Blocking immunosuppressive pathways
a) Monoclonal antibodies and cancer
In order to maintain homeostasis, the immune system response is balanced by stimulating and inhibiting molecule expression. In presence of a stimulating antigen, immune response is triggered, leading the recruitment of other immune cells subsets to eliminate the target. Once the threat has been removed, inhibitory mechanisms will be set in order to restore the homeostasis. The mechanisms used to downregulate the immune response are collectively called immune checkpoints.
These immune-checkpoints (ICP) are highjacked by tumor cells to escape the host’s immune response. Among these molecules, the most described is PD-L1 (Programmed Death-Ligand 1) expressed by the tumors, which binds with the PD-1 receptor, present in B and T cells, inducing tolerance. The PD-1/PD-L1ICP couple was one of the first to be targeted using monoclonal antibodies and used in immunotherapy to treat several solid cancers. Blocking antibodies against immune checkpoints are named immune checkpoint inhibitors (ICIs).
b) IVS-4001: an HLA-G-specific antibody
The HLA-G molecule has been recently described as an emerging immune checkpoint. Its expression is restrained to the fetal-maternal interface, where it protects the semi-allogenic fetus from the maternal immune system, and immune-privileged tissues. HLA-G was demonstrated to be capable of inhibiting any immune response.
A wide type of cancers express HLA-G to protect themselves. HLA-G has been associated to the micro-environment (Tumor Micro-Environment, TME) settlement, to shield the tumor from host’s immune response. Thus, blocking HLA-G’s function is critical for restoring the patient’s anti-tumor response.
For this purpose, IVS-4001 is a neutralizing ICI, aiming at inhibiting the immunosuppressive functions of HLA-G and disrupting the TME. As a consequence, the patient’s response will be restored and deplete the tumor cells. This is the first in class monoclonal antibody to bind to immunosuppressive B2M-free HLA-G isoforms, by blocking their interaction with ILT4 receptor, present in myeloid cells.
A glossary is available for technical definitions.
