Science ＆ Technology
HuLA immune is creating innovative pharmaceuticals / diagnostics through the investigation of novel immune mechanisms.
Ⅰ． Autoimmune disease treatment using ”neo-self theory”A Project using ”Neo-Self Theory”
Autoimmune diseases are diseases in which the immune system no longer functions properly and attacks its own proteins as a target.
In 2014, Professor Arase and his colleagues discovered a new mechanism that may explain the basis of autoimmune diseases (Reference 1). By stimulating cytokines produced by infectious diseases, HLA-II molecules are ectopically expressed on the cell membrane in cells that normally do not have a foreign antigen presentation function (eg, vascular endothelial cells, etc.). At that time, the mechanism by which the HLA-II molecule forms an abnormal complex with the self-protein and is presented on the cell surface as a "neoself antigen" is called the neoself theory 1) (Fig. 1). We believe that "neoself antigens" are the starting point for the production of "neoself antibodies" and the formation of autoimmune diseases. We named it "neo-self antibody" because it is an antibody against self ("self") antigens based on a new ("neo") concept.
Anti-Phospholipid Syndrome (APS) is known as an autoimmune disease that causes thrombosis and recurrent pregnancy loss. Although it can be inferred from clinical symptoms that it is APS, there are patients in whom autoantibodies are not detected by the current APS diagnostic method, but research results have been reported in which neoself-antibodies are frequently detected in these patients 2), 3),. From this, it is widely recognized that neoself antigens are deeply related to the pathophysiology of autoimmune diseases. More recently, it has been suggested that thrombosis, which is observed when COVID-19 is infected and becomes severe, is similar to the pathology of APS, and we also focused on the involvement of neoself-antibodies in infectious diseases.
HuLA immune uses neo-self theory as a platform for therapeutic / diagnostic agents for various autoimmune diseases (APS, MPO-ANCA vasculitis 4), type 1 diabetes, etc. 5)) that have been considered to be incurable. We are promoting research and development (patented).
II. COVID-19: Newly discovered Infectivity-enhancing AbsProjects using Infectivity-enhancing Abs
"1) Infectivity-enhancing Abs targeting N-terminal domain (NTD) of Spike protein (S protein)"
At Osaka University, where HuLA immune is collaborating, novel infectivity-enhancing Abs targeting a specific epitope present in the NTD of S protein was discovered in COVID-19 patients 6). The structural changes in the receptor binding region (RBD) of the S protein caused by the binding of this antibody to NTD significantly enhance the binding to the human receptor (ACE2). This discovery was the first in the world to capture the mechanism of ADE (antibody-dependent enhancement) in SARS-CoV-2.
"We will upgrade this infectivity-enhancing Abs measurement technology to clinical tests and aim to utilize it for the following purposes.
・Quality assessment of convalescent patient plasma
・Evaluation of (re) infection risk when neutralizing antibodies effect is attenuated by mutant strain
・Monitoring of vaccine efficacy persistence
・Severity risk assessment before and after infection"
2) Application to vaccines that do not induce infectivity-enhancing Abs
By modifying the epitope sequence on the NTD of the S protein that causes the above-mentioned infection-enhancing effect and changing the antigenicity, it is possible to develop a next-generation safer vaccine that does not induce an infection-enhancing antibody. Promptly providing safe and effective vaccines in the global corona disaster is an extremely important issue, so we will speedily promote technical alliances with vaccine manufacturers.
6) Liu et al. Cell 2021 Link