OUR TECHNOLOGY

COMPIT

Our aim is to develop an in vitro human platform for (co-)cultures of human tissue and immune cells that can be customised to different drug modules to test drug immunomodulatory mechanism and/or immunologic risks.

The Evolving Immunology: Emerging Needs in Preclinical Testing

We focus on two major areas that involve immune response studies:

1. EFFICACY

2. IMMUNE MEDIATED RISK

Experimental immunology is essential in developing therapeutics that are designed to modulate or exert an immune response for example in immuno-oncology. Understanding the immune response is also pivotal in assessing the impact of drug induced tissue damage, a major reason for immune risk. It is important to assess drug impact on tissue because

– It can cause acute cytotoxicity with organ failure

– It can generate an immune response leading to idiopathic (chronic) pathology

The industry is in great need of human-based preclinical immunology platforms. Non-human in vivo testing for drug efficacy testing or toxicology by-passes the translational problems that may be resolved by in vitro human platforms. The percentage of drugs failing at clinical phases for efficacy or risk problems that could be identified at preclinical stage is significantly high.

EFFICACY (immunologic) STUDIES

Small and large molecules are designed to enhance or inhibit immune response in various therapeutic areas such as cancer, autoimmunity or inflammatory conditions. These drugs require a normal or tumour tissue model (e.g. lung, liver, kidney, heart, etc.) to interact with an immune response model to test:

Anti tumour effect

Anti-inflammatory/regulatory effect

Pro-inflammatory progression

Readouts that are usually sought are:

  • Immune checkpoints
  • Dendritic cell maturation and activation
  • T cell activation and Th differentiation e.g. Th1, Th2 and Th17 or Treg
  • Macrophage switch and phagocytic impact

RISK (immunologic) STUDIES

Currently preclinical and clinical studies that are focused on understanding immune related risks are:

Anti-drug antibody (drug immunogenicity)

– Cytokine release syndrome

Cytokine mediated toxicity

– Tissue damage and tissue-specific immune response

– Macrophage polarisation M2-M1

Defining Immunogenicity

“The immune system receives signals to respond from the ‘tissue’ and the immune system is far less concerned with things that are foreign than with those that do damage”

Our Model: COMPIT

Moving towards TRANSLATIONAL IMMUNOLOGY

The COMPIT (Comprehensive In vitro Immune testing) process is designed as a preclinical human-based platform to facilitate and study the interaction of human tissues with immune cells and drug impact on tissues and immune response. This model provides flexibility in conditions that can be customized for efficacy studies or immunologic risk assessment.

The COMPIT Model is based on human cells in co-culture that consists of:

Cells representing a tissue (lung, smooth muscle, liver, kidney, etc.)

Cells of the immune system – Dendritic cells (DCs), T cells, monocytes,  macrophages, B cells

  Primarily, cell lines are used in the model

COMPIT structure

  • Experimental Immune modelling
  • In vitro human cell cultures (tissues, myeloid cells, lymphocytes)
  • Lab on a chip (semi dynamic, migration studies)
  • Tissue viability/damage and cytotoxicity assessment
  • Analysis of markers of immune maturation and activation (immune response)
  • Th response analysis

COMPIT is an in vitro human cell culture based system consisting of various immune and protein assays that can be customised according to an experimental model to study drug efficacy (immunology) or immune safety.

Example of how we use COMPIT in immune safety assessment

Advantages of Cell Line Based Approach

The use of cell lines in initial studies offers the advantage of minimal inter-experimental variability, lower initial cost and ease in reproducibility. We use lymphocytic cell lines for various immune response assays such as dendritic cell maturation, T cell activation, phagocytosis, etc. We are among the few groups who can generate and demonstrate the use of dendritic cells from monocytic cell lines and T cells in activation studies.

Successive experiments are done using primary human cells e.g. PBMCs.

COMPIT READ OUTS

The end-points of COMPIT are read-outs of assays that measure cell or insolubles and solubles in cell extracts or cell fluids. Cell surface receptors, intracellular cytokines or cell secreted proteins are measured through standard methods such as flow cytometry, immuno sorbent assays, immunoblotting method, optical density, immuno/histochemistry, chemiluminescence or mass spectrometry as appropriate and relevant to the experimental design. These along with migratory features are visualised by microscopy imaging. The end assays or functional studies are associated with assessing particular immune responses such as:

  • Dendritic cell maturation and T cell activation
  • T cell proliferation
  • Th differentiation such as Th1, Th2, Th17 or Treg
  • Macrophage polarisation (M1 or M2)
  • Phagocytosis, antibody dependent cellular phagocytosis (ADCP)
  • Antibody dependent Cellular Cytotoxicity (ADCC)
  • Cytokine release and cytokine mediated cytotoxicity