CD47-targeted cancer immunogene therapy: Secreted SIRPα-Fc fusion protein eradicates tumors by macrophage and NK cell activation

Billerhart, Magdalena; Schönhofer, Monika; Schueffl, Hemma; Polzer, Wolfram; Pichler, Julia; Decker, Simon; Taschauer, Alexander; Maier, Julia; Anton, Martina; Eckmann, Sebastian; Blaschek, Manuel; Heffeter, Petra; Sami, Haider; Ogris, Manfred

doi:10.1016/j.omto.2021.09.005

Cited by 16 publications

(13 citation statements)

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“…4 ): (1) Using the strategy of CD47 antagonist prime and maintenance dosing ( e.g ., 5F9 and IBI-188); (2) Modifying the drug structure of CD47 monoclonal antibody (e.g ., AO-176, TJ011133, SRF231, and AK117); (3) Fusion protein of CD47/SIRPa combining with different antibodies, such as CD20, CD19, could be of a promising strategy in the immunotherapy targeting CD47/SIRPa axis ( e.g. , IMM0306, NI-1701) [ 17 , 74 ]; (4) Development of SIRPα/Fc fusion protein antibodies; (5) Development of small-molecule inhibitors ( e.g ., RRX-001, QPCTL antibodies); (6) Introduction of new drug delivery methods ( e.g ., CD47 nanobody [ 55 ], plasmid vector [ 75 ], and CD47/SIRPα blocking peptide [ 76 ]); (7) Since binding of CD47 to SIRPγ enables T cell activation and proliferation [ 5 ], blockade of SIRPα-CD47 interaction while preserving SIRPγ binding to CD47 may be a strategy for cancer immunotherapy ( e.g. , SIRP-1 and SIRP-2) [ 77 ]; (8) SIRPα engages with CD47 in either cis or trans behavior in different scenarios.…”

Section: Challenges and Future Perspectives Of Cd47/sirpα Immune Chec...mentioning

confidence: 99%

“…(5) Development of small-molecule inhibitors (e.g., RRX-001, QPCTL antibodies); (6) Introduction of new drug delivery methods (e.g., CD47 nanobody [55], plasmid vector [75], and CD47/SIRPα blocking peptide [76]); (7) Since binding of CD47 to SIRPγ enables T cell activation and proliferation [5], blockade of SIRPα-CD47 interaction while preserving SIRPγ binding to CD47 may be a strategy for cancer immunotherapy (e.g., SIRP-1 and SIRP-2) [77]; (8) SIRPα engages with CD47 in either cis or trans behavior in different scenarios. SIRPα expressed in macrophages exhibits trans binding to CD47 that are expressed in other types of 'self ' cells, leading to local SIRPα accumulation and inhibition of 'self 'cell engulfment including the tumor cells [35,78].…”

Section: Future Perspectivesmentioning

confidence: 99%

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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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Section: Challenges and Future Perspectives Of Cd47/sirpα Immune Chec...mentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

The landscape overview of CD47-based immunotherapy for hematological malignancies

2023

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“…CD47 is overexpressed on BC cells, which inhibits macrophage phagocytosis through binding itself to its receptor, SIRPα 135 . Targeting the CD47 / SIRPα axis not only blocks innate immune but also causes T‐cell activation 136,137 . Monotherapy by CD47 blockade leads to a reduction in tumor growth and an increase in OS 138 .…”

Section: Therapeutic Strategies Targeting Tams For Bcmentioning

confidence: 99%

Antitumor therapy for breast cancer: Focus on tumor‐associated macrophages and nanosized drug delivery systems

Zhan

Jin

et al. 2023

Cancer Medicine

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Background In breast cancer (BC), tumor‐associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention. Aims This review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs. Materials & Methods The existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment. Results TAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti‐tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies. Discussion TAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs. Conclusion TAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

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“…(3) NK cells mediate the ADCC effect: although NK cells express less SIRPα, tumor cells can still inhibit the function of NK cells through the CD47-SIRPα interaction, and the disruption of the CD47-SIRPα axis restores NK cell function . Several studies have shown that aCD47 and SIRPα fusion protein can activate NK cell FcγR to exert the ADCC effect. (4) aCD47 can directly induce tumor cell apoptosis in a caspase-independent manner …”

Section: Therapy Strategies Targeted On the Cd47-sirpα Axismentioning

confidence: 99%

Recent Advances of Tumor Therapy Based on the CD47-SIRPα Axis

et al. 2022

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Cancer is still a major disease that is currently difficult for humans to overcome. When the expression of the cluster of differentiation 47 (CD47) is upregulated, tumor cells interact with the macrophage inhibitory receptor signal regulatory protein α (SIRPα) to transmit the "Don't eat me" signal, thereby avoiding phagocytosis by the macrophages. Therefore, when the CD47-SIRPα axis is inhibited, the macrophages' phagocytic function can be restored and can also exert antitumor effects. This Review mainly introduces recent advances in tumor therapy targeted on the CD47-SIRPα axis, including the antibody and fusion protein, small molecule, gene therapy, cell therapy, and drug delivery system, to inhibit the function of CD47 expressed on tumor cells and promote tumor phagocytosis by macrophages. In addition, this Review also summarizes the current approaches to avoid anemia, a common side effect of CD47-SIRPα inhibitions, and provides ideas for clinical transformation.

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CD47-targeted cancer immunogene therapy: Secreted SIRPα-Fc fusion protein eradicates tumors by macrophage and NK cell activation

Cited by 16 publications

References 50 publications

The landscape overview of CD47-based immunotherapy for hematological malignancies

The landscape overview of CD47-based immunotherapy for hematological malignancies

Antitumor therapy for breast cancer: Focus on tumor‐associated macrophages and nanosized drug delivery systems

Recent Advances of Tumor Therapy Based on the CD47-SIRPα Axis

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