The SIRP alpha Fc fusion protein can block the immunosuppressive CD47-SIRP alpha signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide "TKKTLRT " is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRP alpha Fc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT-SIRP alpha Fc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT-SIRP alpha Fc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD-SIRP alpha Fc accumulated in tumor tissue more effectively compared to unmodified SIRP alpha Fc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD-SIRP alpha Fc presented more stable and effective antitumor efficacy than SIRP alpha Fc, along with significantly increased CD11b(+)F4/80(+) macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRP alpha Fc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD-SIRP alpha Fc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.
[1]Fudan Univ, Minhang Hosp, Shanghai, Peoples R China.
[2]Fudan Univ, Shanghai Engn Res Ctr Immunotherapeut, Sch Pharm, Shanghai, Peoples R China.
[3]ImmuneOnco Biopharm Shanghai Co Ltd, Shanghai, Peoples R China.
[4]Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai, Peoples R China.
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