Autoimmune disease occurs when a person’s immune system inappropriately perceives one or more “self” proteins as foreign and mounts an immune attack against them. Currently, most autoimmune patients are treated by broadly suppressing their immune system, leaving them vulnerable to infection, cancer, and metabolic dysregulation. Further, such approaches only modify symptoms rather than treat the underlying disease.

The first autoimmune indication we are pursuing is myasthenia gravis (MG), a rare disease that causes muscle weakness because the immune system makes antibodies that block the function of a key muscle receptor called the acetylcholine receptor (AChR). Symptoms include trouble chewing and swallowing, droopy eyelids, muscle weakness, and slurred speech. Refractory patients have no disease modifying therapies available, and instead are treated by immunosuppressive agents. To fulfill this pressing unmet need, GRObio is developing ProGly-AChR – the first disease-modifying therapy for MG that is highly efficacious without immune suppression. ProGly-AChR uses our ProGly platform chemistry to produce a tolerogenic version of the AChR antigen that induces proliferation of tolerogenic immune cells, which reeducate a patient’s immune system to recognize AChR as a self-protein and reverses the autoimmune process.

Immunogenicity arises when the immune system recognizes a therapeutic as foreign. Many enzyme, gene, and cell therapies are immunogenic, which often manifests as anti-drug antibodies (ADA) directed against the therapeutic. ADA can severely limit the efficacy of a drug and can also cause serious safety issues for patients. The problem is particularly pronounced for therapies that require chronic administration, as ADA typically increase over multiple treatments.

The first indication we are pursuing to eliminate therapeutic immunogenicity is gout, a type of arthritis that causes debilitating inflammation of joints due to excess uric acid buildup. Symptoms include intense pain, discoloration or redness, stiffness, swelling, and extreme tenderness. Therapeutic treatment for severe, refractory gout can include uricase enzyme to break up uric acid crystal deposits and reduce serum uric acid levels. However, the majority of patients receiving uricase treatment, such as Krystexxa® (pegloticase), develop anti-drug antibodies (ADAs) that clear the enzyme from circulation, compromising treatment safety and efficacy and leaving patients without treatment options.  GRObio is using our ProGly NSAAs to develop ProGly-Uricase that prevents anti-uricase ADAs to provide a novel, safe and effective uricase for patients with severe, refractory gout.

We use the computational protein design tools and high-throughput screening workflows in our Biofoundry to engineer ProGly therapies that are tolerogenic while retaining their full activity in the intended physiological environment. We have shown that this approach can be applied to highly immunogenic proteins to prevent ADA, to block pre-existing ADA from binding to ProGly therapies, and to prolong their circulating time and functional half-life. We are now extending our work to address the immunogenicity of additional enzyme, gene and cell therapies.