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mAbs targeting NK cells

Scientific principle : Activating the immune « Natural Killer »

Present in large population throughout the body (they account for 5 to 10% of all lymphocytes), and, like the γδ T lymphocytes (with which they form the so-called “nonconventional” lymphocyte group), NK cells are able of:

  1. Directly and selectively killing cancerous or virus-infected cells;
  2. Bind one of the two ends of cytotoxic antibodies such as rituximab and trastuzumab, and then lyse (i.e. kill) cells recognized by these antibodies. This property is known as antibody-dependent cellular cytotoxicity (ADCC);
  3. Monitor and control other components of the immune system, particularly via the production of cytokines (the “hormones” of the immune system).

The mechanism that regulates NK cell activity is atypical in that it results from equilibrium between “activating” and “inhibiting” signals simultaneously received from the target cell through activatory receptors and inhibitory receptors (notably KIR), respectively. Natural killer cells sum up the signals they receive from their targets.

The ligands of these receptors are respectively "self" molecules (markers of the "self", specific to each individual called MHC molecules for Major Histocompatibility Complex) and surface molecules expressed by malignant cells or cells infected by certain pathogens. The activation of a NK cell is thus the result of an imbalance between the “normality” (i.e. belonging to “self”) and the abnormality (being cancerous or infected) of the cell encountered.


Even though the characteristics of NK cells have been known since the beginning of the 1980s, it was not until the mid-nineties (following discoveries by Alessandro Moretta and Eric Vivier – two of Innate Pharma’s founding scientists) that we learned how NK cell activation was controlled.
 

Therapeutic potential

Cancer
Two approaches are possible for activating NK cells for development prospects in oncology indications: (i) the use of inhibitory receptor antagonists and (ii) the use of activating receptor agonists.

The former approach was selected by Innate Pharma, and an antibody activating NK cells was developed: IPH 2101, currently in Phase I and Phase II clinical trials. Pre-clinical and indirect clinical data have oriented the product development towards onco-hematological indications (leukemias and myelomas).

Inflammation and autoimmune diseases
Blocking the activation of NKs requires the use of activating receptor antagonists. This mechanism could be of interest for indications outside the field of oncology, in some chronic inflammation processes such as certain autoimmune diseases (e.g., diabetes and rheumatoid arthritis). Two antibody programs are out-licensed to Novo Nordisk A/S and developed in inflammatory conditions and autoimmune diseases.

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