ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• CD47 is a cell surface protein acting as an immune checkpoint in cancer, suppressing innate immune functions by binding SIRPα on myeloid cells.
• CD47-SIRPα signaling also contributes to suppressing adaptive antitumor responses, though its precise mechanisms are not fully understood.
• Therapeutic targeting of the CD47 pathway holds promise for stimulating antitumor immunity and improving cancer treatment outcomes.

Purpose of the Study:

• To evaluate the efficacy and safety of ALX148, a novel molecule designed to block CD47-SIRPα interactions.
• To investigate the mechanisms by which ALX148 modulates innate and adaptive immune responses against tumors.
• To assess the potential of ALX148 in combination with other cancer therapies.

Main Methods:

• ALX148, a fusion protein of a modified SIRPα D1 domain and human IgG1 Fc, was developed to bind CD47.
• In vitro assays assessed ALX148's binding affinity, inhibition of SIRPα binding, and enhancement of phagocytosis.
• In vivo studies utilized murine tumor xenograft and syngeneic models to evaluate ALX148's antitumor activity, alone and in combination with antibodies, and assessed safety in non-human primates.

Main Results:

• ALX148 demonstrated high-affinity binding to CD47 across species and effectively inhibited SIRPα binding, enhancing macrophage phagocytosis of tumor cells.
• ALX148 showed no adverse effects on normal human blood cells in vitro or on blood cell parameters in animal studies.
• In vivo, ALX148 significantly enhanced the antitumor activity of targeted antitumor and immunotherapeutic antibodies in various tumor models.
• ALX148 promoted dendritic cell activation, shifted tumor-associated macrophages to an inflammatory phenotype, increased T cell effector function, and reduced suppressive cells within the tumor microenvironment.

Conclusions:

• ALX148 effectively blocks CD47-SIRPα signaling, bridging innate and adaptive immunity for a broad antitumor response.
• ALX148 demonstrates a favorable safety profile and enhances the efficacy of existing cancer therapies.
• ALX148 represents a promising therapeutic candidate for cancer treatment by modulating the tumor immune microenvironment.