Crystal Structure of Human CD47 in Complex with Engineered SIRPα.D1(N80A)

Yu, Jifeng; Li, Song; Chen, Dianze; Liu, Dandan; Guo, Huiqin; Yang, Chunmei; Zhang, Wei; Zhang, Li; Zhao, Gui; Tu, Xiaoping; Peng, Liang; Liu, Sijin; Bai, Xing; Song, Yongping; Jiang, Zhongxing; Zhang, Ruliang; Tian, Wenzhi

doi:10.3390/molecules27175574

Cited by 9 publications

(8 citation statements)

References 32 publications

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“…The ideal CD47-based therapeutic modalities could specifically activate macrophage phagocytosis of tumor cells but not RBCs followed by T cell activation. With the determination of CD47/SIRPα complex structure, two glycosylation sites were identified 36 . Recently, several groups reported some SIRPα mutants and CD47 antibodies showed different binding ability to CD47 on tumor cells and normal cells, indicating different glycosylation model on CD47 in malignancy and normal cells.…”

Section: Discussionmentioning

confidence: 99%

Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment

Wang¹,

Zhang²,

Cao³

et al. 2023

Theranostics

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Background: Even though PD-1/PD-L1 is an identified key "don't find me" signal to active adaptive immune system for cancer treatment, the overall response rate (ORR) for all cancer patients is still limited. Other effective therapeutic modalities to bridge the innate and adaptive immunity to improve ORR are urgently needed. Recently, CD47/SIRPα interaction is confirmed as a critical "don't eat me" signal to active innate immunity. However, the red blood cell (RBC) toxicity is the big concern for the development of CD47-based anti-cancer therapeutics. Methods: Here, we report the development of a CD47/PD-L1 bispecific antibody 6MW3211 to block both PD-1/PD-L1 and CD47/SIRPα signals, and studied the effects of 6MW3211 on anti-tumor immune functions in vitro and in vivo. The pharmacokinetic and toxicity profiles of 6MW3211 were evaluated in GLP non-human primate (NHP) studies. Results:The dual immune checkpoint inhibitory signaling blocker 6MW3211 shows high binding affinity to PD-L1 and low binding affinity to CD47. This inequivalent binding affinity design makes 6MW3211 preferentially bound to PD-L1 on tumor cells followed by disrupting the interaction of CD47/SIRPα. Complex structure determination and flow cytometry assay demonstrated that 6MW3211 has no binding to either human or rhesus monkey RBCs. 6MW3211 effectively blocked both PD-1/DP-L1 and CD47/SIRPα signaling and promoted macrophage phagocytosis of tumor cells. Potent therapeutic efficacies of 6MW3211 in three different mouse models were further observed. Moreover, 6MW3211 was demonstrated to have a fairly good safety profile in a GLP NHP study. In addition, multiplex fluorescent immunohistochemistry (mIHC) staining shows that PD-L1 and CD47 co-express on several different types of human tumor tissues. Conclusions: These results support the development of 6MW3211 for the treatment of PD-L1 and CD47 double positive cancers.

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Section: Discussionmentioning

confidence: 99%

Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment

Wang¹,

Zhang²,

Cao³

et al. 2023

Theranostics

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“…Anti-CD80 monoclonal antibody (66,406-1-Ig, Proteintech), anti-CD163 monoclonal antibody (GB13340, Servicebio), anti-CD8 monoclonal antibody (GB12068, Servicebio), anti-CD31 monoclonal antibody (GB113151, Servicebio), VEGFA Monoclonal antibody (19,003-1-AP, Proteintech), anti-CD47 monoclonal antibody (ab218810, Abcam), carboxyfluorescein diacetate succinimidyl ester (CFDA SE) (C0051, Beyotime), PerCP anti-CD68 (333,813, BioLegend), PE anti-CD11b (101,208, BioLegend), granulocyte–macrophage colony-stimulating factor (GM-CSF) (C003, novoprotein), FITC-labeled anti-CD47 (CC2C6, BioLegend), Human Lymphocyte separation medium (7,111,011, DAKEWE). The fusion protein SIRPα-Fc has been engineered based on the initial extracellular domain of SIRPα and is currently undergoing Phase I/II clinical trial (NCT05140811) [ 32 ]. SIRPα-VEGFR1 is constructed by combining the extracellular domain of SIRPα with that of VEGFR1 (GenBank accession number: MG920788).…”

Section: Methodsmentioning

confidence: 99%

Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer

Zhang,

Xu,

Chang

et al. 2024

Cancer Immunol Immunother

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Background CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. Methods The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. Results In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. Conclusions Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.

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“…IMM01 is a recombinant human SIRPα IgG1 fusion protein that has strong dual-functional anti-tumor activity through phagocytosis with improved potency upon N-glycosylation removal [10]. IMM01 exhibits promising preclinical characteristics regarding its link between receptor occupancy, tumor exposure and efficacy.…”

Section: Imm01mentioning

confidence: 99%

“…When CD47 binds to SIRPα, the "don't eat me" signal is activated, inhibiting macrophage-mediated phagocytosis (Fig. 2) [10,11].…”

mentioning

confidence: 99%

The landscape overview of CD47-based immunotherapy for hematological malignancies

2023

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Extensive clinical and experimental evidence suggests that macrophages play a crucial role in cancer immunotherapy. Cluster of differentiation (CD) 47, which is found on both healthy and malignant cells, regulates macrophage-mediated phagocytosis by sending a "don't eat me" signal to the signal regulatory protein alpha (SIRPα) receptor. Increasing evidence demonstrates that blocking CD47 interaction with SIRPα can enhance cancer cell clearance by macrophages. Additionally, inhibition of CD47/SIRPα interaction can increase antigen cross-presentation, leading to T-cell priming and an activated adaptive antitumor immune response. Therefore, inhibiting CD47/SIRPα axis has a significant impact on tumor immunotherapy. Studies on CD47 monoclonal antibodies are at the forefront of research, and impressive results have been obtained. Nevertheless, hematotoxicity, especially anemia, has become the most common adverse effect of the CD47 monoclonal antibody. More specific targeted drugs (i.e., bispecific antibodies, SIRPα/Fc fusion protein antibodies, and small-molecule inhibitors) have been developed to reduce hematotoxicity. Here, we review the present usage of CD47 antagonists for the treatment of lymphomas and hematologic neoplasms from the perspectives of structure, function, and clinical trials, including a comprehensive overview of the drugs in development.

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Crystal Structure of Human CD47 in Complex with Engineered SIRPα.D1(N80A)

Cited by 9 publications

References 32 publications

Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment

Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment

Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer

The landscape overview of CD47-based immunotherapy for hematological malignancies

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