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Small molecules targeting γδ T cell

Scientific principle: activating killer lymphocytes

The therapeutic basis of the γδ platform is the specific activation of a subpopulation of immune cells (γ9δ2 T lymphocytes) which have natural anti-tumor and anti-infectious activity.

Like NK cells, γδ T lymphocytes are called “unconventional” lymphocytes because they show different properties relative to “classical” T lymphocytes (αß T) of the adaptive immune system. The αß  and γδ names originate from the nature of their antigen receptors (a combination of an alpha and a beta chain, and of a gamma and a delta chain, respectively). These antigen receptors, whose function is to detect and signal the presence of pathogen agents to eliminate, provide γδ T lymphocytes with specific properties:


1/Powerful and fast killers with immunity regulation capacities
The γδ lymphocytes play a large role in both anti-tumoral and anti-infectious protection in two ways:

  • directly, by eliminating their targets in minutes (unlike lymphocytes of the adaptive immune system that require maturation in a secondary lymphoid organ for activation) – this is called direct cytotoxicity, and
  • indirectly, by massively secreting pro-inflammatory cytokines (the “hormones” of the immune system), which in turn stimulate the other immune cells, in particular those of the adaptive immunity.


2/Specificity for unconventional antigens, expressed at all stages of the disease
The receptor of γδ lymphocytes recognizes original danger signals called “phosphoantigens”. These are
either produced by viruses or bacteria or are expressed in abnormally high amounts by “stressed” cells (whether cancerous or infected). What is important is that they are unchanged, at all stage of the disease.

Innate Pharma focuses specifically on the study of the γ9δ2 T population, which represents the main γδT pool in the blood stream in adults.
 

  


Small molecule agonist of γ9δ2 T cells developed at innate Pharma:
IPH 1101 


Therapeutic potential


A potential use in several oncology indications ...
Experimental data has shown that γ9δ2 T cells, notably after stimulation by products of the IPH 1101 type, are able to kill a wide variety of cancer cells of various origins. Oncology (cancer) is the first therapeutic area for which IPH 1101 is developed.

... and in infectious diseases
In addition to oncology indications, the biological properties of γ9δ2 T cells have led us to consider clinical developments in infectious diseases. We want to take advantage of the ability of γ9δ2 T cells to kill cells infected by viruses and to release soluble mediators, in particular interferons and chemokines, which play an important role in anti-infectious immunity. The Company has achieved the proof of this concept in the IPH 1101-203 Phase IIa clinical trial (more info).

A strong rationale for combining with cytotoxic antibodies
The mechanism of action of rituximab-like therapeutic monoclonal antibodies involves cell effectors, the first line of which includes NK cells, which can be indirectly recruited and activated by the involvement of γ9δ2 T lymphocytes. Consequently, the mechanism of action of compounds targeting γ9δ2 Ts enables us to consider combinations with antibodies to stimulate the anti-tumor activity of cytotoxic antibodies. The Company has achieved the proof of this concept in the IPH 1101-202 Phase I/II clinical trial (more info).

Potential in vaccine adjuvantation
Along with the direct use of  γ9δ2 T activators as anti-tumor or anti-infectious agents, we may consider developing these compounds as vaccine adjuvants, administered in combination with an antigenic preparation to stimulate the immune response against these antigens and to orientate the response towards the generation of cytotoxic cells, which is a particularly important challenge for the efficacy of future vaccines. Cooperation between  γ9δ2 T cells and the antigen-presenting cells involved in the initial steps of the adaptive immune response specific to an antigen is the basis for the rationale for exploring this type of application both in oncology (therapeutic vaccines) and for infectious diseases (therapeutic or prophylactic vaccines).


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