Bioconjug Chem. 2022 Nov 16;33(11):1973-1982. doi: 10.1021/acs.bioconjchem.2c00020. Epub 2022 Mar 14.
CD47 on healthy cells, cancer cells, and even engineered particles can inhibit phagocytic clearance by binding SIRPα on macrophages. To mimic and modulate this interaction with peptides that could be used as soluble antagonists or potentially as bioconjugates to surfaces, we made cyclic "nano-Self" peptides based on the key interaction loop of human CD47. Melanoma cells were studied as a standard preclinical cancer model and were antibody-opsonized to adhere to and activate engulfment by primary mouse macrophages. Phagocytosis in the presence of soluble peptides showed cyclic > wildtype > scrambled activity, with the same trend observed with human cells. Opsonized cells that were not engulfed adhered tightly to macrophages, with opposite trends to phagocytosis. Peptide activity is nonetheless higher in human versus mouse assays, consistent with species differences in CD47-SIRPα. Small peptides thus function as soluble antagonists of a major macrophage checkpoint.
健康细胞、癌细胞甚至工程化颗粒上的 CD47 可以通过与巨噬细胞上的 SIRPα 结合来抑制吞噬清除。为了模拟并调节这种与肽的相互作用，这些肽可以作为可溶性拮抗剂或潜在地作为生物缀合物用于表面，我们基于人类 CD47 的关键相互作用环制造了环状“纳米自我”肽。我们研究了黑色素瘤细胞作为标准的临床前癌症模型，并使其抗体包被以附着并激活原发性小鼠巨噬细胞的吞噬作用。在存在可溶性肽的情况下，吞噬作用显示出环状>野生型>乱序活性，在人类细胞中也观察到相同的趋势。未被吞噬的包被细胞紧密附着在巨噬细胞上，与吞噬作用相反。然而，与小鼠检测相比，肽在人类中的活性更高，这与 CD47-SIRPα 在物种上的差异一致。因此，小肽可以作为主要巨噬细胞检查点的可溶性拮抗剂。
