Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• CD47 is an immune checkpoint receptor frequently overexpressed in various cancers.
• CD47's interaction with SIRPα on macrophages inhibits cancer cell phagocytosis and promotes immune evasion.
• Widespread CD47 expression poses challenges for therapeutic antibody development due to tolerability and "antigen sink" issues.

Purpose of the Study:

• To develop novel bispecific antibodies for targeted cancer therapy.
• To overcome the limitations of targeting ubiquitously expressed CD47.
• To create antibodies that selectively block the CD47-SIRPα interaction on malignant cells.

Main Methods:

• Generation of dual-targeting bispecific antibodies (κλ bodies) with tumor-specific antigen targeting (e.g., CD19, mesothelin).
• Engineering of native IgG1 molecules to combine tumor targeting, selective CD47 blockade, and Fc-mediated immune activation.
• In vitro and in vivo evaluation of antibody efficacy in killing cancer cells and interaction with healthy cells.
• Pharmacokinetic and tolerability studies in non-human primates.

Main Results:

• Bispecific κλ bodies efficiently kill cancer cells in vitro and in vivo.
• These antibodies exhibit weak interaction with healthy cells expressing physiological CD47 levels.
• The antibodies maintain tumoricidal capabilities even in the presence of a CD47 "antigen sink".
• Administration in non-human primates demonstrated a typical IgG pharmacokinetic profile and good tolerability.

Conclusions:

• Dual-targeting bispecific antibodies offer an efficacious and safe approach for targeting CD47 in cancer.
• This bispecific design enables selective CD47 neutralization on malignant cells, minimizing off-target effects.
• The strategy can be adapted for targeting other ubiquitously expressed therapeutic targets in cancer therapy.