IgA Nephropathy (IgAN)
IgAN is a progressive autoimmune kidney disease that affects an estimated 125,000 to 150,000 individuals in the U.S. and over 2 million globally. The disease is driven by the production of abnormally glycosylated IgA1 antibodies, which form pathogenic immune complexes that accumulate in the glomerular mesangium. This accumulation activates the complement system—primarily through the alternative and lectin pathways—leading to inflammation, fibrosis, and progressive renal injury.
Clinical manifestations of IgAN are highly variable, ranging from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Nearly 50% or patients ultimately progress to end-stage kidney disease (ESKD). There remains a significant unmet need for disease-modifying therapies that target the underlying immune dysregulation in IgAN. Specifically, treatments that can selectively deplete the B cells, plasmablasts, and plasma cells responsible for producing pathogenic IgA and IgG immune complexes hold considerable promise.
B-cell–directed therapies, including bispecific T-cell engagers (TCEs), offer the potential for deeper and more durable immunologic responses. By directly eliminating the antibody-producing cells driving disease, TCEs could emerge as a transformative therapeutic approach and potentially redefine the standard of care in IgAN.
Myasthenia Gravis (MG)
MG is a rare, chronic autoimmune neuromuscular disorder marked by weakness and fatigue. It affects approximately 125,000 to 150,000 people in the U.S. and 1.4 million globally. The condition arises when the immune system produces autoantibodies that attack the communication between nerves and muscles, primarily targeting acetylcholine receptors at the neuromuscular junction. In some cases, antibodies may also target other proteins, such as muscle-specific kinase (MuSK). This disruption impairs the transmission of nerve impulses, leading to muscle weakness. MG symptoms can be transient and may spontaneously remit in the early stages, they typically become more persistent as the disease progresses, with symptom-free intervals becoming less frequent.
Treatment includes steroids, immunosuppressants, complement inhibitors, and FcRn inhibitors, which are experiencing significant commercial adoption. However, patients become refractory to treatment and these treatments rarely lead to disease remission..
B-cell depletion targeting CD20 with rituximab has shown clinical benefit. TCEs targeting BCMA or CD20 offer a novel mechanism with the potential for deeper clinical responses and disease remission.
Rheumatoid Arthritis (RA)
RA is a chronic systemic autoimmune disease that affects approximately 1.3 million people in the U.S. and 18 million worldwide. It causes persistent inflammation in the joints, leading to cartilage destruction, bone erosion, and disability—most commonly impacting the hands and wrists. Symptoms can develop at any age, with peak onset between 30 and 50 years.
The treatment and management of RA is based on the guidelines from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Both guidelines highlight the importance of initiating disease-modifying antirheumatic drug (DMARD) therapy, with first line being the conventional synthetic DMARD, methotrexate. For patients who don’t respond adequately, additional DMARDs or biologics such as TNF inhibitors (e.g., Humira) are added. Nearly 50% of patients discontinue newly started DMARDs within 12–18 months due to side effects or lack of efficacy, and 20–30% are refractory to all available options, representing a large unmet medical need.
Emerging clinical data support the potential of T-cell engagers (TCEs) targeting BCMA or CD20 to provide meaningful responses in RA patients who have failed multiple prior therapies.
Systemic Lupus Erythematosus (SLE)
SLE is a complex autoimmune disease that causes widespread inflammation across multiple organ systems. Some patients with SLE also have lupus nephritis which is a disease affecting the kidneys. Over 200,000 people in the U.S. and 3 million globally are living with SLE.
Current treatments are focused on symptom control and flare prevention, including NSAIDs, corticosteroids, immunosuppressants, and hydroxychloroquine. While these options help manage the disease, there is still no cure, and many patients continue to experience significant disease burden.
CD20-targeting therapies such as obinutuzumab (Gazyva) have shown promise in SLE, and new modalities like CD20 TCEs (e.g., Lunsumio) and B-cell depleting approaches including CAR-T and bispecific TCEs have demonstrated clinical activity in highly refractory patients.
Systemic Sclerosis (SSc)
SSc, also known as scleroderma, is a rare chronic autoimmune disease that affects approximately 80,000 to 100,000 people in the U.S. and over 2.5 million worldwide. The disease is characterized by progressive fibrosis of the skin and internal organs, as well as widespread vascular dysfunction and immune system activation. Patients may present with limited or diffuse cutaneous forms of disease, with the latter associated with more severe complications involving the lungs, heart, kidneys, and gastrointestinal tract.
While onset can occur at any age, SSc most commonly presents between ages 30 and 50, with women disproportionately affected. Disease severity and progression vary across individuals, with interstitial lung disease (ILD) being the leading cause of SSc-related mortality.
There are currently no FDA-approved therapies that modify the underlying disease process across all organ systems. The lack of broadly effective and targeted therapies highlights a significant unmet medical need as patients continue to experience worsening symptoms and progression to irreversible organ damage.
Emerging clinical data suggest that BCMA targeting TCEs may be effective therapies for SSc through the deep tissue depletion of pathogenic immune cells leading to meaningful disease control and potentially reversal of fibrosis.