Targeting CD24 Activates Macrophages to Reduce Tumor Burden in Preclinical Models of Solid Tumors

PURPOSE: CD24 is a "don't eat me" signal overexpressed across multiple solid tumors and contributes to immune evasion by suppressing macrophage-mediated phagocytosis. Targeting the CD24/Siglec-10 axis represents a novel immuno-oncology strategy to restore innate immune surveillance. EXPERIMENTAL DESIGN: We developed PHST001, a humanized IgG4 monoclonal antibody targeting CD24, and evaluated its activity using in vitro phagocytosis assays, xenograft and immune-competent syngeneic mouse models, and ex vivo systems incorporating human immune cells and tumor samples. Nonclinical safety parameters were assessed to evaluate translational feasibility. RESULTS: PHST001 binds CD24 with high affinity and blocks Siglec-10 engagement, resulting in enhanced macrophage-mediated phagocytosis across multiple tumor indications and subtypes, inhibition of primary and metastatic tumor growth, and prolonged survival in preclinical models. PHST001 demonstrated a favorable nonclinical safety profile and exhibited anti-tumor activity as both monotherapy and in combination with standard-of-care treatments, including chemotherapy, radiotherapy, and antibody-drug conjugates (ADCs). Antitumor responses were associated with engagement of tissue-resident macrophages, and in syngeneic models, induction of tumor-reactive T-cell responses, supporting a role for CD24 in coordinating innate and adaptive immune suppression. CONCLUSIONS: These findings establish CD24 as a critical regulator of tumor immune evasion and support the clinical development of PHST001 as a CD24-targeted immunotherapy. A Phase I clinical study (NCT06840886) evaluating the safety and tolerability of PHST001 in adult patients with relapsed or refractory solid tumors is ongoing.