Harnessing Bispecific Antibody XmAb18087 for Targeted Immunotherapy in Neuroendocrine Tumors: Insights from Preclinical Studies

XmAb18087 is a humanized bispecific antibody developed to target SSTR2, a receptor highly present in neuroendocrine tumors (NETs) and small cell lung cancer (SCLC). This innovative therapy aims to overcome limitations of current treatments, such as short half-life and side effects due to off-target effects. The antibody is designed to engage T cells, triggering a cytotoxic response against SSTR2-positive tumor cells. It features an Fc domain for longevity and is engineered to avoid binding to Fcγ receptors, thus minimizing Fc-mediated side effects.

In vitro studies have shown that XmAb18087 effectively stimulates T cell-mediated cytotoxicity against SSTR2-positive cell lines, including medullary thyroid carcinoma, lung carcinoma, and CHO cells engineered to overexpress SSTR2. The antibody also induces the activation markers CD69 and CD25 on T cells, confirming its ability to activate the immune response specifically against the target cells.

Animal studies using NSG mice with human peripheral blood mononuclear cells (PBMCs) have demonstrated that XmAb18087 can reduce tumor burden in an A549 xenograft model. In cynomolgus monkeys, the antibody has shown to rapidly activate peripheral T cells and induce cytokines, such as IL6 and TNF, indicating a systemic immune response. Repeat dosing studies suggest that the effects of XmAb18087 persist for at least a week, as evidenced by a decreased response to a second dose.

The findings from human cells, mice, and monkeys support the potential of XmAb18087 as a new immunotherapy for SSTR2-positive cancers, including NETs and SCLC. The immune response markers observed in monkeys could serve as valuable indicators of the therapeutic effect in clinical trials.