Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint
Background The CD47-SIRPα pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRPα axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expressi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004054.full |
| _version_ | 1797771642488750080 |
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| author | Juan Chen Gang Chen Na Li Yao Chen Lei Nie Zhen-Hua Wu Xiao-Feng Mei Xiao-Ze Wang Ting-Ting Guo Mei-Zhu Jiang Ji-Teng Wang Hai-Bin Wang |
| author_facet | Juan Chen Gang Chen Na Li Yao Chen Lei Nie Zhen-Hua Wu Xiao-Feng Mei Xiao-Ze Wang Ting-Ting Guo Mei-Zhu Jiang Ji-Teng Wang Hai-Bin Wang |
| author_sort | Juan Chen |
| collection | DOAJ |
| description | Background The CD47-SIRPα pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRPα axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expression of CD47, the antigen sink and hematologic toxicity, such as anemia and thrombocytopenia, are main problems for developing CD47-targeting therapies. Considering the limited expression of SIRPα, targeting SIRPα is an alternative approach to block the CD47-SIRPα pathway, which may result in differential efficacy and safety profiles.Methods SIRPα-targeting antibody BR105 was generated by hybridoma fusion and following humanization. BR105 was characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. The functional activity was determined in in vitro phagocytosis assays by using human macrophages. The effect of BR105 on human T cell activation was studied using an OKT3-induced T-cell proliferation assay and an allogeneic mixed lymphocyte reaction. Human SIRPα-humanized immunodeficient mice were used in cancer models for evaluating the in vivo antitumor efficacy of BR105. Safety was addressed in a repeat-dose toxicity study in cynomolgus monkeys, and toxicokinetic analysis was further evaluated.Results BR105 shows broad binding activity across various SIRPα variants, and potently blocks the interaction of SIRPα and CD47. In vitro functional assays demonstrated that BR105 synergizes with therapeutic antibodies to promote phagocytosis of tumor cells. Moreover, the combination of BR105 and therapeutic antibody significantly inhibits tumor growth in a xenograft tumor model. Although BR105 may slightly bind to SIRPγ, it does not inhibit T cell activation, unlike other non-selective SIRPα-targeting antibody and CD47-targeting agents. Toxicity studies in non-human primates show that BR105 is well tolerated with no treatment-related adverse effects noted.Conclusions The novel and differentiated SIRPα-targeting antibody, BR105, was discovered and displays promising antitumor efficacy in vitro and in vivo. BR105 has a favorable safety profile and shows no adverse effects on T cell functionality. These data support further clinical development of BR105, especially as a therapeutic agent to enhance efficacy when used in combination with tumor-targeting antibodies or antibodies that target other immune checkpoints. |
| first_indexed | 2024-03-12T21:39:36Z |
| format | Article |
| id | doaj.art-8d9f5a8b6e934679ac09893e0c492864 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:39:36Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-8d9f5a8b6e934679ac09893e0c4928642023-07-27T03:30:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004054Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpointJuan Chen0Gang Chen1Na Li2Yao Chen3Lei Nie4Zhen-Hua Wu5Xiao-Feng Mei6Xiao-Ze Wang7Ting-Ting Guo8Mei-Zhu Jiang9Ji-Teng Wang10Hai-Bin Wang11BioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Corp, San Diego, California, USA1Peking Union Medical College Hospital, ChinaDepartment of Hematology and Rheumatology, Wu zhong People`s Hospital, Wuzhong, Ningxia, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBioRay Pharmaceutical Co., Ltd, Taizhou, Zhejiang, ChinaBackground The CD47-SIRPα pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRPα axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expression of CD47, the antigen sink and hematologic toxicity, such as anemia and thrombocytopenia, are main problems for developing CD47-targeting therapies. Considering the limited expression of SIRPα, targeting SIRPα is an alternative approach to block the CD47-SIRPα pathway, which may result in differential efficacy and safety profiles.Methods SIRPα-targeting antibody BR105 was generated by hybridoma fusion and following humanization. BR105 was characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. The functional activity was determined in in vitro phagocytosis assays by using human macrophages. The effect of BR105 on human T cell activation was studied using an OKT3-induced T-cell proliferation assay and an allogeneic mixed lymphocyte reaction. Human SIRPα-humanized immunodeficient mice were used in cancer models for evaluating the in vivo antitumor efficacy of BR105. Safety was addressed in a repeat-dose toxicity study in cynomolgus monkeys, and toxicokinetic analysis was further evaluated.Results BR105 shows broad binding activity across various SIRPα variants, and potently blocks the interaction of SIRPα and CD47. In vitro functional assays demonstrated that BR105 synergizes with therapeutic antibodies to promote phagocytosis of tumor cells. Moreover, the combination of BR105 and therapeutic antibody significantly inhibits tumor growth in a xenograft tumor model. Although BR105 may slightly bind to SIRPγ, it does not inhibit T cell activation, unlike other non-selective SIRPα-targeting antibody and CD47-targeting agents. Toxicity studies in non-human primates show that BR105 is well tolerated with no treatment-related adverse effects noted.Conclusions The novel and differentiated SIRPα-targeting antibody, BR105, was discovered and displays promising antitumor efficacy in vitro and in vivo. BR105 has a favorable safety profile and shows no adverse effects on T cell functionality. These data support further clinical development of BR105, especially as a therapeutic agent to enhance efficacy when used in combination with tumor-targeting antibodies or antibodies that target other immune checkpoints.https://jitc.bmj.com/content/10/3/e004054.full |
| spellingShingle | Juan Chen Gang Chen Na Li Yao Chen Lei Nie Zhen-Hua Wu Xiao-Feng Mei Xiao-Ze Wang Ting-Ting Guo Mei-Zhu Jiang Ji-Teng Wang Hai-Bin Wang Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint Journal for ImmunoTherapy of Cancer |
| title | Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint |
| title_full | Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint |
| title_fullStr | Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint |
| title_full_unstemmed | Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint |
| title_short | Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint |
| title_sort | preclinical characterization of the novel anti sirpα antibody br105 that targets the myeloid immune checkpoint |
| url | https://jitc.bmj.com/content/10/3/e004054.full |
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