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FAQS IMBG2019-03-22T14:39:49+01:00

ABOUT IMMUNOBIOGRAM®

What is INMUNOBIOGRAM®?2019-03-22T10:07:27+01:00

INMUNOBIOGRAM® (IMBG) is an In Vitro Diagnostic (IVD) immunoassay that combines a biotechnological KIT and a software for data interpretation and report elaboration.

IMBG provides information that will help physicians to personalize the immunosuppressive therapy in patients with inflammatory diseases, and help them to take informed decisions to select the most adequate immunosuppressive drugs (IS) for each patient to improve clinical outcomes.

IMBG offers a personalized comparative evaluation of the patient´s sensitivity/resistance profile to a panel of the most commonly used IS in clinical practice, allowing physicians to predict and monitor the patients‘ response to a specific IS.

The immunoassay is performed with a 10 ml peripheral blood sample, and allows to measure the response of immunologically stimulated PBMCs to a panel of  IS used for the treatment of an inflammatory disease in clinical practice. PBMCs are included in a hydrogel that is distributed into several channels in a plate, and IS delivery devices are placed in the edge of those channels. The hydrogel is capable of generate a spontaneous IS concentration-gradient due to a passive-diffusion process. An indicator of cell-proliferation/viability reveals the capacity of IS-gradient to inhibit the patient´s immune activation cells state.

INMUNOBIOGRAM® has been designed to test the patient´s profile of sensitivity/resistance to each immunosuppressant as a tool that, taken together with other important variables, can help physicians to make more precise therapeutic decisions.

Which is the added value of the INMUNOBIOGRAM® (IMBG) in immunological disorders?2019-03-22T10:08:53+01:00

Precision Medicine is the current major trend to maximize health outcomes in chronic medical conditions. This means that the time of “one drug for all” is over, instead, human diversity responses must be considered. Different patients need different drugs, and this is the driver of new medical management.

Chronic inflammation is the “poor sister” of the big human diseases family. Infectious diseases, cancer, and many other diseases have been managed under precision medicine protocols for decades. Culture and antibiograms are mandatory to prescribe antibiotics, and nowadays nobody thinks of cancer treatment without biomarkers and targeted therapies. On the contrary, chronic inflammation remains treated with immunosuppressive drugs mostly based on clinical guidelines, drug blood levels and trial/error approaches.

Inflammatory diseases are clearly lacking a tool to determine the potency (efficacy) of immunosuppressive drugs over the immune cells of the patients, which are actually the target cells of the immunosuppressants/ immunomodulators. This assay is able to identify those immunosuppressants that may be more efficacious for each patient at a specific point in time.

What is the rationale behind the INMUNOBIOGRAM® (IMBG)?2019-03-22T10:13:03+01:00

The logic behind IMBG resembles the one of an antibiogram, a pharmacodynamics in vitro bioassay that evaluates the usefulness of different antibiotics to treat a specific infection in a patient. The antibiogram is extensively used in clinical practice, as a very valuable tool in guiding antimicrobial therapy for each patient. It provides the profile of susceptibility or resistance patterns of pathogens to commonly used antimicrobials.

Previous scientific studies have shown that “cellular pharmacodynamics of immunosuppressive drugs is an efficient strategy to predict the clinical efficacy of drugs in many immunological disorders and organ transplantations. Unexpectedly large individual deviations in PBMC sensitivity to the drugs, paralleled with deviations in the clinical efficacy of the drugs have been observed in most cases of immunological disorders”

“Therefore, the examination in vitro of drug sensitivity before drug administration can be a valuable tool to predict the clinical efficacy of drugs in these patients” (Hirano T, 2007)

How does the INMUNOBIOGRAM® (IMBG) works?2019-03-22T12:54:43+01:00

IMMUNOBIOGRAM® is an endpoint bioassay. It is done with a 10 ml peripheral blood sample per patient. The readout of the bioassay translates in numbers the inhibition of the patient´s T cells proliferative response after exposure to each immunosuppressive drug.

This bioassay is done with a sample of 3D cell culture of PBMCs, some are physiologically stimulated (control +) and the other are not stimulated and serve as control (control -).

A hydrogel containing the PBMCs is loaded in longitudinal channels and immunosuppressive drugs (IS) delivery devices are placed at the edge of the different channels.  In each channel an IS concentration gradient takes place due to a passive diffusion process.

After 18-20h of exposure to IS, an indicator of cell proliferation/viability reveals the capacity of IMSs gradient to inhibit the activation of T cells. A quantifiable signal is obtained and properly measured with fluorimetry.

A mathematical model and a software for the data interpretation has been developed to

evaluate the IMBG dose/response curves to IS, and toperform a cluster analysis of patients based on this cellular response.

Overall, this software can qualify the patient´s sensitivity /resistance profile to each IS tested.

How long does it take the INMUNOBIOGRAM® (IMBG) procedure?2019-03-22T12:55:43+01:00

The whole IMBG procedure takes 3-4 days, plus the time needed for the physiological stimulation of LT cells, which depends on the immunological state of each patient (4-5 days time frame).

Which are the requirements to perform the IMMUNOBIOGRAM® (IMBG)?2019-04-01T17:51:55+01:00

The whole IMBG procedure takes 3-4 days, plus the time needed for the physiological stimulation of LT cells, which depends on the immunological state of each patient (4-5 days time frame).

-LAB COMPONENTS

Cell incubator (37ºC, 5% CO2), biosafety cabinet for cell culture and blood processing, microscope, centrifuge, small bath, and a fluorimeter. In addition, all small devices and  components for cell manipulation.

-SPECIFIC NEEDS

To process de IMBG NO specific instrument is needed. Any standard clinical lab can run the test, provided they follow the “instructions” included in our CE Mark and ISO 13485 Quality Certification.

-CONTAMINATION PROBLEM

In order to keep sterility and workers’ safety during the IMBG process, it is necessary to work within a biological safety cabinet, to sterilize all the materials, to filter all the reagents and to ensure a proper hygiene and training of lab technicians. In case of a cultured PBMCs’ contamination, the sample should be discarded to avoid a potential influence on the IMBG-test’s results.

-BIOSAFETY CABIN

A biosafety cabin is absolutely required. Not only to prevent sample contamination from the operator, but also for the operator safety considering that blood samples are potentially hazardous.

-WHICH QUALIFICATION IS REQUIRED FOR A LAB TECHNICIAN? 

The Laboratory Technician, should have a basic/mid-level knowledge or experience in a laboratory setting and in cell culture management. Under Biohope supervision, only one month is needed to train a lab technician to run the test.

Which is the differential value of the IMMUNOBIOGRAM® (IMBG) technology?2019-04-01T17:51:24+01:00

Some papers support that the study in vitro of the pharmacodynamic effect of IS on stimulated PBMCs derived from each patient, can provide a useful way to differentiate patients in relation to who shows clinical resistance to immunosuppressive therapies.

Previous approaches have not evaluated all IS within the same bioassay (experiment) and do not use methods easy to commercialize. They use 96-Well Assay Plates and progressive dilutions of IS to test the effect over PBMCs. That severely complicates the handling and evaluation of up to 7 IS in terms of time and costs. Results also rely on the discrete number of concentration points of the same drug (predefined by the researcher) and not in a continuous concentration gradient, so it is complicated to build reliable dose/response curves. Further, this approach provides much variability in results with little precision, and difficult to standardize.

The value of IMBG relies on the design of a biomodel that:

  • Simplifies considerably the IS efficacy evaluation in terms of handling, costs and time.
  • Simultaneously adds precision and robustness.
  • Allows IMBG to be interpreted also considering clinical variables.

IMBG is a model similar to the antibiograms used in the infectious diseases to guide the prescription of antibiotics.

This biomodel is based on:

  •  A novel design of a “channeled well”, a 3D semisolid matrix to hold the PBMC culture, and a simple device to release the IMs into the cell culture. These are the basis for our patent, which was published by the European Patents Agency in January 2019.
  • The development of a biotech standardized method (IVD) to quantify this effect in a valid, reliable and comparable way
  • The development of mathematical algorithms that evaluate dose/response curves AND are capable of clustering patients in sensitive/resistant groups combining biological results with clinical data

Altogether, IMBG has become an innovative in vitro immune assay that combines a biotechnological kit and a software for data interpretation that currently cannot be duplicated in a normal reference lab unless having access to all the biotechnological and mathematical development proven by Biohope.

Which clinical studies have been performed and what are the next steps in the IMMUNOBIOGRAM® clinical development?2019-04-01T17:50:47+01:00

IMBG has being studied in KIDNEY TRANSPLANT under a comprehensive clinical plan program, which includes a first proof of concept clinical study in 70 patients (BH-PILOT STUDY 2015), and in a multicenter international validation study, to be finished in 2Q 2019 (TRANSBIO STUDY). The BH-PILOT STUDY 2015 and the TRANSBIO STUDY will ensure that the IMMUNOBIOGRAM®  is ready for implementation in a clinical laboratory and reproducible.

IMBG is also being studied in RHEUMATOID ARTHRITIS under a clinical plan program, which includes an ongoing first proof of concept clinical study in 100 patients (BH-PILOT STUDY 2018 IN RHEUMATOID ARTHRITIS).  This clinical study aims to evaluate the feasibility and clinical utility of a specifically-developed IMBG for Rheumatoid Arthritis.

It is foreseen to conduct a subsequent validation multicenter and international study in Rheumatoid Arthritis.

The clinical program has been designed to cover the essential aspects of the technology for the IMBG to be used in a reliable way. It is very important to consider that IMBG is not aimed to guide directly the physician prescription. The kit offers efficacy/potency information to be considered along with epidemiological, immunological, clinical and pharmacokinetic variables, which altogether combined, will drive the decision.

 

Bibliography2019-03-06T18:09:31+01:00

Hirano T. Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine. International Immunopharmacol 2007, 7: 3-22

Kurata Y, M Kato, T Kuzuya, Y Miwa, K Iwasaki, M Haneda. Pretransplant Pharmnacodynamic 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. Transplantation. 1988 Dec;46(6):853-7.

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