Building on prior evidence that anti-PD-1 and anti-CD47 antibodies can synergize by stimulating both the innate and adaptive immune systems and that tumor cells co-express both targets, Liu et al. developed a bispecific antibody (IAB) targeting both molecules. In vitro, IAB promoted T cell activation and macrophage phagocytosis. In an immunocompetent MC38 mouse model, intratumoral injection of IAB led to partial or complete antitumor responses in most mice. Both CD8+ T cells and macrophages contributed to the anti-tumor effect of IAB.

The host immune system generally serves as a barrier against tumor formation. Programmed death-ligand 1 (PD-L1) is a critical "don't find me" signal to the adaptive immune system, whereas CD47 transmits an anti-phagocytic signal, known as the "don't eat me" signal, to the innate immune system. These and similar immune checkpoints are often overexpressed on human tumors. Thus, dual targeting both innate and adaptive immune checkpoints would likely maximize anti-tumor therapeutic effect and elicit more durable responses. Herein, based on the variable region of atezolizumab and consensus variant 1 (CV1) monomer, we constructed a dual-targeting fusion protein targeting both CD47 and PD-L1 using "Knobs-into-holes" technology, denoted as IAB. It was effective in inducing phagocytosis of tumor cells, stimulating T-cell activation and mediating antibody-dependent cell-mediated cytotoxicity in vitro. No obvious sign of hematological toxicity was observed in mice administered IAB at a dose of 100 mg/kg, and IAB exhibited potent antitumor activity in an immune-competent mouse model of MC38. Additionally, the anti-tumor effect of IAB was impaired by anti-CD8 antibody or clodronate liposomes, which implied that both CD8+ T cells and macrophages were required for the anti-tumor efficacy of IAB and IAB plays an essential role in the engagement of innate and adaptive immune responses. Collectively, these results demonstrate the capacity of an elicited endogenous immune response against tumors and elucidate essential characteristics of synergistic innate and adaptive immune response, and indicate dual blockade of CD47 and PD-L1 by IAB may be a synergistic therapy that activates both innate and adaptive immune response against tumors.

Author Info: (1) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. b School of Bioscience and Bioengineering, South China University of

Author Info: (1) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. b School of Bioscience and Bioengineering, South China University of Technology , Guangzhou , China. f Center for Drug Evaluation , China Food and Drug Administration , Beijing , China. (2) c Shanghai Sinomab Biotechnology Co. , Shanghai , China. (3) c Shanghai Sinomab Biotechnology Co. , Shanghai , China. (4) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. b School of Bioscience and Bioengineering, South China University of Technology , Guangzhou , China. (5) c Shanghai Sinomab Biotechnology Co. , Shanghai , China. (6) d Shanghai Zhangjiang Biotechnology Co. , Shanghai , China. (7) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. d Shanghai Zhangjiang Biotechnology Co. , Shanghai , China. (8) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. g Institute of Molecular and Cell Biology , 61 Biopolis Drive, Proteos 138673 , Singapore. (9) c Shanghai Sinomab Biotechnology Co. , Shanghai , China. (10) c Shanghai Sinomab Biotechnology Co. , Shanghai , China. (11) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. d Shanghai Zhangjiang Biotechnology Co. , Shanghai , China. (12) a State Key Laboratory of Antibody Medicine and Targeted Therapy , Shanghai , China. e School of Pharmacy, Liaocheng University , Liaocheng , China. g Institute of Molecular and Cell Biology , 61 Biopolis Drive, Proteos 138673 , Singapore.

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