Projects

1."Application of Neo-Self Theory to various autoimmune diseasesWhat is Neo-Self Theory?

HuLA immune is conducting research and development on the following diseases based on its patent for drug screening, and is seeking business partners.

Antiphospholipid Antibody Syndrome (APS)

APS is a disease that causes thrombosis and infertility due to the production of autoantibodies against β2GPI, which is involved in blood clotting and other processes.

It was found that autoantibodies (β2GPI neo-self-antibodies) against the complex of β2GPI and HLA-DR (β2GPI neo-self-antigen) were frequently detected in patients with sero-negative APS, in whom autoantibodies could not be detected by the current diagnostic method (aPL), even though they were suspected to have APS based on clinical symptoms. In particular, it was found that autoantibodies against the complex of β2GPI and HLA-DR (β2GPI neo-self antigen) were frequently detected in APS. In particular, 23% of patients with infertility are positive for β2GPI neo-self antibodies, which is the cause of the highest proportion of infertility1) .
In addition, although the test for autoantibodies to the β2GPI/HLA DR complex is a single indicator, it covers about 84% of APS patients who are positive by the current diagnostic method using five indicators 2).

Furthermore, recent findings have pointed to a link with severe disease (induction of thrombosis) in COVID-19 infection, and since there are findings that HLA-DR is induced by viral infections, we are investigating the involvement of β2GPI neo-autoantibodies3) .

Based on the above evidence, HuLA immune has been working on the following projects

① HuLA immune has been providing contract services (for research use) for neo-self antibody testing using this β2GPI neo-self antigen since January of this year. 

In addition, since β2GPI neo-self antigen is deeply involved in the pathogenesis of APS

② We have established an original technology to obtain antibodies against the complex of HLA class II, a membrane protein, and β2GPI, and have obtained candidates for therapeutic agents that inhibit the binding of β2GPI neo-self antigen and β2GPI neo-self antibody, and are proceeding with preclinical evaluation. By modifying the immune response in an antigen-specific manner, we can achieve cures for diseases that are currently only treated symptomatically.

References
1) Tanimura K et al. Arthritis. Rheumatol 2020      Link     
2) Tanimura K et al. Blood 2015      Link     
3) El Hasbani G et al. Clin Med Insights Arthritis Musculoskelet Disord 2020      Link     


MPO-ANCA Vasculitis

MPO-ANCA vasculitis is a disease caused by autoantibodies against antineutrophil cytoplasmic myeloperoxidase (MPO-ANCA), which leads to inflammatory reactions in small blood vessels.
In ANCA-associated vasculitis, autoantibodies against MPO/HLA-DR complex (MPO neo-self antigen) have been found to be present in patients4) .

HuLA immune is conducting drug discovery screening for drugs that inhibit the binding of MPO neo-self antigen to MPO neo-self antibody.


Type 1 Diabetes

In type 1 diabetes, the presence of autoantibodies has been observed before insulin secretion from Langerhans and other organs in the pancreas is impaired, and neo-self antigens/antibodies are thought to be involved in the process of onset and progression of the disease.

HuLA immune has already obtained antibodies that have shown therapeutic effects in a diabetic mouse model5), and by applying the results obtained in this mouse model, we are working on the discovery of a therapeutic drug for type 1 diabetes.

References
4) Hiwa R et al. Arthritis Rheumatol. 2017      Link     
5) Matsumoto Y et al. BBRC 2021      Link     

2. New infection-enhancing antibodies for COVID-19 (AMED adopted theme) 

Based on the discovery of new infection-enhancing antibodies in COVID-19, we are working to establish a method for measuring infection-enhancing antibodies and to develop improved vaccine technology with superior safety performance that does not induce infection-enhancing antibodies. As the response to COVID-19 is a top priority for society, we are actively pursuing business alliances and other measures to ensure rapid business development.

Infectivity-enhancing antibody testing

A research group led by Professor Hisashi Arase of Osaka University and HuLA Immunity reported the presence of infectivity-enhancing antibodies in antibodies derived from COVID-19 patients against the N-terminal domain (NTD) of the SARS-Cov2 Spike protein6) . Infectivity-enhancing antibodies promote the infectivity of the virus by markedly enhancing the binding of the receptor binding domain (RBD) of the S protein to the receptor ACE2, and this finding is the first to reveal the antibody-dependent infection enhancement (ADE) mechanism of SARS-Cov-2.

The measurement of infectivity-enhancing antibodies in serum is being developed as a unique test method for HuLAimmune because it is expected to be used as a new marker for severe disease in COVID-19 and as a means of selecting patients for vaccination. At the same time, we will clarify the position of infectivity-enhancing antibody measurement in clinical practice in AMED research. We also plan to evaluate the significance and risk of COVID-19 infection in healthy individuals who have never been infected with COVID-19, as we have found that there are some individuals who are positive for COVID-19 due to previous infection with other viruses.


Improved vaccine technology

By modifying the epitope of the infection-enhancing antibody described above, it is possible to produce a safer vaccine that does not induce infection-enhancing antibodies (patent pending). Since this technology can be applied to vaccines of various modalities that contain Spike protein, we will develop this business based on licensing it out to vaccine manufacturers.

References
6) Liu et al. Cell 2021      Link     

In order to conduct "research using human cells" properly, we have established a research ethics review board based on the government's basic guidelines ("Ethical Guidelines for Medical Research Involving Human Subjects," etc.) to strictly deliberate on the ethical and scientific validity of each research plan.

The rules of the committee, the list of committees, and the outline of the proceedings will be announced through the ethics committee reporting system of the Ministry of Health, Labor and Welfare.