Antigen specific treatment of achr myasthenia gravis with an engineered biologic

The National Institute of Neurological Disorders and Stroke awarded Sierra Biopharma Inc. $360,661 on July 15, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to develop an engineered biologic for antigen-specific treatment of acetylcholine receptor (AChR) myasthenia gravis.

The funded work develops a novel Fc fusion protein combining an engineered main immunogenic region (MIR) mimic peptide with human Fc properties. The therapeutic agent targets pathogenic anti-MIR antibodies, which account for 50–70 percent of anti-AChR antibodies in myasthenia gravis sera and represent a major pathogenic component of the disease. The biologic employs a two-pronged approach: binding to and neutralizing these pathogenic antibodies while destroying associated B cells. Preliminary data demonstrate that Sierra Biopharma's engineered MIR mimic peptide specifically binds to pathogenic anti-MIR antibodies in experimental autoimmune myasthenia gravis animal models and patient myasthenia gravis sera, and clears these antibodies from sera in vitro.

This Phase I SBIR award seeks to establish the feasibility of a targeted, non-immunosuppressive treatment for an autoimmune orphan disease affecting approximately 60,000 patients in the United States, as an alternative to current therapies that suppress the entire immune system and carry significant toxic side effects. Work is performed in Davis, California, with performance through June 30, 2028.

Abstract

Myasthenia gravis (MG) is an autoimmune orphan disease with approximately 60,000 cases in the united states and an estimated 1.4 million cases worldwide. MG symptoms include use-induced muscle fatigue and in the case of myasthenic crisis, respiratory failure requiring intubation and mechanical ventilation. At present, there is no cure for MG. Current therapies have many toxic side effects and suppress the entire immune system, leaving patients susceptible to infections and other diseases. Patients need a non-immunosuppressive alternative. MG is an antibody-mediated autoimmune disease that attacks the neuromuscular acetylcholine receptors (achrs), leading to the simplification of the folded post-synaptic membrane and loss of achr density. In MG sera, 50-70% of the anti-achr antibodies (ABS) bind to an immunological hot spot on the achr two α-subunits called the main immunogenic region (MIR). These anti-MIR ABS have been shown to be a major if not the main pathogenic component of MG sera. As such, an AB-specific biologic designed to specifically neutralize and clear these pathogenic anti-MIR ABS and destroy the associated b cells offers a targeted non-immunosuppressive treatment for MG. Preliminary data: sierra biopharma, INC. Has engineered a MIR mimic peptide of the conformational-sensitive MIR domain and demonstrated that the MIR mimic peptide specifically binds to pathogenic anti-MIR ABS in the animal model, experimental autoimmune myasthenia gravis (eamg), and inpatient MG sera. IT also clears these ABS from the sera of eamg rats in vitro. Our therapeutic agent is a novel FC fusion protein that combines the targeting properties of the engineered MIR mimic peptide with the biological and pharmacological properties of a human FCƔ1 into an AB- AB-specific immunotherapeutic biologic. The biologic uses a two-pronged approach to treating MG. First, IT binds to the combining sites of anti-MIR ABS forming, an antigen-antibody immune complex to neutralize and clear a substantial fraction of the pathogenic ABS. Secondly, IT binds b cell receptors on anti-MIR-associated b cells and induces their destruction via complement-dependent cytotoxicity, AB-dependent t cell cytotoxicity, and/or apoptosis. Overall impact: the biologic represents a novel AB-specific treatment for MG. Unlike current therapies, the lead biologic treats MG patients without leaving them immunocompromised. IT is a first-line therapeutic that can induce remission of MG without many of the side effects associated with current therapies. The biologic will be produced, characterized, and tested in vitro and eamg rats for proof of concept. Once validated in eamg, the lead compound will enter further preclinical investigation in phase II, leading to an IND and subsequent clinical trial of the drug.