Impact case study database

In 2014, OANG tested 8,944 samples for autoantibodies against 8 targets. Of these, more than 95% were UK patients. By 2019, the OANG testing had expanded to 24,552 samples on 12 targets, including approximately 10,000 for the Nationally Commissioned Service for patients with neuromyelitis optica (NMO) which focuses on aquaporin-4 antibodies [A], and is the only UK provider of this optimised live-cell based assay. OANG’s test identifies 80 new UK patients/year with aquaporin-4 antibodies. Given that aquaporin-4 antibodies have an overall incidence of 1.3/million person-years (equivalent of 85 new cases/year in the UK), these accurate tests are capturing the whole of the relevant UK patient population. In addition, this aquaporin-4 antibody test is run on 30,000 samples/year at the Mayo Clinic (USA), covering about 60% of USA test requests [B].

OANG’s assay to detect MOG antibodies is the most specific worldwide in comparison to four international testing centres with an interest in MOG antibody testing [5]. OANG is the only provider of MOG-antibody IgG1 testing in the UK. UK test requests for MOG autoantibodies have increased by 61%/year over the last 5 years and this test received statutory approval in the USA in 2018. It is now run on 25,000 samples/year, approximately 55% of USA requests [B].

“The Oxford Autoimmune Neurology Diagnostic Laboratory has had a significant impact, not only on the field of autoimmune neurology but also on the development and optimization of platforms for neural antibody testing, many of which have been incorporated into the current Mayo Clinic Neuroimmunology Laboratory testing platforms.”

Director of the Neuroimmunology Laboratory, Mayo Clinic. [B]

Since the OANG’s original report in 2008, a 2018 literature review identified descriptions of 186 patients with glycine receptor antibodies who were almost universally responsive to immunotherapies. Although rare, the consistent clinical findings and response to immunotherapy in patients from multiple countries has led to the establishment of glycine receptor antibody testing in major testing centres in Germany (Jan 2019, [Ci]), and the USA (Aug 2020; [A], [Cii]).

These autoantibody findings dramatically alter patient care. Three clinically similar diseases: multiple sclerosis, aquaporin-4 antibody and MOG antibody disorders all respond to different therapies and require different durations of administration. Patients with MOG-antibodies typically require short-term immunotherapies. Patients with aquaporin-4 antibodies have lifelong disease relapses which respond to long-term immunotherapies but worsen with treatments that are effective in multiple sclerosis (MS). In particular, misdiagnoses of NMO patients as MS means many patients suffer preventable disability or death and can respond to costly MS treatments such as interferons with catastrophic worsening [D]. OANG’s improved live cell-based assay for aquaporin-4 antibody detection has led to 50% more patients identified with NMO in the USA each year - this equates to 1,658 extra patients captured between 2014 and 2020 using live cell-based assays [4; E].

Importantly for patient benefit, the time to diagnosis was reduced (1 versus 18 months). In 2019, class I evidence led to FDA approval for three effective immunotherapies which treat NMO, highlighting the impact of the new diagnostic criteria. A neurology clinician at the Massachusetts General Hospital summarised the benefits to patients being that, “ without the MOG assay, these patients would be left without a diagnosis or treatment, and would have a poor prognosis”, including hundreds of his patients alone [F(i)].

OANG’s work has revealed that of all patients with VGKC antibodies, only those with either LGI1- or CASPR2-antibodies benefit from immunotherapies [1, 3, 6], and that treating the remaining 80-95% with VGKC-antibodies is harmful, or at least non-beneficial [G]. Consequently, VGKC testing was ceased by the Mayo Clinic in 2019 [H] and replaced by the OANG tests for LGI1 and CASPR2 antibodies, now performed on approximately 50,000 samples per year [B]. Many other centres worldwide have followed suit, including the Oxford NHS Trust immunology laboratory in 2020 [H]. Hence, the approximately 30,000 and approximately 100,000 VGKC-antibody tests performed in the UK and USA, respectively, are now preferentially tested for OANG’s discovery of LGI1/CASPR2 antibodies. The new tests help avoid unnecessary immunotherapies in approximately 20,000 individuals/year in the USA, Europe and the UK [G].

The OANG’s development and evaluation of the most accurate aquaporin-4 and MOG autoantibody assays [4, 5] led to their uptake during the current REF Impact period in South Korea [Fiii], USA (Mayo Clinic, Minnesota [B], Harvard, Boston [Fi]) and Canada [Fii]. In South Korea, this has led to an increase in identification of patients with NMO (by 18.5%) and a 10% increase in the disease diagnosis, patients who would previously been left undiagnosed and untreated. The OANG’s aquaporin-4-antibody test has been established at the British Columbia Neuroimmunology laboratory in Vancouver, Canada, now providing 100 tests/month. Cell-based assays are now recommended as gold standard in the 2015 international guidelines for diagnosis of NMO spectrum disorders [I, 2,090 citations]. These highly cited criteria have improved the diagnosis of NMO globally, with validation studies from every continent demonstrating improved patient identification: e.g. France (97% accuracy vs. 82%), in a single centre in one year in India (91 vs. 30 patients), and in four countries in Latin America (104 vs. 64 patients).

a. Commercial clinical trials: Identification of LGI1 and CASPR2 antibodies [1, 6] has been used as an inclusion criterion for an industry-funded clinical trial in the field [G]. Patients benefited from a reduced frequency of seizures on the test immunotherapy (intravenous immunoglobulins), which confirmed the previous OANG data [6]. This result now permits approximately 250 US patients per year access to immunotherapies otherwise denied by insurers [B].

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b. New technologies to support drug discovery: OANG’s LGI1- and CASPR2-antibody tests have been commercialised and sold in 57 countries worldwide [K]. The OANG-pioneered membrane-tethering technology, used in the development of the LGI1-antibody assay [1], has been taken up by Retrogenix Ltd, to detect binding partners of soluble molecules and off-target binding of biotherapeutics [K]. Since 2017 this technology has been integrated into nearly every client project run by Retrogenix including screening 1,000 drug molecules in more than 400 projects with more than 200 clients worldwide. The data generated supported 75 successful commercial clinical trial applications in the last 2 years. Retrogenix describe the benefit to their clients who “ have been able to make more informed decisions as to which molecules to progress within their pipelines, and into the clinic. This reduces their failure rates, and allows safer drugs to enter clinical trials, meaning an economic benefit, and even more importantly, less likelihood that patients will encounter unexpected toxicities.” [L].

Correct patient diagnosis and treatment leads to better patient outcomes, often with a return to activities of normal daily living. Accurate assays have also provided savings to the NHS since 2019 by treating patients who are CASPR2 or LGI1 antibody positive, and not treating (80-95%) those with VGKC antibodies (without CASPR2 or LGI1 reactivities) where there is no evidence of benefit on immunotherapy.