Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy
CD47 and its receptor signal regulatory protein α (SIRPα) act as a dominant antiphagocytic, “don’t eat me” signal. Recent studies reveal CD24 as a novel target for cancer immunotherapy by macrophages in ovarian cancer and breast cancer. However, whether simultaneous blockade of CD47 and CD24 by a bi...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
|
| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770523000967 |
| _version_ | 1797564939744837632 |
|---|---|
| author | Yun Yang He Wu Yan Yang Yan Kang Runjia He Bei Zhou Huaizu Guo Jing Zhang Jianqin Li Chunpo Ge Tianyun Wang |
| author_facet | Yun Yang He Wu Yan Yang Yan Kang Runjia He Bei Zhou Huaizu Guo Jing Zhang Jianqin Li Chunpo Ge Tianyun Wang |
| author_sort | Yun Yang |
| collection | DOAJ |
| description | CD47 and its receptor signal regulatory protein α (SIRPα) act as a dominant antiphagocytic, “don’t eat me” signal. Recent studies reveal CD24 as a novel target for cancer immunotherapy by macrophages in ovarian cancer and breast cancer. However, whether simultaneous blockade of CD47 and CD24 by a bispecific antibody may result in a potential synergy is still unclear. In the present study, we for the first time designed and developed a bispecific antibody fusion protein, PPAB001 for cotargeting CD47 and CD24. Data demonstrate that simultaneous blockade of CD47/SIRPα and CD24/Siglec-10 signaling by PPAB001 potently promoted macrophage phagocytosis of tumor cells. Compared to single CD47 or CD24 targeting agents, PPAB001 was more effective in inhibiting tumor growth in both mouse 4T-1 syngeneic and human SK-OV-3 xenogeneic tumor models. Mechanistically, we found that PPAB001 therapy markedly increased the proportion of tumor-infiltrating macrophages and upregulated interleukin-6 and tumor necrosis factor-α levels that were representative macrophage inflammatory cytokines. Notably, an increased ratio of M1/M2 in tumor-infiltrating macrophages in the mice treated with PPAB001 suggested that the dual blockade may promote the transition of macrophages from M2 to M1. Taken together, our data supported the development of PPAB001 as a novel immunotherapeutic in the treatment of CD47 and CD24 double-positive cancers. |
| first_indexed | 2024-03-10T19:04:55Z |
| format | Article |
| id | doaj.art-2e58db2bf8064133a0ba132a5303ef8b |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-03-10T19:04:55Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-2e58db2bf8064133a0ba132a5303ef8b2023-11-20T04:11:53ZengElsevierMolecular Therapy: Oncolytics2372-77052023-12-0131100747Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapyYun Yang0He Wu1Yan Yang2Yan Kang3Runjia He4Bei Zhou5Huaizu Guo6Jing Zhang7Jianqin Li8Chunpo Ge9Tianyun Wang10International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, China; State Key Laboratory of Macromolecular Drugs and Large-Scale Manufacturing, Shanghai 200120, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaState Key Laboratory of Macromolecular Drugs and Large-Scale Manufacturing, Shanghai 200120, China; NMPA Key Laboratory for Quality Control of Therapeutic Monoclonal Antibodies, Shanghai 200120, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, ChinaInternational Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, China; Corresponding author: Tianyun Wang, International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453000, China.CD47 and its receptor signal regulatory protein α (SIRPα) act as a dominant antiphagocytic, “don’t eat me” signal. Recent studies reveal CD24 as a novel target for cancer immunotherapy by macrophages in ovarian cancer and breast cancer. However, whether simultaneous blockade of CD47 and CD24 by a bispecific antibody may result in a potential synergy is still unclear. In the present study, we for the first time designed and developed a bispecific antibody fusion protein, PPAB001 for cotargeting CD47 and CD24. Data demonstrate that simultaneous blockade of CD47/SIRPα and CD24/Siglec-10 signaling by PPAB001 potently promoted macrophage phagocytosis of tumor cells. Compared to single CD47 or CD24 targeting agents, PPAB001 was more effective in inhibiting tumor growth in both mouse 4T-1 syngeneic and human SK-OV-3 xenogeneic tumor models. Mechanistically, we found that PPAB001 therapy markedly increased the proportion of tumor-infiltrating macrophages and upregulated interleukin-6 and tumor necrosis factor-α levels that were representative macrophage inflammatory cytokines. Notably, an increased ratio of M1/M2 in tumor-infiltrating macrophages in the mice treated with PPAB001 suggested that the dual blockade may promote the transition of macrophages from M2 to M1. Taken together, our data supported the development of PPAB001 as a novel immunotherapeutic in the treatment of CD47 and CD24 double-positive cancers.http://www.sciencedirect.com/science/article/pii/S2372770523000967CD47CD24macrophagesbispecific antibodyantitumor immunity |
| spellingShingle | Yun Yang He Wu Yan Yang Yan Kang Runjia He Bei Zhou Huaizu Guo Jing Zhang Jianqin Li Chunpo Ge Tianyun Wang Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy Molecular Therapy: Oncolytics CD47 CD24 macrophages bispecific antibody antitumor immunity |
| title | Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy |
| title_full | Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy |
| title_fullStr | Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy |
| title_full_unstemmed | Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy |
| title_short | Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy |
| title_sort | dual blockade of cd47 and cd24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy |
| topic | CD47 CD24 macrophages bispecific antibody antitumor immunity |
| url | http://www.sciencedirect.com/science/article/pii/S2372770523000967 |
| work_keys_str_mv | AT yunyang dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT hewu dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT yanyang dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT yankang dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT runjiahe dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT beizhou dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT huaizuguo dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT jingzhang dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT jianqinli dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT chunpoge dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy AT tianyunwang dualblockadeofcd47andcd24signalingusinganovelbispecificantibodyfusionproteinenhancesmacrophageimmunotherapy |