From CD4 anergy to trans CD4 immunotherapy
Discovery of the mechanism leading to CD4 immunodeficiency in HIV patients
After 30 years deadlock, the laboratory of Jacques THÈZE at the Pasteur Institute has identified the mechanism leading to CD4 anergy in HIV patients and established that this molecular machinery is not active in the few patients controlling spontaneously HIV infection (named HIV elite controllers). Since that date, DIACCURATE has uncovered a new universe of targets in infectious diseases and cancers and developed a first antibody drug candidate that specifically blocks PLA2GIB, the blood soluble enzyme that disrupts and locks CD4 lymphocytes of HIV patients.
As early as 2020, DIACCURATE intends to demonstrate its capability to convert infected HIV patients into HIV controllers and to confirm the broad therapeutic potential of this new approach, now called trans CD4 immunotherapy.
First drug candidate:
anti-PLA2G1B neutralizing antibody
First Phase I/IIa clinical trial in HIV patients
CD4 T lymphocytes control all branches of immune responses
The CD4 T lymphocytes play a central role in the immune response to microbial infections and cancers. They are called helper (Th) cells because the vast majority of them do not kill pathogens and cancer cells but trigger antimicrobial and antitumor immune response. In their absence, adaptive immune responses do not develop, and innate responses remain suboptimal.
CD4 T lymphocytes display a large degree of plasticity: in response to developmental and environmental cues, naïve CD4 T cells differentiate into multiple subsets characterized by distinct molecular profiles (cell surface receptors, transcription factors and secreted cytokines) and related functions. Thus, once armed, they promote B cell antibody production, activate cytotoxic T cells and control innate immunity while some sub-populations, such as regulatory T cells (Treg) or, under certain circumstances, Th17 cells, promote tumor growth and survival.
A common feature in infections and cancers: CD4 anergy
CD4 exhaustion is often associated with tumor progression and chronic infections. Gradually, the CD4 T cells lose their ability to produce and use cytokines, express multiple inhibitory receptors, face metabolic derangements… then become dysfunctional. In HIV patients, CD4 T lymphocytes are infected and killed by the virus but later on, non-infected CD4 T cells become anergic, die by apoptosis, resulting in lymphopenia and viral immune evasion.
Today, Diaccurate is pioneering a new immunotherapy approach, called trans CD4 immunotherapy, which aims to prevent CD4 anergy or restore CD4 altered functions in HIV patients and beyond.
Prevent and restore CD4 functions in HIV patients and beyond
In 2013, the team of Jacques THÈZE at the Pasteur Institute has identified the cellular and molecular mechanism leading to CD4 anergy and CD4 lymphopenia, the hallmark of the immunodeficiency following HIV infection. In the plasma of HIV patients, a soluble enzyme, named phospholipase A2 group 1B (PLA2G1B) induces large and abnormal membrane microdomains at the surface of CD4 T lymphocytes which appear as if they were hurt. These “bumpy cells” become unable to respond to physiological signals like those delivered by the interleukins (IL2, IL7…) and the T-Cell Receptor (the surface molecule that recognizes and binds foreign antigen) leading to CD4 anergy.
The molecular signature of HIV patients: “bumpy” CD4 T cells. Stimulated Emission Depletion (STED) microscopy shows that more than 80% of CD4 lymphocytes from HIV-infected patients presented at their surface large and abnormal membrane microdomains and stimulation by IL-7 does change this organization of the membrane. By contrast, CD4 T cells purified from healthy donors do not exhibit any membrane macrodomain at the resting state while physiological membrane macrodomains of small size (around 100 nm) appears after IL-7 stimulation.
Since then, Diaccurate has demonstrated that the same molecular machinery is switched off in HIV elite controllers patients (the few patients that spontaneously control viral replication without antiretroviral therapy), characterized comparable mechanism in cancer and sepsis and demonstrated the preclinical proof-of-concept of a humanized PLA2G1B neutralizing antibody.
Using this new immunotherapy approach, the objective is to achieve for the very first time the functional cure of HIV patients and established trans CD4 immunotherapy as a new therapeutic option for infectious diseases and cancer with partial or total CD4 immunodeficiency.