A Long Acting B Cell Depleting BiTE (Bi-Specific T Cell Engager) Significantly Ameliorated EAE Symptoms without Potential CRS Risk

Background: B cells play critical roles in the pathophysiological progression in autoimmune diseases including multiple sclerosis (MS). B cell depletion by monoclonal antibodies (such as anti-CD20) has been proved to bring clinical benefits for autoimmune disease patients

Objectives: To develop a novel pegylated anti-CD3 x anti-CD19 compound which could significantly ameliorated symptoms on the animals of Experimental Autoimmune Encephalomyelitis (EAE, the animal model of MS) without the potential risk of developing cytokine release syndromes

Methods: Using our patented pegylated bispecific antibody technology, we developed the compound. In vivo efficacy was evaluated on EAE model.

Results: Compared to the non-pegylated parental compound blinatumomab (approved for treating B cell lineage leukemia or lymphoma), the pegylated compound binds to CD3e on T cells and CD19 on target cells with much reduced affinity than blinatumomab and selectively depletes B cells with high level CD19 expression in PBMC, which has been reported to be antibody secreting plasma cells. By measuring the released cytokines of the healthy donor derived whole blood incubated for 2hrs, 6hrs and 24hrs with different concentrations of the compound, we found that the compound barely induced cytokines in contrast to blinatumomab that induced significantly high-level cytokines. While Blinatumomab significantly stimulated T cell proliferation in vitro, this compound barely activated T cell proliferation. Preclinical tox study results showed that the compound did not induce any observable toxicity. To investigate the potential therapeutic efficacy to MS, we treated the MOG1-125 induced EAE animals (using hCD3ehCD19 transgenic mice) on day 7 and day 11 respectively by this compound. The results demonstrated that this compound is effective in both pre-onset and post-onset treatment to EAE. Interestingly, this compound not only deplete or reduce B cells in vivo, but also inflammatory T cells and total T cells. Pharmacokinetics study revealed that in vivo elimination half-life of the compound in wild type C57BL/6 mice was equivalent to one week in humans for the single dose of 1mg/kg

Conclusions:

In summary, this compound would be the first therapeutic BiTE with safety profile for MS and other autoimmune diseases.