ABOUT IMMUNOBIOGRAM® RT
IMMUNOBIOGRAM® (IMBG) is an In Vitro Diagnostic immunoassay that combines a biotechnological KIT and a software for data interpretation.
IMBG is a service provided by BH that will help physicians to adapt the immunosuppressive drugs (IS) in patients with Rheumatoid Arthritis (RA), allowing to select for each patient the most adequate IS and doses to reach clinical remission and reduce the side effects of treatment.
IMBG offers a personalized comparative evaluation of patient sensitivity/resistance profile to a panel of IS most commonly used in RA in clinical practice, allowing to predict and monitor patients‘ response to IS and supporting clinicians to take informed decisions to optimize the immunosuppressive therapy
Kidney transplantation is the treatment of choice for patients with end stage renal failure. It has by large demonstrated to improve patients QoL and decrease treatment costs.
However, these patients have a persistent risk of graft rejection due to immune-mediated kidney injury. The immune system of the recipient can recognize as strange the donor-specific- antigens expressed by the graft, mainly from the human leukocyte antigen (HLA) complex (alloantigens). An alloimmune response is developed in the recipient against the donor graft alloantigens that is responsible for graft tissue damages, and can lead to the failure of the transplanted organ.
To limit the risk of rejection, transplanted kidney patients require long term treatment with different immunosuppressive drugs (IS) and doses. Treatment with IS has driven overall improvements in graft survival, mainly during the first-year after kidney transplantation, but long-term survival has improved only slightly over decades. Recent data from registers show that graft failure at 10 years from transplant occurs in about 57 % patients in USA (Annual Report 2018 USRDS) and in about 50% in Spain, (Registre de malalts renals de Catalunya) (deceased donors, unadjusted).1,2,3,4
On the other hand, immunosuppression can lead to different side effects that cause a substantial clinical burden for the patients, and negatively affect patient and allograft survival, metabolic toxicities (hypertension, hyperlipidemia, diabetes, bone loss), and serious adverse events like malignancies and opportunistic infections.
Currently, prescribed IS regimens are based on standard clinical guidelines, drug blood levels and empirical use. There is a lack of biomarkers to help health professionals to stablish a personalized therapeutic immunosuppression plan for each patient according to the individual response profile to IS.
IMBG has been developed to test the patient´s profile of sensitivity/resistance to each immunosuppressant. It is a tool that, taken together with other important variables, can help physicians to make more precise therapeutic decisions, and contribute to decrease the risk of rejection due to under-immunosuppression, and decrease the burden of IS adverse events due to over-immunosuppression.
The search for predictive markers associated with allograft rejection is a key focus in transplant research. Post-transplant monitoring relies mainly on serial serum creatinine (Cr) measurements and in biopsies.
- Serum Creatinine level is a highly insensitive indicator of the degree of damage in the kidney. It has a lag time ranging from weeks to months while on-going damage is occurring, and changes are non-specific with regards to the cause of the injury.
- Surveillance biopsies are the gold standard to detect graft rejection, but they are performed infrequently after kidney transplantation. Biopsies are invasive, expensive, and subject to inter-grader variability; performing invasive biopsies is not suitable for frequent monitoring.
- To date, the only validated and accepted marker by the clinical community is the -de novo – appearance of DSA (Donor Specific Antigens), which advises about the risk of graft rejection.
- Currently there is no validated test to measure or monitor the adequacy of the immunosuppression regimen. The failure of the regimen may result in under-immunosuppression and cause graft rejection, or in over-immunosuppression and increase the risk of opportunistic infections and malignancies.
- Immuknow® is an IVD approved by the US Food and Drug Administration (FDA) (not in the EU) under the 510K pathway in 2002. This bioassay quantifies the amount of intracellular ATP that is released from CD4+ T cells in response to a non-specific mitogenic stimulus. It only identifies if there is a certain risk of rejection (due to underimmunosuppression), but it doesn´t provide a specific result regarding the sensitivity/resistance profile of each patient to the IS they are taking.
- Other tools (like Trugraf) that test on gene-expression “signatures” have been developed, but again only identify if there is a certain risk of rejection, and only differentiate between a state of transplant eXcellence (TX= adequately immunosuppressed) from not-TX
- Molecular biomarkers have been studied in the graft, urine and blood of kidney transplant recipients, but recent reviews have highlighted the need for robust multicenter validation studies, while underscoring the potential role for biomarker monitoring of immunosuppressive therapy and transplant outcomes. They are not used in daily clinical practice (Menon 2017).
Significant progress has occurred over the decades in renal transplantation, mostly driven by improvements in short-term (one year) graft and patient survival. Further improvements in long-term survival have to come through improvements in long-term graft maintenance.
The multifactorial nature of chronic renal allograft loss makes specific interventions difficult. In the absence of any good tools to individualize immunosuppression to each patient, modest progress has occurred in long-term graft survival. An individualized immunosuppression regimen based on the patients´ response to IS can contribute notably to decrease graft rejection rates and to avoid the appearance of severe adverse events.
IMBG has been initially tested in an observational, proof of concept study, which included patients with kidney transplant and with proven bad clinical evolution due to active rejection mechanisms, and patients with good clinical evolution.
We have two studies in place:
- BH Pilot 2015: published results show that there is a direct correlation between high risk patients (patients with active rejection mechanisms) and drug resistance in IMBG, as well as there is a correlation between low risk patients and drug sensitivity patterns.
- TRANSBIO study: it is an ongoing international study that will allow to test the correlation between drug resistance in IMBG and bad clinical evolution (defined as a progressive deterioration in renal function plus rejection signs in biopsy or an increase in DSA strength by Luminex). Also, it allows to test a correlation between drug sensitivity in IMBG and good clinical evolution (patients without rejection episodes, negative DSA, stable renal function and no changes in treatment). IMBG reproducibility will be also tested.
BH-PILOT STUDY 2015 and TRANSBIO STUDY will allow to ensure that IMBG is ready for implementation in the clinical laboratory and reproducible. TRANSBIO will allow to compare IMBG in kidney transplanted patients with good vs bad clinical evolution.
Additionally, 2 local studies are planned to be conducted during 2019/2020. The first one will allow to get prospective data about the clinical evolution of the patients included in BH-Pilot 2015 and to analyze the correlation between the sensitivity/resistance profile detected in IMBG and the patients´ clinical evolution 2 years later. The second one will compare the IMBG from the same patients when performed from a fresh or a frozen blood sample and between two different centers.
BH-Pilot 2015 was a clinical study performed during 2015-2016 in “La Paz” and “Puerta de Hierro” University Hospitals (Madrid). The study included 70 patients at least 1 year after the renal transplant (immunosuppression maintenance period). They were classified into three categories depending on their immunological risk evaluation:
- High-risk patients (history of rejection, positive HLA antibodies, impaired renal function, or any combination of the previous criteria)
- Controlled patients (with conventional maintenance immunosuppression)
- Low-risk patients (lack of risk criteria and treated with low levels of IS for years).
Data of patients’ clinical and immunological history were collected; an extensive battery of biomarkers (proteomics, metabolomics and cell phenotyping) was performed to complement the risk information, and 10 ml of blood was taken to be tested with the IMBG
The study outcomes indicated a positive proof of concept for the IMBG that can be summarized in the following points:
1) IMBG provides an individualized patient response pattern to immunosuppressive medication.
2) Sensitivity ranges can be determined in each patient for each of the drugs and doses tested.
3) Significantly associated low-sensitivity patterns to IMSs in IMBG have been observed in patients with high risk-profile who present worse clinical evolution.
4) Patients with a low-risk profile show better sensitivity scores to IS in IMBG compared with standard patients and high-risk patients.
The classification of the immunoassay profiles can be reproduced accurately by a neural network and be completely automatized.
The outcomes of the study indicate that the IMBG enables the measurement of the sensitivity/resistance profile of patients to immunosuppressant medication, and can detect patients with bad prognosis due to IS low sensitivity.
In the TRANSBIO study bad clinical evolution will be considered when patients show a progressive deterioration in renal function (with a significative increase of creatinine and/or proteinuria), show signs attributable to any kind of immunological response compatible with a rejection in biopsy, or an increase in strength of DSA expressed as Luminex MFI and with titters of more than 3000 UI.
Good clinical evolution will be considered for patients without rejection episodes, with a negative DSA, with a stable renal function and with no changes in their treatment.
In September 2017 a meeting was held with the main investigators of the TRANSBIO validation study and very positive feedback was received. The attendees were 7 renowned nephrologists of the following hospitals in Europe and USA:
- Hospital Puerta de Hierro (Spain)
- Hospital Vall d´Hebron (Spain)
- Hospital del Mar (Spain)
- Hospital La Paz (Spain)
- Universitätsklinikum Essen (Germany)
- Medical University Borowska (Poland)
- University Hospital of Copenhagen (Denmark)
- Massachusetts General Hospital, Harvard Medical School (Boston).
During the TTS 2018 congress presentation encouraging comments from several top KOL ( Charité Universitätsmedizin Berlin, Germany; University Hospitals Leuven, Belgium; Necker Hospital in Paris, France) were received.
The TRANSBIO study results will be discussed in an investigator meeting during ESOT 2019
Find attached the link to clinicaltrials.gov, where main milestones of the study are described
Final results from the BH-PILOT STUDY 2015 were first presented at the 27th International Congress of the Transplantation Society, TTS 2018 (1-5th July, Madrid) by Prof. Julio Pascual from Hospital del Mar, Barcelona: “IMMUNOBIOGRAM® : A Novel Precision Medicine Tool to Help Guidance of Immunosuppression in Renal Transplantation. Results of “BH-Pilot 2015” Proof-of-Concept Clinical Study”
A poster and an oral communication were presented at the 5th European Congress of Immunology 2018, (2-5th September 2018, Amsterdam).
Oral presentation: ‘IMMUNOBIOGRAM® a new immunological tool to personalize immunosuppressive therapy in kidney transplant recipients”.
Poster: “IMMUNOBIOGRAM® as a diagnostic assay for detection of resistance to immunomodulatory treatment in patients with chronic inflammatory diseases”
An abstract was presented at the Basic Science Transplantation Congress BST 2018: “IMMUNOBIOGRAM®: a new immunological tool to personalize immunosuppressive therapy in kidney transplant recipients”, that took place in 11-13 October 2018, Rotterdam.
Final results of the TRANSBIO STUDY in RENAL TRANSPLANTATION are to be presented in 2019/2020 in the European Society for Organ Transplantation Congress (ESOT), American Transplant Congress (ATC), and the International Congress of The Transplantation Society (TTS).
It is planned to publish a paper with the results of the BH-PILOT and TRANSBIO studies.
The clinical program has been designed to cover all the essential aspects of the technology to generate the data needed for the IMBG to be used in a reliable way. It is very important to consider that IMBG will NOT directly guide the physician prescription. The IMBG offers efficacy/potency information to be used with epidemiological, immunological, clinical and pharmacokinetic (TDM) variables, which altogether combined, will drive the decision.
To improve patients showing a RT hard outcome (in terms of graft failure or proven signs of immune rejection by a biopsy) the physician will have to consider not only the clinical decisions about the IS regimen to be used, but also a pool of epidemiological (ie donors age, type-death or living donor-, recipient characteristics), clinical, and immunological variables (ie level of HLA mismatch, dnDSA appearance). Clinical decisions have always been made taking into account these important variables, and pharmacodynamic (IMBG) and pharmacokinetic (TMD) data will complement them, and help physicians to make more precise therapeutic decisions.
The test has been clinically tested in patients after more than one year of the transplant. The reason is that currently the major challenge for clinicians is to improve the graft survival after one year, reducing the risk of chronic allograft injury due to rejection, and avoiding at the same time immunosuppressive adverse effects like infections and malignancies. It is planned for the IMBG to be tested as well for its use in patients before transplantation.
It can be used to identify and monitor patients at risk of rejection (who might require an increase of immunosuppression or a change in the immunosuppressive regime prescribed), and in patients with low risk to profit from a gradual reduction of immunosuppression and avoidance of severe side effects.
Estimated monitoring frequency will depend on the patient profile. An IMBG should be done to all patients at baseline, once the immunological system has got stabilized after the induction therapy (6 months post RT). In the maintenance phase it is estimated that 1 IMBG per year should be performed in high immunological risk patients. Patients who present immunological events (ie. dnDSA) or adverse events which can lead to a change in immunosuppressive regimen can require an additional IMBG before undertaking a treatment change. The development of de novo (dn) DSA beyond one-year post-transplantation has been demonstrated to be strongly associated with graft loss through antibody-mediated rejections, and is often related with underimmunosuppression.
The rationale behind the IMMUNOBIOGRAM® (IMBG) resembles the one of an antibiogram, a pharmacodynamic in vitro bioassay which evaluate the usefulness of different antibiotics to treat a specific infection in a patient. Antibiogram is used extensively in clinical practice, as it is a very valuable tool in guiding antimicrobial therapy for each patient. It provides the profile of susceptibility or resistance patterns of pathogens to antimicrobials commonly used. Even though some antibiotics can have synergistic actions, this synergy can take place at different levels: it can be related with their mechanisms of action, with their pharmacokinetic and pharmacodynamic issues like cytochrome P450 isoenzyme liver metabolism, with their route of elimination and with other factos. Therefore, it is not possible to predict their whole synergistic potential only based on the analysis of their combination in vitro.
An antibiogram does not test the combination of antibiotics. Final antibiotic selection is decided by taking into account the pathogen susceptibility to each antibiotic from the antibiogram and selecting those with a better potential combination in clinical practice.
A concomitant evaluation of pharmacodynamics and pharmacokinetics of the drugs can be an advisable tool to perform successful patient-tailored immunosuppressive therapy.
Even so, as it is possible to study in vitro the effect of IS combinations with the IMBG, combinations of them will be tested in a further step as a complementary information.
The immunosuppressive drugs tested by the IMBG in renal transplantation are the following:
- Mycophenolate mofetil
The IMBG has been clinically tested in the renal transplantation maintenance period (after >1 year post RT). The reason is that currently the major challenge for clinicians is to improve the graft survival after one year, reducing the risk of chronic allograft injury due to rejection and avoiding at the same time immunosuppressive adverse effects like infections and malignancies. Graft survival during first year has reached very good results.
That´s why the IS tested in IMBG are Tacrolimus, Cyclosporin, Mycophenolate, Sirolimus, Everolimus, Azathioprine and Methylprednisolone, which are the ones used for renal maintenance therapy in clinical practice.
It is planned to test the use of the IMBG in patients just before transplantation in the near future. The inclusion of the IL-2 inhibitor products will be approached in this phase of IMBG development.
A report will be provided with the patient´s sensitivity/ resistance profile to each of IS tested.
Results are obtained by clusterization in categories under a semi-quantitative method, which includes the result of the bioassay and some common clinical data.
The IMBG is not meant to replace the therapeutic drug monitoring (TDM), as TDM measure pharmacokinetics of the drugs but gives no information about the pharmacodynamic effect of them in the immune system. A concomitant evaluation of pharmacodynamics and pharmacokinetics of the drugs can be an advisable tool to perform successful patient-tailored immunosuppressive therapy.
The IMBG can support clinicians in the selection of the optimal combination/posology of immunosuppressant drugs and it will be a complementary tool to TDM, which allows that a selected drug reaches in blood the therapeutic levels needed to be effective.
Biohope expects to achieve CE marking Self-Certification on June 2019, as the company will accomplish all the needed legal requirements. The TRANSBIO study results (ongoing International Study) will be more than enough to get it by that date. We also have a QA team fully dedicated to the development of the technical file regarding our Kit, which will be produced according to the already in place ISO13485 standard.
Biohope expects to present the IMBG file for FDA approval in 2020.
We expect the IMBG will be available in 1Q 2020
A pharmacoeconomic model has been developed to estimate the potential impact of the IMBG in clinical outcomes and cost savings in the follow-up period of patients with RT. Cost savings are expected to happen :
- In patients with high immunological risk that show low-sensitivity patterns to the IS they are taking . They will benefit from a change in IS regimen to decrease the graft rejection risk.
- In patients with good clinical evolution and a high sensitivity pattern their IS regimen. They will benefit from dose adjustments/reductions to decrease the risk of IS adverse reactions like metabolic disorders, opportunistic infections or malignancies.
The pharmacoeconomic model was based in the following assumptions:
- Probabilistic second-order Monte Carlo simulation
- Hypothetical cohort of 1,000 patients 1 year after renal transplantation
- Spanish NHS Perspective
- Time horizon of 5 years
- Only Direct Costs are included*
- All model assumptions were validated by a Spanish clinical experts’ panel
Direct costs associated with graft failure (dialysis, retransplantation), IS therapy, and Adverse Events management were obtained from Spanish sources
Key results of the analysis were
- The use of the the IMBG would entail a potential risk reduction of graft failure with a saving of costs per HR patient in 5 years of € 20,279 (95% CI € 17,512-23,105) and a 100% saving probability
- The use of the IMBG would entail an expected reduction in the AE rate that would generate savings per non-HR patient in 5 years of € 3,328 (95% CI € 451-7,957) and a 99.5% saving probability
This pharmacoeconomic model will be presented in the next congress of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR 2019)
This model can be easily adapted for different countries and health care systems as long as data of transplantation maintenance costs are available
- E. Lamb, S. Lodhi and H.-U. Meier-Kriesche Long-Term Renal Allograft Survival in the United States: A Critical Reappraisal. American Journal of Transplantation 2011; 11: 450–462
- Wang JH, Skeans MA, Israni AK. Current Status of Kidney Transplant Outcomes: Dying to Survive. Adv Chronic Kidney Dis. 2016 Sep;23(5):281-286.
- Trends in 1-, 5-, & 10-year kidney transplant graft survival, 1999-2015 (unadjusted) USA- Anual Report 2018. USRDS Figure 6.25. Volume 2: End-Stage Renal Disease in the United States. Accessed on January 2019
- Registre de malalts renals de Catalunya. Informe estadístic 2016. Barcelona: Servei Català de la Salut. Organització Catalana de Trasplantaments (OCATT)
- Madhav C. Menon, Barbara Murphy, and Peter S. Heeger. Moving Biomarkers toward Clinical Implementation in Kidney Transplantation. J Am Soc Nephrol 2017 28: 735–747
- Kurata Y, M Kato, T Kuzuya, Y Miwa, K Iwasaki, M Haneda. Pretransplant Pharmacodynamic Analysis of Immunosuppressive agents using CFSE based T cell proliferation assay. Clinical Pharmacology & Therapeutics 2009; 86 (3): 285-289
- Gulimire Muhetaer, Hironori Takeuchi, Sakae Unezaki, Shigeyuki Kawachi, Hitoshi Iwamoto, Yuki Nakamura et al.Clinical Significance of Peripheral Blood Lymphocyte Sensitivity to Glucocorticoids for the Differentiation of High-risk Patients With Decreased Allograft Function After Glucocorticoid Withdrawal in Renal Transplantation. Clinical Therapeutic 2014;36 (8): 1264-1272
- Francis DM, Dumble LJ, Bowes L, Clunie GJ, Macdonald IM. Adverse influence of recipient lymphoid resistance to in vitro immunosuppression on the outcome of kidney transplants. 1988 Dec;46(6):853-7.
- Aurelie Premaud, Matthieu Filloux, Philippe Gatault , Antoine Thierry , Matthias Büchler, Eliza Munteanu et al. An adjustable predictive score of graft survival in kidney transplant patients and the levels of risk linked to de novo donor-specific anti-HLA antibodies. PLoS ONE 12(7): e0180236. https://doi. org/10.1371/journal.pone.0180236