AbelZeta Pharma, Inc. presented promising preclinical data for its novel bispecific CAR-T therapy, C-CAR168, at the American College of Rheumatology (ACR) Convergence 2024 in Washington, DC. The therapy, which targets both CD20 and B-cell maturation antigen (BCMA), is being developed for patients with resistant and refractory Lupus Nephritis (LN) and Systemic Lupus Erythematosus (SLE).
The U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for C-CAR168 in May 2024, allowing AbelZeta to proceed with Phase 1 clinical development.
Innovative Dual-Targeting Mechanism
C-CAR168 represents a novel approach to autoimmune disease treatment by simultaneously targeting two key markers: CD20, present on B cells, and BCMA, expressed on plasma cells. This dual-targeting strategy aims to eliminate both pathogenic B cells and long-lived plasma cells (LLPCs) that contribute to autoimmune responses.
Preclinical studies demonstrated that C-CAR168 effectively induced cell death in cells expressing CD20 and/or BCMA, including the age-associated B cell (ABC) subset that is significantly expanded in autoimmune conditions.
"C-CAR168 was designed to recognize and kill B cells, plasmablasts and LLPCs to eliminate the source of autoantibodies and to provide a definitive treatment in a variety of severe autoimmune diseases resistant to current treatment, including LN and SLE," explained Yihong Yao, PhD, Chief Scientific Officer of AbelZeta.
Strong Preclinical Efficacy and Safety Profile
In immunodeficient mouse models, a single dose of C-CAR168 demonstrated significant activity across multiple dosage levels. The therapy effectively inhibited the growth of cells expressing CD20 and BCMA in various xenograft models.
Comprehensive safety assessments, including membrane proteome array analysis, confirmed that C-CAR168 specifically targets CD20 and BCMA proteins with no significant binding to non-target cells. In vitro assays showed minimal risk of carcinogenicity or unintended cell transformation, supporting a favorable safety profile.
Early Clinical Experience in China
An investigator-initiated trial in China has already begun evaluating C-CAR168 in patients with refractory/relapsing LN. Seven patients have been treated at suboptimal and potentially optimal doses, with encouraging preliminary results.
All treated patients showed depletion of both B cells and plasma cells in the blood. Those with at least three months of follow-up at the suboptimal dose have demonstrated early positive clinical signals, accompanied by a favorable safety profile.
Expanding Therapeutic Applications
Beyond LN and SLE, AbelZeta is exploring additional autoimmune indications for C-CAR168, including Neuromyelitis Optica Spectrum Disorder (NMOSD), Immune-Mediated Necrotizing Myopathy (IMNM), and Systemic Sclerosis (SSc). These investigations will inform the global clinical trial planned for mid-2025.
"We are encouraged by the progress we have made of C-CAR168 thus far. We believe we potentially have an excellent drug for patients suffering a variety of autoimmune diseases with severe manifestations and poor prognoses," said Tony (Bizuo) Liu, Chairman and CEO of AbelZeta. "This progress marks a major stride forward for us to deliver potentially best-in-class and/or best-in-disease innovative cellular therapies for cancer and inflammatory & immunological diseases."
Addressing Unmet Needs in Autoimmune Disease Treatment
Current treatments for severe autoimmune diseases like LN and SLE often have limited efficacy in resistant cases. C-CAR168 represents a potential paradigm shift by targeting the cellular sources of autoantibodies rather than merely managing symptoms or broadly suppressing the immune system.
The CD20 target has already proven effective in both oncology and autoimmune disease settings, while BCMA targeting has shown success in multiple myeloma. By combining these approaches, AbelZeta aims to create a more comprehensive treatment for autoimmune conditions with significant unmet needs.
As C-CAR168 advances into clinical development in the United States following the recent IND clearance, the therapy could potentially offer a new option for patients who have exhausted conventional treatment approaches for severe autoimmune diseases.
