed history of sensitization and negative CDC XM ,negative FCXMor previous postive Tand B FCXM of 250 channel shifts or less and postive DSAs assay ,totaL of 24 cases included 11 patients from sweden and 14 from USA and all recieved IdeS in day 0 4-6 hours prior to transplantion with the dose of 0.24- 0.5 mg/Kg ,in sweden group induction with rATG total 4 doses while USA group induction with almeutzemab 4 days after transplantion in addition in usa group they use 2g/kg of IVIGin day7 and 14- followed by rituximab 375mg / m2 , both using DSA monitring by sold phase assay before the treatment and after transplnation with time intervales day 7 , 30,60, 90 180s day, two groups underwent protocal biopsy for screen of ABMR using BANFF 13 criteria for the histological diagnosis of AMR both groups recieved same triple maintenance IS with target tacrolimus trough level was higher in USA group 10-12, and 8-10 ng in the sweden protocal, donor sources was mixed DD , LD in sweden while in US cohort all DD with longer ischemic time 19 hours , also more postive crossomatch inUSA group.
all patients covered with AB prophylaxis .
this study conculded that highly sensitized kidney transplant treated with IdeS in the two cohart have good overall outcome with similer graft , patient survival .
and incidence of antibody-mediated rejection up to 1.5 years after transplantation, but still need more studies with good sample size and longer FU and more homogenous inclusion criteria to confrim its efficacy on longterm .
IdeS molecules is an enzyme dervied from streptococcus pyogenes, has a specific affinity to human IgG leading to its cleavage by two steps:
.Step one results in a single cleavage of the IgG molecule (scIgG) in which one heavy chain remains intact.
Step two generates a fully cleaved product that cannot mediate complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC) by means of Fcγ receptors. thus preventing antibody mediated injury to allograft.
infection complications, prolonged parvo -19 viremia, blood infection, UTI, catheter – site infection and myalgia
1-longer Cold ischemic time and more DGF also the MFI for anti-HLA class 1 were higher in US patientsand more postive crossmatc .
2-less antibodies rebound and lower level of DSA in USA protocal can be explained by the additional use of IVIG and rituximab, higher trough level of CNI
3- In the Swedish group, 3 patients had AMR at 2 weeks with early rebound of DSAs and positive C4d. But in US group 2 patients fulfilled the criteria for AMR with rise of DSAs after 2 and 5 month later. again can eb explained by the effect of the induction agent and the rituximab and IVIG effect .
Q1: This study used a combined data of two centers in USA and Sweden conducted to evaluate safety and efficacy of Ides to remove anti-HLA antibodies before highly sensitized TX. First a study about dose – finding was performed in Sweden patients and then the before mentioned study was conducted. Patients had 18 to 70 year old, waiting for transplantation, undergoing dialysis and were highly sensitized. DSA were detected by solid-phase assays. Totally 25 patients (14patients in USA and 11 in Sweden arm) were enrolled. Patients received Ides on day one, 4-6 hours before transplantation. They were tested for DSA on days 0(6h and 24h), 7, 30, 60, 90 and 180 after treatment with IdeS. Induction with alemtuzxmab was done in the US cohort. Then received prophylactic antibiotics, IVIg and rituximab. Allograft biopsy was done if indicated and protocol biopsy at 6 month. Patients showed reduced level of anti-HLA antibodies and DSA with IdeS. Twenty four out of 25 patients had successful TX. One patient lost graft due to hyper acute rejection. They had acceptable patient and graft survival and renal function up to 18 months after TX .They concluded that Ides administration to reduce DSAs before transplantation is an effective treatment and by its using more sensitized patients could receive TX in spite of HLA incompatibility.
Q2: Ides is an IgG endopeptidase enzyme derived from streptococcus pyrogens. It is a recombinant protease produced in E.coli which hydrolyzed human IgG in hinge region in to Fab and FC fragment. A few hours after its treatment no intact IgG can be detected .This is useful for removing DSA IgG and desensitization of patients.
Q3: Ides side effects: infection complications, prolonged B19 viremia, blood infection, UTI, catheter – site infection and myalgia.
Q4: Cold ischemic time and DGF and MFI for anti-HLA class 1 were higher in US patients comparing Swedish group. Due to administration of IVIG and rituximab, US group had fewer rebounds and lower level of DSA comparing Swedish group. Amnestic responses were blunted is US patients again as result of IVIG and rituximab administration. In the Swedish group, 3 patients had AMR at 2 weeks with rebound of DSAs and positive C4d. But in US group 2 patients fulfilled the criteria for AMR with rise of DSAs 2 and 5 month later that had good response to treatment. One patient in US group had hyper acute rejection due to IgM and IgA non-HLA antibody against endothelium.
This study involves 2 arms one conducted in USA and the other in sweeden .
It included a total of 14 USA patients and 11 sweedish patients .
Inclusion criteria was highly sensitized patient with cPRA around 95 % ( USA) , and having at least 2 DSAs with MFI of 3000 or more .
All patients received IdeS at a dose of 0.24( USA) ,0.25/0.50 mg/kg ( sweeden ) .
Doses were received 4 to 6 hours before operation .
They showed that ideS allowed for transplantation of 24 out of 25 highly sensitized patients .
They concluded that IdeS could be used in highly sensitized patients succefuly but the admitted that their study included only small no of patients and further larger studies are needed to verify these results .
IdeS is a cysteine protease obtained from streptococcus pyogenes, has a specific affinity to IgG leading to its cleavage ,
Cleaved IgG can’t activate complement or mediate ADCC thus preventing antibody mediated injury to allografts .
Side effects of the therapy included increasing susceptibility of infections , possibity of rebound DSAs after elimination of the drug .
Difference in the outcomes may be related to the long ischemia time and so higher incidence of DGF and higher degree of sensitization with MFIs much higher in the USA group .
Summarise the methodology and the conclusion of this study in your own words.
This study was conducted in 2 cohorts (Sweden: 11 patients and USA: 14 patients) of highly sensitized patients after an initial dose-finding study done among eight patients in Sweden.
The study subjects were given Ides infusion 4-6 hours prior to transplant. The subjects were maintained with Tacrolimus, MMF and steroid.
In the Swedish group, horse ATG was given as induction and donors can be either living or deceased.
In the US group, patients were given pre-transplant IVIG and rituximab, alemtuzumab as induction and post-transplant IVIG and rituximab with all the donors being deceased donors.
The patients were monitored for graft function, DSA levels, serum IgG levels and adverse events. Renal-allograft biopsies were performed to assess for antibody-mediated rejection when allograft dysfunction was noted.
In addition, per protocol biopsies were performed at 6 months in the two studies.
Administration of IdeS before transplantation in highly sensitized patients appeared to be effective a strategy that may improve transplantation rates among patients with HLA incompatibility
2. What is the mechanism of action of this drug?
Ides is an IgG -degrading enzyme. It is a recombinant cysteine protease, derived from Streptococcus pyogenes, produced in E.coli. It cleaves human IgG into Fab and Fc fragments by acting at Gly236 in lower hinge region of its heavy chain. Fc portion of IgG is important for complement binding as well as bonding with Fc receptor, cleaving leads to inhibition of complement mediated cytotoxicity as well as antibody mediated cellular cytotoxicity.
3. What are the side effects of therapy?
The significant side effects seen with Ides include infections especially bloodstream infections, abdominal infections, catheter-site infections, Parvovirus B19 infection and myalgia.
4. Can you explain the difference in the outcome between the Swedish and the American arms?
The US arm had elevated cold ischemia time (CIT), increased DGF, lower anti-HLA antibody levels but lesser rebound than the Swedish arm.
US group had one hyper acute rejection, possibly due to non-HLA antibodies.
US group had 2 AMR and 7 patients showing inflammation on biopsy. Swedish group had 3 AMR with higher C4d+ scores.
In between 2 group, there is differences in protocol:
1) In US group, all are deceased donor, while the Swedish group had both living and deceased donors. This gives us the explanation regarding increased DGF and CIT in US group.
2) Pre and post-transplant IVIG and Rituximab in US group: Hence lower anti HLA antibody levels and lesser rebound of DSA.
Summarise the methodology and the conclusion of this study in your own words.
This study reported the experience of
2 independently performed open-label, phase 1–2 trials (conducted in Sweden and the United States) to examine IdeS use for desensitization and transplantation of a kidney from an HLA-incompatible donor.
Based on the idea that IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab′)2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization.
25 highly HLA-sensitized patients 11 in Sweden and 14 in US received IdeS
before the transplantation of a kidney from an HLA-incompatible donor with median 96% (range, 82 to 100) in the patients in the U.S. study and 81% (range, 22 to 100) in the patients in the Swedish study.
Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids.
Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody reboun.
CONCLUSIONS
IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients.
What is the mechanism of action of this drug?
Intact human IgG, regardless of isotype, is cleaved by IdeS in two steps. Step one results in a single cleavage of the IgG molecule in which one heavy chain remains intact. Step two generates a fully cleaved product that cannot mediate complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity by means of Fcγ receptors.
It ado cleaves B-cell receptors from circulating B cells, lead to inhibition of antigen-specific B-cell IgG responses in vitro.
What are the side effects of therapy?
13 infectious complications were reported that generally responded to treatmen
1 prolonged parvovirus B19 viremia was reported in the Sweden study.
Leucopenia and anemia
Fever , myalgia and abdominal pain
Can you explain the difference in the outcome between the Swedish and the American arms?
Patients in US arm had IVIG and rituximab before transplantation.
U.S. cohort had fewer patients with rebound and lower levels of HLA antibodies after treatment with IdeS
significant differences were seen between the groups of patients in the U.S. study and the Swedish study, indicating that the anamnestic responses were blunted in the patients in the U.S. study at 1 month, which probably reflects the use of intravenous immune globulin plus rituximab before and after transplantation.
US group had 2 AMR detected at 5 months and at 2 months after IdeS treatment and 7 patients with inflammation on biopsy.
Swedish group had 3 patients with AMR with mean of 2 weeks after transplantation that was associated with rebound of donor-specific antibodies and C4d+ on biopsies.
Renal function was generally good in the two groups after transplantation .
Summarise the methodology and the conclusion of this study in your own words.
Methodology:
single-group phase 1–2 studies, one conducted in the United States and one conducted in Sweden to examine the effectiveness and safety profile of Ides in 25 highly sensitized patients (14 patients in the United States and 11 in Sweden), with a median calculated panel-reactive antibody level of 95% , undergoing kidney transplantation from incompitable donors
USA: HLA mismatches, no preformed DSA, Swedish : preformed DSA
recipients in the US arm: negative CDC CXM, negative flow-cytometric cross-match, or a positive T-cell and B-cell flow-cytometric cross-match with approximately 250 channel shifts or less(1) received induction with alemtuzumab, at a dose of 30 mg administered subcutaneously 4 days after transplantation and IVIG on days 7 to 14 after transplantation and rituximab
recipients in the Swedish arm: each with at least two anti-HLA antibodies with a MFI of 3000 or more, and received induction with ATG
all Patients received IdeS intravenously on day 0, usually 4 to 6 hours before transplantation. And all patients received prophylactic antibiotic agents to prevent bacterial infection in the absence of IgG antibodies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids.
Follow up parameters:
Assessment of AMR by protocol biopsy at 6 months post Tx and biopsy under indication, examined byC4d staining with the use of the Banff 2013 criteria. (3)
Measurement of DSA levels via solid-phase assay.(2) , level Of Ides ccleavage and clearance
Frequent monitoring for adverse events and outcomes, routine laboratory tests, vital signs, renal function
and significantly higher levels of class I donorspecific antibodies than those in the Swedish study.
the outcomes of the study In brief showed that the US arm patients exhibited more adverse events, longer ischemia time,higher rates of delayed graft function at 2 weeks to 5 months after transplantation , more cases with AMR , and a total of 38 serious adverse events occurred in 15 patients (5 events were considered as being possibly related to IdeS.
No intact IgG was seen at or after 7 days in 10 patients in the Swedish study. There was a significant reduction in the total IgG level that persisted for 28 days.
Both groups showed similar outcomes as regard graft survival , patient survival, renal function, and the incidence of antibody-mediated rejection up to 1.5 years after transplantation
.
As a Conclusion:
The data presented support the hypothesis that IdeS may reduce or eliminate DSA which may facilitate transplantation from an HLA-incompatible donor without the risk of early antibody-mediated rejection.
Further studies with larger numbers of patients and longer follow up periods are mandatory . (5)
1. What is the mechanism of action of this drug?
a recombinant cysteine protease derived from Streptococcus pyogenes
that cleaves all four human subclasses of IgG ( IgG-degrading enzyme) that hydrolyzes at Gly236 in the lower hinge region heavy chains. (4) That activity is important, since the Fc region of IgG is critical for interaction with Fc receptors and complement binding.
cleaved IgG can no longer activate complement or mediate antibody-dependent cellular cyto-toxicity.(6)
another mechanism of action is that it cleaves B-cell receptors from circulating B cells, with the resultant inhibition of antigen-specific B-cell IgG responses in vitro.(6)
What are the side effects of therapy?
2. Bacterial infectiob ( UTI, abdominal infections, septicemia
3. Viral infection (parvovirus)
4. Leucopenia and anemia
5. Fever , myalgia and abdominal pain
Can you explain the difference in the outcome between the Swedish and the American arms?
US arm patients exhibited more adverse events,
The difference in the outcome could be explained by the lower doses of Ides, and the higher levels of aggressive immunosuppression , using induction with Alemtuzimab , followed by desensitization proetocols IVIG and Riruximab
References:
(1). Vo AA, Petrozzino J, Yeung K, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation 2013;95:8528.
(2). Reinsmoen NL, Lai CH, Vo A, et al. Acceptable donor-specific antibody levels allowing for successful deceased and living donor kidney transplantation after desensitization therapy. Transplantation 2008;86:820-5.
(3). Haas M, Sis B, Racusen LC, et al. Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014; 14: 272-83.
(4). Brezski RJ, Vafa O, Petrone D, et al. Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge. Proc Natl Acad Sci U S A 2009; 106: 17864-9.
(5). Vo AA, Choi J, Cisneros K, et al. Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients. Transplantation 2014;98:312-9.
(6). Järnum S, Bockermann R, Runström A, Winstedt L, Kjellman C. The bacterial enzyme IdeS cleaves the IgG-type of B cell receptor (BCR), abolishes BCR-mediated cell signaling, and inhibits memory B cell activation. J Immunol 2015; 195: 5592-601
Methodology of the study
Cohort study; two separate open-label single-group, phase 1–2 trials .The Study was conducted in Sweden and the United States .To assess the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor .25 patients were included, 11 in Sweden and 14 in USA.
Conclusion
The studies concluded that the use of Ides showed remarkable reduction or elimination of DSA in highly sensitized patients which may allow for promising transplantation among patients with HLA-incompatibility. The study revealed significant reduction in the total IgG levels. Ides was effective in decreasing DSA and allowed HLA incompatible transplant
Mechanism of action: A recombinant cysteine protease that cleaves all four human subclasses of IgG with subsequent inhibition of CDC and ADCC.
Side effects: Myalgia, bacterial and viral infections.
The difference in the outcome between the Swedish and the American arms :Using IVIG and rituximab before and after transplant ,The U.S cohort had significant decrease in DSA at one month post-transplant, had fewer patients with rebound of HLA antibodies and had lower levels of HLA antibodies.
1- This study is a report on two trials that assay the effect of IgG degrading enzyme (ides), an endopeptidase, on desensitization and transplantation of kidney recipients from an HLA-incompatible donor.
This study combined data from two separate open-label, single-group, phase 1–2 studies investigating the safety and efficacy of IdeS to reduce or remove pathogenic donor-specific antibodies in order to allow HLA-incompatible kidney transplantation.
At transplantation HLA antibodies were eliminated and the perfusion of kidney allografts was observed in 24 out of 25 patients.
These studies show a significant reduction in levels of IgG HLA alloantibodies and DSAs after treatment with IdeS. The reduction or elimination of donor-specific antibodies allowed for successful transplantation in 24 of 25 patients. Outcomes in the patients treated with IdeS in the two cohorts were good, including similar graft survival and overall survival among patients, renal function, and incidence of antibody-mediated rejection.
2- Ides, cleaves human IgG into F(ab’)2 and Fc fragments inhibiting complement dependent cytotoxicity and antibody dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization.
Intact human IgG, regardless of isotype, is cleaved by IdeS in two steps. Step one results in a single cleavage of the IgG molecule in which one heavy chain remains intact. Step two generates a fully cleaved product that cannot mediate complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity by means of Fcγ receptors.
IdeS also cleaves B-cell receptors from circulating B cells, with the resultant inhibition of antigen specific B-cell IgG responses.
3- Although serious infections were expected, no significant infection complications were observed in the US cohort and 1 prolonged parvovirus B19 viremia was reported in the Sweden study.
4- Recipients in the U.S. study had a significantly longer cold ischemia time, a significantly higher rate of delayed graft function, and significantly higher levels of class I donor specific antibodies than those in the Swedish study.
The study aims to determine the effect of using IdeS as a therapy to disable pathogenic IgG donor-specific antibodies as a desensitization strategy in highly sensitized patients
it combines data from 2 separate, open label, single group studies, both studies aimed to determine the effectiveness of IdeS in reducing DSA in highly sensitized patients.
It include 25 HLA sensitized patients with long waiting time, received IdeS before HLA incompatible transplant.
IdeS was administered IV on day0 4-6 hours before transplant
all patients received prophylactic antibiotics to prevent bacterial infection
The Swedish cohort received induction with horse antithymocyte while U.S cohort received alemtuzumab
The U.S cohort received IVIG and rituximab post transplant
immunosuppression after transplant was tacrolimus, MMF and steroids
DSA were detected using solid phase assay
renal allograft biopsies were performed when allograft dysfunction was noted, Protocol biopsy was performed at 6 moths in both studies
Conclusion:
IdeS was effective in decreasing DSA and allowed HLA incompatible transplant
It is a cysteine protease derived from the IgG‑degrading enzyme of S. pyogenes, It cleaves all 4 human classes of IgG, it hydrolyzes human IgG in the lower hinge region of the heavy chain so prevent IgG mediated antibody dependent cellular toxicity and complement mediated cytotoxicity
The adverse events that were probably related to IdeS were myalgia, abdominal and catheter site infection and viral infection with parvovirus
The U.S cohort had significant decrease in DSA at one month post transplant, had fewer patients with rebound of HLA antibodies and had lower levels of HLA antibodies.
mostly those differences were due to using IVIG and rituximab before and after transplant.
Summarise the methodology and the conclusion of this study in your own words.
Cohort study; two separate open-label single-group, phase 1–2 trials.
conducted in Sweden(Uppsala or Stockholm) 11 patient and the United States (Los Angeles)14 patient.
Objective:
To assess the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.
The studies concluded that the use of IdeS showed remarkable reduction or elimination of DSA in highly sensitized patients which may allow for promising transplantation among patients with HLA-incompatibility.
What is the mechanism of action of this drug? derived from Streptococcus pyogenes which degrades immunoglobulin G (IgG) in a multistep process. into F(ab′) and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity .
1. What are the side effects of therapy?
Infection .
Malgia
2. Can you explain the difference in the outcome between the Swedish and the American arms? American arm had high risk for rejection because they had higher cPRA 96 VS 81 in Swedish group ,also they had long cold ischemia time and DSA MFI is higher for HLA class1 .Higher doses of Ides in Swedish group. Different induction therapy between two group ,same maintenance therapy .
1. Summarise the methodology and the conclusion of this study in your own words.
Methodology:
This study was conducted after ethical clearance in 2 cohorts (Sweden: 11 patients and USA: 14 patients) of highly sensitized patients after an initial dose-finding study done among eight patients in Sweden. The patients were given Ides infusion 4-6 hours prior to transplant. All the patients were on Tacrolimus, MMF and steroid based maintenance immunosuppression regime. In the Swedish group, induction in form of horse ATG was given and donors were either living or deceased. In the US group, patients were given pre-transplant IVIG and rituximab, alemtuzumab induction and post-transplant IVIG and rituximab with all the donors being deceased donors. The patients were monitored for graft function, DSA levels, serum IgG levels and adverse events. Kidney biopsies were done in case renal dysfunction occurred and analysed for rejection as well as protocol biopsies at 6 months.
Conclusion: Ides use was associated with reduction in DSA and successful HLA incompatible kidney transplantation. Although there were a substantial number of AMR episodes, these were successfully treated.
2. What is the mechanism of action of this drug?
Ides is an IgG -degrading enzyme.
It is a recombinant cysteine protease, derived from Streptococcus pyogenes, produced in E.coli.
It breaks human IgG into Fab and Fc fragments by acting at Gly236 in lower hinge region of its heavy chain.
As Fc portion of IgG is important for complement binding as well as bonding with Fc receptor, its cleaving leads to inhibition of complement mediated cytotoxicity as well as antibody mediated cellular cytotoxicity.
3. What are the side effects of therapy?
The significant side effects seen with Ides include infections especially bloodstream infections, abdominal infections, catheter-site infections, Parvovirus B19 infection and myalgias.
4. Can you explain the difference in the outcome between the Swedish and the American arms?
The US arm had elevated cold ischemia time (CIT), increased DGF, lower antiHLA antibody levels and less rebound than the swedish group.
US group had one hyperacute rejection, due to non-HLA antibodies.
US group had 2 AMR and 7 patients showing inflammation on biopsy. Swedish group had 3 AMR with higher C4d+ scores.
The reason for these findings is due to difference in protocol followed:
1) In US group, all donors were deceased, while the Swedish group had both living and deceased donors: Hence increased DGF and CIT in US group
2) The US group was give pre and post transplant IVIG and Rituximab: Hence lower anti HLA antibody levels as well as less rebound seen.
1-2independent open-label,phase1-2 trials performed in Sweden and USA of total 25 highly sensitize HLA -sensitized patients(11 from Sweden and 14 from USA)to explore effect of Ides impact on sensitization Median c PRA was 95% with pre-existing DSA.
IN Swedish arm:
Induction was achieved by ATG together with one dose of Ides of 0.24 mg/kg or 2 consecutive doses of 0.5 mg/kg 4-6 hours before Tx Maintenance therapy included Tac(trough 10-12), MMF and corticosteroids.
In American arm :
Induction was achieved using alemtuzomab 30 mg /kg from day 4 together with one dose of Ides 0.25 mg/kg .Rituximab and IVIG were given post Tx to avoid DSA rebound.
Maintenance therapy was achieved by Tac (trough 8-10) , MMF and corticosteroids.
In both arms, renal biopsy was done at 6 months in case of renal dysfunction .No DSA were found after Tx. ABMR was treated successfully .Graft loss occurred in one patient and it was associated with non-HLA IgM and IgA ABs.15% of side effects were attributed to Ides were of infectious etiology.
Conclusion:
Ides has beneficial effect on DSA through reduction or elimination allowing Tx to be salvage RRT option for high risk patients in need for Tx due to intolerance to dialysis.
2-Ides is degrading enzyme derived from streptococcus pyogenes that cleaves human Ig subclasses resulting in elimination of Fc- dependent effector function with reduction of DSA levels.
3-Side effects:
infection(bacterial and fungal),pain and reaction at infusion site, headache ,dizziness, anemia, scleral hemorrhage blood pressure changes, dyspnea, myalgia ,elevated liver enzymes rash ,sinus tachycardia ,among others.
4-Longer cold ischemia time in American arm.
Higher risk of rejection in American arm
IV Ig might decrease Ides effect in American arm
Tac trough levels little higher in Swedish arm
Ides different dose regimen : one dose in American arm vs one or 2 doses in Swedish arm
Methodology of the study
Study Type:
Cohort study; two separate open-label single-group, phase 1–2 trials.
Study Area:
The Study was conducted in Sweden(Uppsala or Stockholm) and the United States (Los Angeles).
Study Objective:
To assess the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.
Study Population:
25 patients were included, 11 in Sweden and 14 in USA.
Inclusion Criteria:
Study Methods:
Data analysis:
Statistical analysis of the study was performed using:
Conclusion
The study revealed significant reduction in the total IgG levels that persist for 28 days. US study showed high level of DSA and significant reduction at this level post transplantation at 1 month.
The studies concluded that the use of IdeS showed remarkable reduction or elimination of DSA in highly sensitized patients which may allow for promising transplantation among patients with HLA-incompatibility.
What is the mechanism of action of this drug?
What are the side effects of therapy?
Can you explain the difference in the outcome between the Swedish and the American arms?
Summarise the methodology and the conclusion of this study in your own words.
This paper included two separate (independently in USA and Sweden ) phase 1–2 studies . It is an open-label, single-group, investigated the role of IdeS in reducing DSA in patients with HLA incompatibility .25 patients were included (14 in USA arm and 11 in Sweden). All patients were sensitized . All patients received IdeS and it lead to significant reduction of DSA level.
What is the mechanism of action of this drug?
It is an enzyme which cleaves intact IgG and thus inhibit complement dependent and antibody dependent cellular cytotoxicity .
What are the side effects of therapy?
Blood infection, abdominal infection, catheter-site infection , viral infection with parvovirus and myalgia
Can you explain the difference in the outcome between the Swedish and the American arms?
The acceptance criteria for HLA-incompatible organs: in USA a negative CDC, a negative FCXM, or a positive T-cell and B-cell FCXM with approximately 250 channel shifts or less and usually DSA positivity. In Sweden at least two anti-HLA antibodies with a mean fluorescence intensity of 3000 or more.MFI intensity for HLA class I antibodies at the time of transplantation: higher in USA arm 6000 versus 4000
Induction : Sweden received Atgam which is not susceptible to digestion by IdeS . USA: alemtuzumab
The levels of tacrolimus : Sweden: 10 to 12 ng per milliliter ,USA : 8 to 10 ng per milliliter
IdeS dose of 0.24 mg per kilogram of body weight (in the United States) or at a dose of 0.25 mg per kilogram or 0.50 mg per kilogram (in Sweden; both doses were investigated in a dose-finding study).
Median cPRA: USA 96% (range, 82 to 100) , Sweden : 81% (range, 22 to 100)
Cold ischemia time : longer in USA arm
Delayed graft function was more in USA arm
Summarise the methodology and the conclusion of this study in your own words.
This paper included two separate (independently in USA and Sweden ) phase 1–2 studies . It is an open-label, single-group, investigated the role of IdeS in reducing DSA in patients with HLA incompatibility .25 patients were included (14 in USA arm and 11 in Sweden). All patients were sensitized . All patients received IdeS and it lead to significant reduction of DSA level.
What is the mechanism of action of this drug?
It is an enzyme which cleaves intact IgG and thus inhibit complement dependent and antibody dependent cellular cytotoxicity .
What are the side effects of therapy?
Blood infection, abdominal infection, catheter-site infection , viral infection with parvovirus and myalgia
Can you explain the difference in the outcome between the Swedish and the American arms?
The acceptance criteria for HLA-incompatible organs: in USA a negative CDC, a negative FCXM, or a positive T-cell and B-cell FCXM with approximately 250 channel shifts or less and usually DSA positivity. In Sweden at least two anti-HLA antibodies with a mean fluorescence intensity of 3000 or more.
Induction : Sweden received Atgam which is not susceptible to digestion by IdeS . USA: alemtuzumab
The levels of tacrolimus : Sweden: 10 to 12 ng per milliliter ,USA : 8 to 10 ng per milliliter
IdeS dose of 0.24 mg per kilogram of body weight (in the United States) or at a dose of 0.25 mg per kilogram or 0.50 mg per kilogram (in Sweden; both doses were investigated in a dose-finding study).
Median cPRA: USA 96% (range, 82 to 100) , Sweden : 81% (range, 22 to 100)
Cold ischemia time : longer in USA arm
MFI intensity for HLA class I antibodies at the time of transplantation: higher in USA arm
Dear all, check this visual abstract that summarizes the study
In your words, what is the difference between the two cohorts, US vs. Sweeden? How may this affect treatment decisions?
In your words, what is the difference between the two cohorts, US vs. Sweeden? How may this affect treatment decisions?
The USA arm included 14 patients versus 11 patients in the Sweden arm. USA arm received induction with alemtuzumab while Sweden received horse ATG which is not degraded with Ides. However, there are 7 ABMR with 1 graft loss in USA arm and only 3 ABMR in Sweden . This difference arm may be due to the higher MFI and cPRA of selected patients , the longer cold ischemia time, more DGF and lower IdeS dose in the USA arm.
The US arm had elevated cold ischemia time (CIT), increased DGF, lower anti-HLA antibody levels and less rebound than the swedish group.
US group had one hyperacute rejection, due to non-HLA antibodies.
US group had 2 AMR and 7 patients showing inflammation on biopsy. Swedish group had 3 AMR with higher C4d+ scores.
The reason for these findings is due to difference in protocol followed:
1) In US group, all donors were deceased, while the Swedish group had both living and deceased donors: Hence increased DGF and CIT in US group
2) The US group was give pre and post transplant IVIG and Rituximab: Hence lower anti HLA antibody levels as well as less rebound seen.
The US cohort involve 14 patients while the Sweden involve 11 patients
All are highly sensitized with PRA of 95%
The US patients has longer cold ischemia time, significantly higher rate of delayed graft function and higher level of class I DSA.
In US study, the donor was deceased while in Sweden study, the donor was either live or deceased.
In the US study, the patients received IVIG+Rituximab 1 month before transplantation and alemtuzumab on post transplant day 4, while the Sweden patients received induction with horse ATG. both groups maintained on Tac, MMF, and steroids.
Graft outcomes: in the US study 7 episodes of ABMR and one graft lost due to non HLA antibodies, while in Sweden study there were 3 episodes of ABMR.
Based on patient’s characteristics, patients on the US study need more aggressive IS as they received a deceased donors only and had longer cold ischemia time and higher level of DSA class I, also frequent monitoring of DSA level and protocol biopsy, their graft outcome will be lower than the sweden group.
Methodology
IdeS was given to 25 highly HLA-sensitized patients before the transplantation of a kidney from an HLA-incompatible donor 11 patients were from Sweden and 14 from America.
The American patients were desensitised by Iv Ig and rituximab before and after transplantation, induction by horse antithymocyte globulin was given to the Swedish group and alemtuzumab was given to the American group both received maintenance with MMF , tacrolimus and steroids with frequent monitoring of DSA, renal function , and renal biopsies.
Conclusion
IdeS adminstration before transplantation in highly sensitized patients seems to decrease or eliminate DSA , improving transplantation rates in HLA incompatible patients.
2.What is the mechanism of action of this drug?
It is a recombinant cysteine protease derived from Streptococcus pyogenes produced in Escherichia coli that cleaves specifically all 4 subclasses of IgG ,this proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, there by preventing the main processed of antibody rejection
3.What are the side effects of therapy?
Blood infection and catheter related infection ,Viral infection with parvovirus ,myalgia and infusion reactions
4.Can you explain the difference in the outcome between the Swedish and the American arms?
The patients with antibody rejection occurred in 3 cases in the Swedish study having higher C4d+ scores than did those in the U.S. study whom were 7 patients occurring at 2 weeks to 5 months after transplantation;
US study cases had a longer cold ischemia time ,a higher rate of delayed graft function, and higher levels of class I DSA than those in the Swedish study.
Summarise the methodology and the conclusion of this study in your own words.
Study Design;
combined data from two separate open-label, single-group, phase 1–2 studies .
Aim of the study;
investigating the safety and efficacy of IdeS to reduce or remove pathogenic donor-specific antibodies in order to allow HLA-incompatible kidney transplantation.
Study area;
The studies were performed independently at Cedars–Sinai Medical Center, Los Angeles, and at Uppsala University, Uppsala, Sweden, and Karolinska Institutet , Stockholm.
Approval;
The study protocols (available with the full text of this article at NEJM.org) were approved at each site by an institutional review board or ethics committee.
Patient ;
Inclusion criteria ;
Eligible patients were 18 to 70 years of age, were undergoing dialysis for end-stage renal disease, and were awaiting kidney transplantation on either the United Network for Organ Sharing waiting list (in the United States) or the Scandia transplant waiting list (in Sweden).
All the patients had extensive sensitization, with a median calculated panel-reactive antibody level of 95% (range, 22 to 100), and had a clinically significant sensitization history.
The acceptance criteria for HLA- incompatible organs in recipients in the United States have been reported previously. Briefly, these criteria include a negative complement-cytotoxicity cross-match, a negative flow-cytometric cross-match, or a positive T-cell and B-cell flow-cytometric cross-match with approximately 250 channel shifts or less and usually donor-specific antibody positivity.
In Sweden, patients were eligible if they had had at least two anti-HLA antibodies with a mean fluorescence intensity of 3000 or more.
Randomization ;
A total of 25 patients (14 patients in the United States and 11 in Sweden) met the criteria outlined above and participated in the transplantation studies. Donor-specific antibodies were detected with the use of solid-phase assay systems that were currently in use at the HLA laboratory of each hospital.
Study patients who received a kidney transplant had samples obtained before IdeS treatment for the assessment of donor-specific antibodies and flow-cytometric cross-matching and also underwent studies after treatment that included monitoring for efficacy of IgG cleavage at pre specified time points.
Patients who underwent transplantation received IdeS at a dose of 0.24 mg per kilogram of body weight (in the United States) or at a dose of 0.25 mg per kilogram or 0.50 mg per kilogram (in Sweden; both doses were investigated in a dose-finding study). IdeS was administered intravenously on day 0, usually 4 to 6 hours before transplantation .
Cross-match and donor-specific– antibody tests were conducted at 6 hours and 24 hours and on days 7, 30, 60, 90 (only in the U.S. study), and 180 (only in the U.S. study) after treatment to determine the efficacy of IdeS.
Patients in the Swedish cohort received induction with horse antithymocyte globulin (Atgam, Pfizer) for 4 days after transplantation. Horse antithymocyte globulin is not susceptible to digestion by IdeS (unpublished data). Patients in the U.S. cohort received induction with alemtuzumab, at a dose of 30 mg administered subcutaneously 4 days after transplantation.
Patients in the U.S. and Swedish studies continued to receive standard immunosuppression, as reported previously. The levels of tacrolimus in blood were maintained at 10 to 12 ng per milliliter in the Swedish study and at 8 to 10 ng per milliliter in the U.S. study.
All the patients received prophylactic antibiotic agents to prevent bacterial infection in the absence of IgG antibodies. Patients in the U.S. study received intravenous immune globulin at a dose of 2 g per kilogram (maximum dose, 140 g) on days 7 to 14 after transplantation.
Patients in the U.S. study who did not receive rituximab before kidney transplantation received rituximab at a dose of 375 mg per square meter of body-surface area on days 14 to 21 after transplantation.
Assessments in the two studies included ;
C4d staining with the use of the Banff 2013 criteria.
Routine laboratory tests ,measurement of panel-reactive antibodies and donor-specific antibodies, assessment of vital signs, and the collection of data related to adverse events and serious adverse events.
Samples for the analysis of IdeS levels and qualitative analysis of patients’ IgG levels were assessed with the use of sodium dodecyl sulfate–polyacrylamide-gel electrophoresis (SDS-PAGE). IdeS cleavage and clearance of the Fc and F(ab′) 2 fragments were analyzed with the use of enzyme-linked immunosorbent assay (ELISA) methods, as previously described. The SDS-PAGE and Western blot analyses were performed according to the manufacturers’ instructions under non reduced conditions.
In conclusion, the administration of IdeS before transplantation in highly sensitized patients appeared to be effective as a means of reducing or eliminating donor-specific antibodies, a strategy that may improve transplantation rates among patients with HLA incompatibility.
What is the mechanism of action of this drug?
The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab′) and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity .
What are the side effects of therapy?
The possibility of serious infectious complications related to IdeS treatment was an anticipated concern.
Myalgia , which is an ongoing serious adverse event.
All the serious adverse events were resolved (patients recovered) except for the event of Myalgia .
Can you explain the difference in the outcome between the Swedish and the American arms?
The acceptance criteria for HLA-incompatible organs in recipients in the United States have been reported previously. Briefly, these criteria include a negative complement-cytotoxicity cross-match, a negative flow-cytometric cross-match, or a positive T-cell and B-cell flow-cytometric cross-match with approximately 250 channel shifts or less and usually donor-specific antibody positivity.
In Sweden, patients were eligible if they had had at least two anti-HLA antibodies with a mean fluorescence intensity of 3000 or more.
Patients in the Swedish cohort received induction with horse antithymocyte globulin (Atgam, Pfizer) for 4 days after transplantation. Horse antithymocyte globulin is not susceptible to digestion by IdeS (unpublished data). Patients in the U.S. cohort received induction with alemtuzumab, at a dose of 30 mg administered subcutaneously 4 days after transplantation
Patients in the U.S. and Swedish studies continued to receive standard immunosuppression, as reported previously. The levels of tacrolimus in blood were maintained at 10 to 12 ng per milliliter in the Swedish study and at 8 to 10 ng per milliliter in the U.S. study.
Patients in the U.S. study who did not receive rituximab before kidney transplantation received rituximab at a dose of 375 mg per square meter of body-surface area on days 14 to 21 after transplantation.
Phase 1-2 studies examining IdeS’s effectiveness and safety in reducing or removing DSA. A study was conducted separately at Cedars-Sinai Medical Center, Uppsala University, and Karolinska Institutet in Stockholm.
Patients: 25 patients, 18-70 years old, extremely sensitive (cPRA 95%), awaiting kidney transplantation.
the US trial used 0.24 mg/kg, whereas the Swedish study used 0.25 or 0.5 mg/kg, 4-6 hours before transplantation. XM and DSA testing was done 6 hours, 24 hours, 7, 30, 60, 90, and 180 days following therapy.
In Sweden, ATG was used and in the US, Alemtuzumab. Both continue to be immunosuppressed. All get preemptive AB. Both studies performed renal allograft biopsy when allograft impairment was present, and 6 months afterwards.
the result:
38 significant adverse events occurred in 15 individuals (5 likely connected to IdeS). Total IgG and HLA antibodies were removed at the transplant. After transplantation, 24 out of 25 patients had allograft perfusion. 7 individuals in the US and 3 in Sweden had antibody-mediated rejection 2 weeks to 5 months following transplantation, all of whom responded to therapy. Non-HLA IgM and IgA antibodies caused one graft loss.
HLA incompatible transplantation was possible in 24 of 25 individuals with IdeS.
Action mechanism
The IgG-degrading enzyme is a recombinant cysteine protease of Streptococcus pyogenes that cleaves all four human subclasses of IgG.
side effects:
e were 13 infectious complications that generally responded to treatment. However, in the Swedish study, 1 patient had prolonged parvovirus B19 viremia and 1 had persistent myalgias after the IdeS infusion and bacterial infection. also, the rebound of DSA was documented.
the difference in the outcome between the Swedish and the American arms?
U.S. study:
Following transplantation, two patients developed ABMR.
(with increased DSA). decent therapy response, Good renal function
An IgA/IgM non-HLA patient exhibited hyperacute rejection.
Study Swedish:
After 2 weeks, three patients developed ABMR with positive DSA and significant C4d staining on graft biopsies. Good treatment response
Combined data from 2 separated open-label, single group, phase 1-2 study.
Aim of the study: assess safety & role of IdeS in highly sensitized recipients to reduce pathological DSA.
Inclusion criteriaL
USA criteria for HLA incompatible organ:
While Sweden criteria were at least 2 anti-HLA with MFI >3000.
DSA measured by solid phase assay.
First study done in Swede include 8 patients receive IdeS with out transplantation, it done to define the exact dose for post transplantation recipients.
Second study include 25 patients ( 14 from USA &11 from Swede). The dose of IdeS was 0.25mg/kg(USA) & 0.25-0.5 mg/kg (Sweden)given by IV four 4-6 hours before transplantation. Cross-match & DSA repeated on 6-24 hours & on 7,30,60,90, & 180 days.
In Sweden cohort all use eATG( 4 doses post transplant) for induction while USA cohort use alemtuzumab(30 mg S.C. 4 days post transplant), also IVIG 2g/kg on day7-14 post transplant & rituximab 375mg day 14-21 for recipients who didn’t receive it before transplantation.
All patients receive antibiotic to prevent infections. graft biopsy done when there is graft dysfunction in addition to protocol biopsy at 6 weeks for both cohorts.
Conclusion:
Using of pre transplantation IdeS in highly sensitized recipients is effective in reducing or disappearing of DSA with good renal outcome up to 1.5 years.
The out come different in 2 cohort due to:
IdeS is highly specific IgG degradation enzyme that causing failure of Ab recognition by specific opsonization proteolytic cleavage of one IgG heavy chain can prevent IgG mediated action.
Side effects of IdeS; infusion reaction, head ache, dizziness, myalgia, serious bacterial infection, and elevated liver enzymes.
Methods
Two subsequent studies examined the effectiveness and safety profile of the streptococcal IgG endopeptidase IdeS , one conducted in the United States and one conducted in Sweden, in highly sensitized patients.
Eligible patients
-18 to 70 years of age
-Undergoing dialysis for ESRD
-Awaiting kidney transplantation
-Highly sensitized- Median c-PRA >95%
-IdeS was given 4-6 hours before transplantation at a dose of 0.24-0.5 mg per kilogram of body weight.
-Cross-match and DSA tests done at 6 hours, 24 hours and on days 7, 30, 60, 90 and 180 only in USA.
-Induction therapy used in Swedish arm – horse ATG- for 4 days- and Alemtuzumab in the American arm at dose of 30 mg/kg day 4 after transplantation.
-Patients were maintained on tacrolimus, MMF, corticosteroids in both groups.
-American arm received rituximab and IVIG post-transplantation to avoid DSA rebound.
-Renal biopsy was performed in renal function deteriorate and at 6 months posttransplantation .
-No DSA were detected immediately after transplantation.
-Over 6 months period of follow-up, acute antibody mediated rejection occurred only in 10 patients with good response to treatment.
-Graft loss occurred only in1 patient due to non-HLA IgM and IgA antibodies.
Conclusions
The data in this study reported that administration of IDES showed a significant reduction in levels of IgG HLA alloantibodies and DSA in 24 of 25 patients.
IgG endopeptidase can be used as salvage for induction of transplantation of non-transplantable high-risk patients who are running out of accesses, intolerant to HD or develop dialysis-related complications.
Data from healthy volunteers showed no signal for an increased incidence of infection associated with IdeS infusion.
No deaths occurred in this study.
Monthly monitoring for CMV, EBV polyomavirus type BK, and JC viremia was negative.
Mechanism of action
The IgG-degrading enzyme derived from Streptococcus is a recombinant cysteine protease of S. pyogenes produced in Escherichia coli that cleaves all four human subclasses of IgG with strict specificity.
What are the side effects of therapy?
The use of Ides is associated with systemic and local side effects. Local side effects include pain and reaction at infusion site infections. Systemic side effects like increase risk of infection and sepsis. Other side effects include elevated LFTs, muscle aches, flushing and headache.
Can you explain the difference in the outcome between the Swedish and the American arms?
The difference in the outcomes between American and Swedish arms is related to differences in many aspects.
-Recipients in the American arm had longer cold ischemia time which is associated with increased risk or rejection, complement cascade activation, and development of non-HLA antibodies.
-Patients in the American study were at higher risk of rejection comparing to the Swedish group, as cPRA in the American arm was 96% comparing to 81 %.
-DSA MFI was significantly higher for HLA class I in the American arm vs Swedish arm.
-Higher doses of IdeS were used in the Swedish arm
-Different induction regimen between both arms
-Although same maintenance therapy was used but the target tacrolimus levels were different.
Summarise the methodology and the conclusion of this study in your own words.
What is the mechanism of action of this drug?
What are the side effects of therapy?
Can you explain the difference in the outcome between the Swedish and the American arms?
1- Longer cold ischemia time in American arm when compared to Swedish arm
2- Although both groups are highly sensitized high-risk patients, but American arm include higher-risk patients as PRA in the American arm was 96% while in the Swedish arm it was 81% and DSA MFI was significantly higher for HLA class I in the American arm when compared to the Swedish arm.
3- Difference in IdeS dosing regimen between both groups, American arm use one
dose while the Swedish arm use one or 2 doses
4- Different induction regimen between both arms (horse ATG is not subjected to cleavage by IdeS)
5- Different target trough for tacrolimus between both arms
Summarise the methodology and the conclusion of this study in your own words.
Methodology:
Settings & Design: combined data from 2 separate open-label, single group, phase 1-2 studies investigating the efficacy and safety of IdeS to reduce or remove DSA. the studies were performed independently at Cedars-Sinai Medical Center , Los Angeles, and at the Uppsala University, Uppsala, Sweden, and Karolinska Institutet , Stockholm.
Patients: A total of 25 patients( 14 from US and 11 from Sweden), 18-70 years old, awaiting kidney transplantation, highly sensitized( cPRA 95%), had clinically significant sensitization history.
Exclusion criteria: patients who do not meet the above inclusion criteria.
Ethical approval: The US study was approved by the Institutional review board at Cedars-Sinai Medical Center. The Swedish study was approved by the Uppsala regional ethics committee and Swedish Medical Product Agency.
Intervention: IdeS was administered IV ( 0.24 mg/kg( US study), or 0.25 mg/kg or 0.5 mg/kg( in Sweden study) on day 0, 4-6 hours before transplantation. XM and DSA testing were done at 6 hrs, 24 hrs and on days 7, 30, 60, 90( on the US) and 180 ( in the US) after treatment.
Induction therapy was ATG in Sweden and Alemtuzumab on the US studies. both continue to receive standard maintenance immunosuppression. All receive prophylactic AB. Renal allograft biopsy was done when there is allograft dysfunction and protocol biopsies were done 6 months post transplant in both studies.
Results: there was a significant reduction in IgG HLA antibodies and DSA after treatment with IdeS, these findings allow successful transplantation of 24/25 patients.
Conclusion:
The administration of IdeS before transplantation in highly sensitized patients appears to be effective way to eliminate DSA and allow transplanting highly sensitized patients.
What is the mechanism of action of this drug?
It cleaves all four human subclasses of IgG with strict specificity.
What are the side effects of therapy?
Can you explain the difference in the outcome between the Swedish and the American arms?
In Swedish study:
In US study:
Summarise the methodology and the conclusion of this study in your own words.
Methodology-
2 separate open-label,single-group, phase 1–2 study performed independently at Cedars–Sinai Medical Center, Los Angeles, and at Uppsala University, Uppsala, Sweden, and Karolinska Institutet, Stockholm.
Eligible patients were CKD 5D patients with age between 18 to 70 years.
All the patients had extensive sensitization, with a median calculated panel-reactive antibody level of 95%.
Also had a clinically significant sensitization history.
Acceptance criteria for HLA incompatible organ in receiepient was –
a negative complement-cytotoxicity cross-match
a negative flow-cytometric cross-match
a positive T-cell and B-cell flow-cytometric cross-match with approximately 250 channel shifts or less
donor-specific antibody positivity.
A total of 25 patients (14 patients in the United States and 11 in Sweden) met the criteria.
Patients who underwent transplantation received IdeS at a dose of 0.24 mg per kilogram of body weight (in the United States) or at a dose of 0.25 mg per kilogram or 0.50 mg per kilogram
(in Sweden)
Patients in the Swedish cohort received induction with horse antithymocyte globulin for 4 days
after transplantation. Patients in the U.S. cohort received induction with alemtuzumab, at a dose of
30 mg administered subcutaneously 4 days after transplantation.
Patients in the US study also received IvIg and Rituximab either pre transplant or post transplant .
Outcome analysed-
adverse events
donor-specific antibodies
renal function
rejection pathology on renal biopsies done for allograft dysfunction or protocol biopsies.
Conclusion –
Ides is effective in reducing or eliminating donor-specific antibodies, a strategy that may improve transplantation rates among patients with HLA incompatibility.
What is the mechanism of action of this drug?
Ides is a cysteine protease derived from the immunoglobulin G (IgG)-degrading enzyme of
Streptococcus pyogenes that cleaves the heavy chains of all human IgG subclasses but no other
immunoglobulins. The cleavage of IgG leads to elimination of Fc-dependent effector functions,
including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC). By cleaving all IgG,
Ides reduces the level of DSA, thus enabling transplantation.
What are the side effects of therapy?
Infections and infestations- bacterial and fungal
Blood and lymphatic system disorders- anaemia
Immune system disorders – transplant rejection
Nervous system disorders – dizziness, headache
Eye disorders- scleral haemorrhage, visual impairment
Cardiac disorders- sinus tachycardia
Vascular disorders- flushing, hypertension, hypotension
Respiratory, thoracic, and mediastinal disorders- dyspnoea
Skin and subcutaneous tissue disorders- rash
Musculoskeletal and connective tissue disorders – myalgia
General disorders and administration site conditions- infusion site pain
Investigations – Alanine aminotransferase (ALT) increased; Aspartate aminotransferase (AST) increased.
Can you explain the difference in the outcome between the Swedish and the American arms?
In the US arm IVIg which contains neutralising antibodies against Ides, which may inactivate Ides if
IVIg is given before Ides was given within one month prior of Ides. The half-life of IVIg (3-4 weeks) should be considered before Ides administration to patients treated with IVIg.
Also The levels of tacrolimus in blood were maintained at 10 to 12 ng per milliliter in the Swedish study and at 8 to 10 ng per milliliter in the U.S. study, the lower target level of tacrolimus in the first three months could have contributed.
Also recipients in the U.S. study had a
significantly longer cold ischemia time
significantly higher rate of delayed graft function,
significantly higher levels of class I donorspecific antibodies than those in the Swedish study.