Science and Pipeline

Systemic sclerosis (SSc), or scleroderma, is a rare, chronic autoimmune disease characterized by vascular injury, immune system dysregulation, and progressive fibrosis affecting both the skin and vital internal organs, including the lungs, heart, and gastrointestinal tract. Global prevalence is estimated at 17.6 cases per 100,000 people, with highest rates in North America.

Patients with SSc face a substantial disease burden due to skin thickening, dyspnea from pulmonary or cardiac involvement, gastrointestinal dysfunction, kidney disease, limited mobility, chronic pain, and fatigue. The disease also carries one of the highest mortality rates among autoimmune conditions, largely driven by interstitial lung disease (ILD), pulmonary hypertension and cardiac disease. Although some treatments are available to slow the progression of SSc‑associated ILD, current approved therapies address only specific complications rather than addressing and modifying the underlying disease mechanism and fibrotic process.

Substantial clinical evidence implicates the role of aberrant B‑cells in SSc. Although rituximab, a CD20‑targeting antibody, is often used off‑label for SSc, its efficacy is believed to be limited due to insufficient depletion of B‑cells in tissues. CAR‑T therapies and T‑cell engagers can induce profound B‑cell depletion within tissues and may offer meaningful clinical benefit even in highly refractory populations, including patients unresponsive to rituximab. Notably, PRO‑203 has demonstrated deeper tissue B‑cell depletion than rituximab, a finding that may translate into improved disease control and the potential for durable remission.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes widespread inflammation across multiple organ systems, including the skin, joints, kidneys, central nervous system, and cardiovascular system. It affects approximately 200,000 people in the United States and an estimated 3.4 million individuals worldwide, with women making up most cases.

SLE is a lifelong condition characterized by alternating periods of flares and remission. Symptoms vary widely and may include fatigue, joint pain, skin rashes and involvement of major organs such as the kidneys, heart, brain and blood cells. Lupus nephritis (LN), a serious kidney complication, is a key cause of long‑term organ damage and mortality. Aberrant B‑cells play an important role in the pathogenesis of SLE.

Although rituximab, a CD‑20 targeting therapy, is used off‑label for the treatment of SLE and LN, and another CD‑20 targeting therapy, obinutuzumab (Gazyva), has recently been approved for LN in the United States, at least 60% of LN patients still have inadequate clinical response. This may stem, in part, from the inability of such antibodies to achieve deep depletion of B-cells in tissues.

Emerging clinical evidence suggests that CAR‑T cell therapies and T‑cell engagers can achieve deeper and more sustained B‑cell depletion. These approaches have shown the potential to deliver meaningful clinical benefit even in highly refractory patients, including those who have failed rituximab, and may signal the beginning of a new therapeutic era for autoimmune diseases.

• Phase I/II clinical trial in Relapsed and Refractory Non-Hodgkin’s lymphoma(NHL); conducted by InnoCare and Keymed (ICP-B02/CM355)
• Assessed safety, tolerability, PK, and preliminary anti-tumor activity
• Evaluated both IV and SC formulations
• Promising early results, particularly in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)

T-cell engagers (TCEs) are engineered, bispecific antibodies that redirect T-cells to eliminate cells expressing a specific antigen. While initially pioneered in oncology to destroy tumor cells, TCEs are now being explored for autoimmune diseases, where the goal is to selectively deplete pathogenic immune cells.

TCEs are typically designed with two arms (e.g., CD20 and CD3) that engage their targets simultaneously, forming an immune synapse between the T-cell and the target cell, triggering T-cell activation, release of cytotoxic granules, and targeted killing of the bound cell.

Clinical experience with B-cell–directed CAR T therapies has demonstrated that deep and durable B-cell depletion can translate into profound and sustained disease control in autoimmune disorders, underscoring the pathogenic role of residual B-cell populations. While approved agents such as rituximab (anti-CD20 antibody) and other B-cell targeting antibodies, have shown clinical benefit in a broad range of autoimmune diseases, their clinical efficacy is thought to be limited, in part, by their ability to achieve deep B-cell depletion in tissues.

TCEs offer a differentiated immunotherapy approach in autoimmune disease by enabling potent, targeted depletion of pathogenic B-cells while avoiding the complexity of autologous cell therapy. By redirecting endogenous T-cells to eliminate B-cells, these agents have the potential to achieve deeper and more complete B-cell depletion compared to current approved agents. At the same time, unlike CAR T therapies, TCEs are off the shelf biologics, allowing for standardized manufacturing, rapid treatment initiation, and broader scalability.