Targeting CD47 and CD19 with a Bispecific Antibody: Enhancing Tumor Microenvironment for Cancer B Cell Elimination and Memory Immunity

The study highlights the role of CD47 overexpression in various cancers and its association with poor outcomes. It explains that CD47's interaction with SIRPα provides a protective signal for cells, preventing them from being cleared by the immune system, particularly macrophages. Despite tumor-associated macrophages often being linked to cancer development, the presence of therapeutic antibodies can activate their phagocytic and tumor-killing capabilities. Targeting the CD47-SIRPα pathway is thus seen as a promising strategy to enhance macrophage-mediated tumor destruction.

However, the development of monoclonal antibodies against CD47 faces challenges due to its widespread presence, which can lead to rapid drug clearance and adverse effects such as anemia. To overcome these issues, the researchers developed NI-1701, a bispecific antibody designed to bind effectively only to CD19+ B cells. This is achieved by combining a high-affinity anti-CD19 targeting component with an anti-CD47 component with optimized affinity.

In vitro studies showed that NI-1701 can effectively kill CD19+ tumor B cells through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cell-mediated cytotoxicity (ADCC). In vivo studies also demonstrated significant tumor reduction when NI-1701 was used as a single agent or in combination with other treatments. The antibody was found to control tumor growth in mice with implanted Raji cells, with an effect dependent on the simultaneous binding to both CD19 and CD47. It was observed that NI-1701 altered the tumor microenvironment by increasing macrophage activity against tumor cells, promoting an antitumor phenotype, and reducing suppressor cells.

Further studies in a disseminated model showed that NI-1701 could eliminate tumor cells from various organs in mice with B-Acute Lymphocytic Leukemia (B-ALL) or those transplanted with primary B-ALL cells. It also proved more effective than the BTK inhibitor ibrutinib in a Diffuse Large B-Cell Lymphoma (DLBCL) patient-derived xenograft (PDX) mouse model.

Combination therapy with NI-1701 and other clinically validated drugs was explored, with the bispecific antibody showing greater efficacy than Rituximab in controlling tumor growth. A synergistic effect was observed when the two were combined, leading to tumor regression in some cases.

Safety studies indicated that NI-1701 had a favorable binding profile to B cells with no adverse effects on erythrocytes, platelets, or causing hemagglutination at therapeutic concentrations. Non-human primate studies showed favorable elimination kinetics and no impact on hematological parameters at doses up to 100mg/kg.

The research concludes that NI-1701 offers a novel bispecific approach to safely and effectively target CD47 with high selectivity for a B cell-associated antigen, leading to significant tumor cell killing in preclinical models. The effects on the tumor microenvironment and the potential for inducing long-term tumor immunity suggest that targeting myeloid lineage cells is a promising strategy in immune-oncology. NI-1701 is currently in preclinical studies, with plans for a Phase I clinical trial in patients with CD19+ B cell malignancies in early 2017.