Novel Anti-CD47 Fusion Protein CO-005 Overcomes Rituximab Resistance in Lymphoma Models

CO-005, a humanized anti-CD47 fusion protein, demonstrated potent antitumor activity in preclinical models of B-cell lymphoma, including tumors resistant to rituximab, according to a new study published in ImmunoTargets and Therapy. The therapy is designed to overcome resistance mechanisms that limit the effectiveness of anti-CD20 monoclonal antibodies like rituximab.

The research, conducted by scientists at Caedo Oncology AS in Oslo, Norway, evaluated CO-005 in multiple lymphoma xenograft models using NOD-scid IL2Rγnull (NSG) mice. The study found that CO-005 induced potent and durable antitumor activity, including in rituximab-resistant tumor models. The therapy works by simultaneously disrupting the CD47–SIRPα immune checkpoint and inducing direct programmed cancer cell death (PCCD), a mechanism distinct from other anti-CD47 agents.

CO-005 induces type III programmed cell death through several cellular processes, including receptor capping, calcium flux, reactive oxygen species generation, actin cytoskeleton dependence, and surface calreticulin exposure. These mechanistic features are shared with therapeutic anti-CD20 antibodies but occur independently of CD20 signaling, making the therapy potentially effective against tumors with low or heterogeneous CD20 expression that have developed resistance to standard treatments.

In vivo experiments showed that CO-005 triggered robust intratumoral programmed cell death and remodeled the tumor microenvironment. This remodeling was characterized by increased infiltration of macrophages and neutrophils, enhancing innate immune activation and supporting a dual-mechanism mode of action that couples direct cancer cell killing with myeloid immune cell engagement.

The study addressed a significant clinical challenge: despite the success of anti-CD20 monoclonal antibodies like rituximab in treating B-cell non-Hodgkin lymphomas, therapeutic resistance and relapse remain major problems. Resistance arises through multiple mechanisms, including impaired Fc receptor signaling, depletion or dysfunction of effector cells, and compensatory upregulation of alternative immune checkpoints like CD47. CD20 expression can also become heterogeneous or be lost following treatment, rendering tumors partially or completely refractory to CD20-directed therapies.

CO-005 was developed to bypass CD20 dependence while maintaining robust immune effector engagement. The therapy combines intrinsic cytotoxic activity with immune checkpoint inhibition and immune activation, positioning it as a mechanistically distinct therapeutic with potential to expand treatment options for B-cell lymphoma patients who have failed standard anti-CD20 therapies.

The research was published in ImmunoTargets and Therapy, Volume 15, 2026. The study authors include researchers from Caedo Oncology AS and the Department of Chemistry, Bioscience and Environmental Engineering at the University of Stavanger.