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Method for preclinical testing of immunomodulatory drugs

An immunomodulatory drug and drug technology, applied in biological testing, drug combination, immunoglobulin, etc.

Inactive Publication Date: 2012-07-18
THERAMAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] From a broader perspective, known human PBMC cultures do not respond to soluble TGN1412 with cytokine release, suggesting that this system does not respond to agents that activate all lymphocytes in the same way that the intact immune system in humans responds

Method used

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  • Method for preclinical testing of immunomodulatory drugs
  • Method for preclinical testing of immunomodulatory drugs
  • Method for preclinical testing of immunomodulatory drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: Comparative Example

[0060] In order to induce the release of cytokines, the present invention and this comparative example use the standard system of PBMC stimulation because this system is used by researchers all over the world to study the response of human PBMC to immunomodulatory agents. The system uses freshly prepared PBMC, which is separated from heparinized venous blood by centrifugation on a density gradient (Lymphocyte Separation Medium LSM 1077, PAA Laboratories, Pasching, Germany) according to the manufacturer's instructions. Or, using fresh white blood cell concentrate as the raw material for sucrose purification, basically the same result is obtained, where the fresh white blood cell concentrate is used as a by-product in the preparation of platelet concentrate from the leukopenia system (Caridian Gambro BCT) , Lakewood, CO, USA) (Dietz et al., 2006). PBMC were cultured in 96-well tissue culture plates (Greiner bio-one, Frickenhausen, Germany), ...

Embodiment 2

[0065] Example 2: Response by TGN1412 after pre-culture

[0066] for Figure 1B In the test, the PBMC obtained from healthy donors was mixed with 10% in 1.5ml medium in a 24-well flat-bottomed tissue culture plate. 7 / ml culture for 2 days, then rinse and readjust to 10 6 / ml. The same test as described in Example 1 was performed using these cells.

[0067] Figure 1B It is shown that, surprisingly, in the absence of obvious stimulation, the responsiveness to TGN1412 can be restored by simply pre-culturing PBMC for 2 days. When the cells were prepared on December 4, 2008, the number of PBMCs obtained exceeded the number required for this experiment, and the excess cells were stored in culture medium at 37°C for two days. When using these stored cells to perform the same test as previously using fresh cells ( Figure 1A ), something completely unexpected happened: now TGN1412 induces a comparable level of cytokine release such as OKT3. Figure 1B Examples of such tests are provided...

Embodiment 3

[0069] Example 3: Reproducibility of key observations

[0070] figure 2 Summarized the effect of pre-culture on the responsiveness to TGN1412 for 7 individual healthy donors. Data from 7 individual healthy donors are shown, each represented by a symbol. The conditions of antibody stimulation and pre-culture are shown in Figure 1. When there are donor-specific changes in both OKT3 response and TGN1412 response, it is clear that in all cases, fresh donor cells cannot respond to TGN1412 stimulation with cytokine release, and after 2 days of pre-culture This state of refusal disappeared. As illustrated by the huge difference in the level of the cytokine storm experienced by volunteers in the London TGN1412 trial (Suntharalingam et al., 2006), donor-specific changes can be expected.

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Abstract

The invention teaches a method for testing a prospective or known immunomodulatory drug for T-ceil activation, comprising the steps of contacting in-vitro a peripheral blood mononuclear cell (PBMC) culture with a predetermined amount of the prospective or known immunomodulatory drug and observing the PBMC culture for T-ceil activation using a readout system, upon contact with the prospective or known immunomodulatory drug, wherein the ceil density of a PBMC preculture is adjusted such that cell-cell contact of the PBMC is enabled and wherein the PBMC preculture is cultured for at least 12h.

Description

Technical field [0001] The present invention relates to a method for testing expected or known immunomodulatory drugs for T-cell activation, comprising the following steps: in vitro peripheral blood mononuclear cell (PBMC) culture with a predetermined amount of said expected or known immunomodulatory Drug contact; and when in contact with the expected or known immunomodulatory drug, use a readout system to observe the PBMC culture for T-cell activation, wherein the cell density of the PBMC preculture is adjusted so that the PBMC can Cell-cell contact, and wherein the PBMC pre-culture is cultured for at least 12h. The present invention further relates to methods for testing drugs that reduce the cytokine storm in vitro. [0002] In this specification, many documents including patent applications and manufacturer manuals are cited. Regardless of the fact that the contents disclosed in these documents are related to the patentability of the present invention, the entire contents of...

Claims

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Application Information

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IPC IPC(8): G01N33/50G01N33/68
CPCC07K16/2818G01N33/6872G01N33/5044A61P37/00A61P37/06
Inventor 托马斯·许尼希
Owner THERAMAB
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