Safety and Efficacy of Combined B Cell Depleting theRapy And Daratumumab In Autoimmune Encephalitis

Autoimmune encephalitis (AE) is a broad spectrum of immune-mediated neuropsychiatric diseases, usually associated with antibodies against surface proteins, ion channels, synapses or intracellular proteins of neuronal cells. Anti-N-methyl-D-aspartate receptro (NMDAR) encephalitis is the most common type of AE.The clinical manifestations include behavioral changes, psychiatric symptoms, epileptic seizures, memory and cognitive deficits, abnormal movements, autonomic dysfunction and decreased consciousness. Most children and adult patients present with a syndrome that combines the above symptoms and can be severe.

Early initiation of immunotherapy is necessary to improve clinical prognosis and reduce its recurrence.

However, no disease-modifying therapy specifically for AE has been approved. A variety of therapies have emerged for severe autoimmune encephalitis, including anti-CD20 monoclonal antibody rituximab, proteasome inhibitor bortezomib, anti-CD38 monoclonal antibody daratumumab, anti-IL-6R monoclonal antibody tocilizumab, low-dose IL-2, and intrathecal methotrexate. The evidence for the efficacy of these drugs mostly comes from case reports, and there are currently no high-quality randomized controlled clinical studies reported.

Studies have found that anti-NMDAR antibody is produced by autoreactive B cells and plasma cells. Among these cells, long-lived plasma cells in the intrathecal, meningeal, and brain parenchyma are responsible for the production of pathogenic antibodies in severe cases. The B cell-depleting therapeutic antibody rituximab targets CD20-positive B cells. CD138-positive plasma cells lack CD20 surface receptors, are not targeted by rituximab, and are also resistant to other immunosuppressive therapies. Daratumumab is an anti-CD38 antibody that can target long-lived plasma cells and has shown good therapeutic responses in autoimmune hemolytic anemia, systemic lupus erythematosus, and autoimmune encephalitis, with an acceptable safety profile. Daratumumab not only works by clearing plasma cells, but also regulates certain T cell functions.

RADIA study is an investigator-initiated, randomized, controlled, open-label, multicenter clinical trial to investigate the safety and efficacy of anti-CD20 mAb ofatumumab in combination of anti-CD38 mAb daratumumab in patients with severe anti-NMDAR encephalitis.

Inclusion criteria

• Aged 12 years and above
• Meet the diagnosis of autoimmune encephalitis and the target antigen is a neuronal surface antigen
• Have received at least 3 days of 500-1000mg high-dose methylprednisolone impulse treatment and IVIG (0.4g/kg/d for 5 consecutive days) or at least 5 plasma exchange/immunoadsorption or at least 2 times of efgartigimod treatment
• mRS ≥ 3 points and neuropsychiatric manifestations inadequate to symptomatic treatment
• Informed consent or guardian signed informed consent

Exclusion criteria

• Severe active or chronic infection in the opinion of the investigator.
• Concurrently/previously participated in another clinical study involving investigational therapy within 4 weeks or 5 published half-lives of the investigational therapy (whichever is longer) before randomization.
• Women who are lactating or pregnant, or intend to become pregnant at any time within six months from study enrollment to the last dose of study drug.
• Known history of allergy or reaction to any component of the investigational drug formulation, or history of allergic reaction after any biological treatment.
• Any of the following at screening (one repeat test may be performed during the same screening period to confirm results prior to randomization):

Aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN)

Alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)

Total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome)

Platelet count < 75,000/μL (or < 75 × 109/L)

Hemoglobin < 8 g/dL (or < 80 g/L)

Total white blood cell count < 2,500 cells/mm3

Total immunoglobulins < 600 mg/dL

Absolute neutrophil count < 1200 cells/μL

CD4 T lymphocyte count < 300 cells/µL

Receipt of any experimental B cell depleting agent, unless CD19 B Cell levels have returned to above the lower limit of normal before randomization A history of severe drug allergies or anaphylaxis to two or more foods or drugs (including known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamines, and methylprednisolone or equivalent glucocorticoids).

A known history of primary immunodeficiency (congenital or acquired) or underlying conditions, such as human immunodeficiency virus (HIV) infection or splenectomy, that predispose the participant to infection.

Any of the following received within 3 months before randomization Natalizumab (Tysabri®) Cyclosporin Methotrexate Mitoxantrone Cyclophosphamide Azathioprine

• Confirmed positive hepatitis B serology (hepatitis B surface antigen and core antigen) and/or positive hepatitis C PCR at screening.
• History of cancer, other than ovarian or extraovarian teratoma (also known as dermoid cyst) or germ cell tumor, or cutaneous squamous cell carcinoma or cutaneous basal cell carcinoma. Treatment of squamous cell carcinoma and basal cell carcinoma should have documented successful curative treatment more than 3 months before randomization.
• Received any live or attenuated vaccine (inactivated vaccine is acceptable) within 3 weeks before enrollment.
• Received BCG vaccine within 1 year before enrollment.