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HLA-G platform

HLA-G: from pregnancy to tumors

Invectys Inc. targets a powerful immune checkpoint named HLA-G. HLA-G is a non-classical MHC class I molecule normally only expressed at the fetal-maternal interface, where it protects the semi-allogenic fetus from the maternal immune system. Otherwise, the father’s antigens would be recognized as foreign and thus destroyed. To avoid this, HLA-G serves as a broad-range immune checkpoint inhibitor (ICI) which shuts down any immune response towards the fetus. HLA-G expression on the placenta not only inhibit all immune cells but also creates a suppressive micro-environment in which the immune system is repressed, thus protecting surrounding cells as well.

HLA-G interacts with 2 main inhibitory receptors: ILT2 and ILT4. ILT2 is expressed on all immune cell subsets whereas ILT4 is only expressed on myeloid cells (cells of the native immune system). The HLA-G/ILT2 interaction inhibits T cells function, protecting cells from the direct cytotoxic of CD8+ cells. Conversely, the HLA-G/ILT4 interaction induces inhibition of myeloid cells maturation and turns them into suppressive Antigen Presenting Cells (APCs), setting up the immuno-suppressive TME. Thus, HLA-G provides protection both directly and indirectly.

HLA-G expression is restricted to immune-privileged sites in healthy individuals. Yet, given its broad immunosuppressive action, tumors neo-express HLA-G to evade immune response. Indeed, more than 70% of cancers use HLA-G as a shield to disrupt the patient’s immune system’s ability to target the tumor cells. As such, HLA-G is defined as tumor specific antigen (TSA) since it is barely expressed on healthy tissues but neo-expressed on tumors implying that HLA-G represents a critical – although complex – target for immunotherapy.

Invectys takes advantage of this widely prevalent target through two different technologies: CAR-T cells and antibodies.

I – Destroying HLA-G-bearing cancer cells: anti-HLA-G CAR-T cells

a) What are CAR-T cells?

Chimeric Antigen Receptors (CARs) are artificial receptors, derived from monoclonal antibodies specific to a tumor antigen, which are implanted on T cells to redirect these cells against said tumor antigen. In practice, CD8+ T cells are first isolated from a patient, and modified to express the CAR directed against said patient’s tumor marker. The modified T cells (now called CAR-T cells, or CAR-Ts) are then reinjected into the patient and will seek and destroy the cells displaying the targeted antigen. For this reason, it is crucial to have a tumor specific antigen not expressed on healthy cells to avoid any side effects. Given the characteristics of HLA-G, it is the best tumor specific antigen to cancerous cells. These CAR-Ts are called autologous, as they are based on the patient’s own cells.

Invectys has developed a 3rd-generation CAR construct allowing anti-HLA-G CAR-T cells to target and kill HLA-G-bearing cells. These are the first in class CAR-T cells engineered to target the immune checkpoint HLA-G.

Our CAR-T cells are currently under late stage of preclinical development and was granted a $28 million funding to initiate clinical trial in 2022 against advanced carcinoma.

b) In vivo results

Anti-HLA-G CAR-T cells have demonstrated in vivo their ability to migrate to tumor sites and destroy HLA-G-bearing cells. Mice treated with anti-HLA-G CAR-T cells have shown a near-total absence of tumor growth.

Bioluminescence imaging of cancer-induced mice injected with anti-HLA-G CAR-T cells

 

c) unique benefits

  • Invectys’ CAR-T cells are not hindered by the immuno-suppressive effects related to the HLA-G interaction with the ILT2 receptor which could be expressed by T cells.
  • Since HLA-G expressing tumor cells were shown to induce suppressive APC, regulatory T cells and suppressive NK cells displaying HLA-G on their surface, by eliminating HLA-G+ cells, Invectys’ CAR-T cells disrupt the HLA-G related immuno-suppressive microenvironment created by the tumor, allowing the restoration of the patient’s immune response.
  • HLA-G represents the best tumor specific antigen to date since it is almost not expressed on healthy tissues. Adverse events related the “on-target, off-tumor” effects will be very limited if not absent.
  • These CAR-T cells cover the main immune-suppressive HLA-G isoform expressed by carcinoma

d) External recognition

Our CAR-T cell projects were awarded by multiple independent organisms:

  • Cancer Prevention Research Institute of Texas award 2020
  • “Best Project” award at the MATWIN 2019 competition
  • CAR-T poster selected for top 10 at ESMO Immuno Oncology, Geneva, December 2019
  • Awarded by the EU-funded (France, Germany, Italy & United Kingdom) collaborative research project CARAT (Chimeric Antigen Receptors for Advanced Therapies)

 

II – Blocking the immuno-suppressive action of the immune checkpoints HLA-G and ILT4: anti-HLA-G antibodies and anti-ILT4 nanobodies

Invectys has developed a library of antibodies designed to prevent HLA-G from interacting with ILT4 inhibitory receptor. ILT4 is normally expressed only on Antigen Presenting Cells (DC, Monocytes, macrophages)and is strongly upregulated on tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN) and on myeloid-derived suppressor cells (MDSC) key elements of the immuno-suppressive micro-environment.

Strikingly, ILT4 is also neo-expressed on tumors to give themselves greater proliferation and dissemination capabilities following its interaction with HLA-G and / or ANGPTL-2 pro tumoral proteins.

Invectys developed a library of (i) monoclonal antibodies targeting HLA-G to inhibit the HLA-G/ILT4 interaction and of (ii) nanobodies targeting ILT4 to block the ILT4 interaction with HLA-G and ANGPTL-2 proteins: – 15E7 is the first in class monoclonal antibody demonstrated its ability to bind to B2M-free HLA-G isoforms blocking their interaction with ILT4 receptor.

INMAB’s monoclonal antibodies are Immune Checkpoint Inhibitors (ICIs). They are aiming to target and disable HLA-G proteins on the surface of cancer cells. In turn, they will cancel out the suppression of the immune system by HLA-G, allowing it to attack the tumor cells.

INMAB’s capabilities will neutralize the immunosuppressive functions of HLA-G and restore immune cell functions:

  • 15E7 is the first in class monoclonal antibody demonstrated its ability to bind to B2M-free HLA-G isoforms blocking their interaction with ILT4 receptor
  • B8 is the first in class nanobody specific for ILT4 inhibitory receptor demonstrated to block not only ILT4’s interaction with HLA-G and ANGPTL-2, pro-tumoral proteins. Additionally, works from Jounce and Merck suggests that this nanobody should reprogram immuno-suppressive immune cells into anti-tumoral cells (works presented at ESMO 2020)

 

Both antibodies are currently in pre-clinical stage and are scheduled to begin clinical trials in 2023.

A glossary is available for technical definitions.