The Science Behind AOI Bio.
– Neoself Theory

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Neoself Theory

First discovered in 2014 by AOI Bio’s research partner Prof. Hisashi Arase (Osaka University), Neoself antigens are whole misfolded proteins complexed with HLA Class II molecules expressed ectopically.

  • Classical Antigen Presentation via
    MHC Class II on APCs

  • Aberrant Manifestation of MHC Class II
    and Neoself Expression

Jin et al. Proc. Natl. Acad. Sci. USA. (2014)

Neoself antigens are recognized by a population of B cells, which then causes activation of various immune cascades including autoantibody production and complement mediated cell damage.

Jin et al. Proc. Natl. Acad. Sci. USA. (2014)

β2GPI Neoself Antibody
in Infertility
and Obstetric Complications

β2GPI has long been recognized as the principal autoantigen in antiphospholipid syndrome (APS), a leading cause of recurrent pregnancy loss (RPL) and a suspected contributor to recurrent implantation failure (RIF). Unfortunately, the sensitivity of current β2GPI related tests remain lacking.
However, we were able to develop a high-sensitivity test utilizing the Neoself theory. The β2GPI Neoself Antibody test can detect 85% of APS patients while keeping false-positive rates down to 1%.

  • Anti-β2GPI Neoself
    Antibody Titer

  • Anti-β2GPI
Antibody Titer (IgG)

  • Anti-Cardiolipin
Antibody Titer (IgG)

Tanimura et al. Blood (2015)

A separate clinical trial shows that AOI Bio.’s β2GPI Neoself Antibody test again performs better in detecting β2GPI positive RPL patients than both conventional anti-β2GPI antibody testing and anti-cardiolipin testing combined. The β2GPI Neoself Antibody test identifies the origin of RPL as APS for over 20% of RPL patients without a previously known cause.

Tanimura et al. Arthritis & Rheumatology (2020)

Anticoagulant therapy may offer an effective treatment option for β2GPI Neoself Antibody-positive RPL patients. Clinical studies have demonstrated that low-dose aspirin (LDA) or LDA combined with heparin therapy can significantly increase the likelihood of live births in this patient population.

Pregnancy Outcomes by Treatment Method for
β2GPI Neoself Antibody-Positive Patients

No. of Pregnancies Live Births or
Ongoing Pregnancies		 Miscarriages
With
Anticoagulant Therapy		 LDA Only 12 12(100%) 0(0%)
LDA + Heparin 19 17(89.5%) 2(10.5%)
Total 31 29(93.5%) 2(6.5%)
No Anticoagulant Therapy 8 4(50%) 4(50%)
Tanimura et al. Front. Immunol. (2024)

Additionally, RIF patients who test positive for β2GPI Neoself Antibodies show improved outcomes with anticoagulant therapy. Without intervention, β2GPI Neoself Antibody-positive patients tend to experience poorer implantation outcomes; however, low-dose aspirin therapy has been shown to markedly enhance implantation success rates.

Implantation Success Rates in ART Patients
(Successful Transplants/Embryos Transferred)

β2GPI NS Ab LDA (+) LDA (-) p-value
Positive 52.6%(10/19) 21.1%(4/19) 0.044
Negative 47.7%(21/44) 39.4%(71/180) 0.327
Ono et al. Presentation at The 67th Annual Meeting of the JSRM (2022)

β2GPI Neoself Antibody Test

AOI Bio. has developed a proprietary method to measure β2GPI Neoself Antibody titers in blood. A custom cell line expressing β2GPI Neoself antigens is used in conjunction with a control cell line that expresses the same HLA Class II molecule, but without the misfolded antibody on top. Antibodies from the serum are incubated with both cells, and the difference in the amount of antibodies biding to each cell is calculated. This number is the β2GPI Neoself Antibody titer for the patient.

Publications

  • References

    1. Jin H, et al. Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility. PNAS. 111, 3787-92 (2014)
    2. Tanimura K, et al. β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. Blood. 125, 2835-44 (2015)
    3. Tanimura K, et al. β2-Glycoprotein I/HLA-DR Complex As A Major Autoantibody Target in Obstetric Antiphospholipid Syndrome. Arthritis & Rheumatology. 72, 1882-91 (2020)
    4. Tanimura K, et al. Low-dose aspirin and heparin treatment improves pregnancy outcome in recurrent pregnancy loss women with anti-β2-glycoprotein I/HLA-DR autoantibodies: a prospective, multicenter, observational study. Frontiers in Immunology. 15:1445852 (2024)

  • Further Readings

    1. Tanimura K, et al. Anti-β2-glycoprotein I/HLA-DR Antibody and Adverse Obstetric Outcomes. International Journal of Molecular Sciences. 24:10958 (2023)
    2. Yoneda K, et al. Association of anti-β2-glycoprotein I/HLA-DR complex antibody with arterial thrombosis in female patients with systemic rheumatic diseases. Arthritis Research & Therapy. 25:195 (2023)
    3. Mori S, et al. Neoself-antigens are the primary target for autoreactive T cells in human lupus. Cell. 187, 6071-87 (2024)
    4. Ono Y. et al. Anti-β2-glycoprotein I/HLA-DR antibody in infertility. Journal of Reproductive Immunology. 158:103955 (2023)

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