Anti-SIRPα Antibodies as A Potential Weapon for Cancer Immunotherapy via Accelerated Screening in Humanized Mouse Models
Signal regulatory protein α (SIRPα) is a transmembrane protein and is especially abundant in myeloid cells such as macrophages and DCs, whereas it is expressed at very low levels in T, B and NK cells. SIRPα inhibits phagocytosis in macrophages upon interacting with its ligand CD47 that is commonly upregulated on the surface of malignant cells. Thus, antibodies that block the CD47-SIRPα interaction should enhance macrophage phagocytosis in the tumor microenvironment and inhibit tumor growth.
We are interested in subverting the negative feedback of CD47-SIRPa axis, especially in the treatment of cancer patients. Using Biocytogen’s antibody research platform, we obtained many high-affinity anti-human SIRPα mAb by high-throughput flow cytometry screening. Next, these murine antibodies were screened directly in single or double humanized mice models (B-hSIRPα or B-hSIRPα/hCD47) bearing a syngeneic humanized cancer cell line (MC38-hCD47). We discovered candidates that have potent anti-tumor activity in vivo. Then chimeric antibodies and humanized antibodies were further constructed and examined in vivo. In addition, we proved that the synergistic anti-tumor activity of anti-human SIRPα mAbs in combination with anti-mouse PD-1 mAb in B-hSIRPα/hCD47 mice. In brief, our existing studies demonstrate that SIRPα is an ideal target in the preclinical cancer models. The translational merits of these novel anti-SIRPα antibodies are waiting for clinical evaluation.