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Molecular Pharmacology

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Research ArticleArticle

Selection and Characterization of FD164, a High-Affinity Signal Regulatory Protein α Variant with Balanced Safety and Effectiveness, from a Targeted Epitope Mammalian Cell-Displayed Antibody Library

Zhihong Wang, Naijing Hu, Xinying Li, Haitao Wang, Caiping Ren, Chunxia Qiao, Guojiang Chen, Jing Wang, Liuzhong Zhou, Jiaguo Wu, Dingmu Zhang, Jiannan Feng, Beifen Shen, Hui Peng and Longlong Luo
Molecular Pharmacology September 2021, 100 (3) 193-202; DOI: https://doi.org/10.1124/molpharm.120.000202
Zhihong Wang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Naijing Hu
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Xinying Li
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Haitao Wang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Caiping Ren
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Chunxia Qiao
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Guojiang Chen
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Jing Wang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Liuzhong Zhou
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Jiaguo Wu
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Dingmu Zhang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Jiannan Feng
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Beifen Shen
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Hui Peng
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Longlong Luo
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.W., N.H., X.L., C.Q., G.C., J.W., L.Z., J.W., D.Z., J.F., B.S., L.L.); School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (H.W., H.P.); Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin, China (H.P.); Department of Hematology, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China (H.W.); and Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China (C.R.)
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Abstract

Phagocytic resistance plays a key role in tumor-mediated immune escape, so phagocytosis immune checkpoints are a potential target for cancer immunotherapy. CD47 is one of the important phagocytosis immune checkpoints; thus, blocking the interaction between CD47 and signal regulatory protein α (SIRPα) may provide new options for cancer treatment. Using computer-aided targeted epitope mammalian cell-displayed antibody library, we screened and obtained an engineered SIRPα variant fragment crystallizable fusion protein, FD164, with higher CD47-binding activity than wild-type SIRPα. Compared with wild-type SIRPα, FD164 has approximately 3-fold higher affinity for binding to CD47, which further enhanced its phagocytic effect in vitro and tumor suppressor activity in vivo. FD164 maintains the similar antitumor activity of the clinical research drug Hu5F9 in the mouse xenograft model. Furthermore, FD164 combined with rituximab can significantly improve the effect of single-agent therapy. On the other hand, compared with Hu5F9, FD164 does not cause hemagglutination, and its ability to bind to red blood cells or white blood cells is weaker at the same concentration. Finally, it was confirmed by computer structure prediction and alanine scanning experiments that the N45, E47, 52TEVYVK58, K60, 115EVTELTRE122, and E124 residues of CD47 are important for SIRPα or FD164 recognition. Briefly, we obtained a high-affinity SIRPα variant FD164 with balanced safety and effectiveness.

SIGNIFICANCE STATEMENT Up to now, few clinically marketed drugs targeting CD47 have been determined to be effective and safe. FD164, a potential signal regulatory protein α variant fragment crystallizable protein with balanced safety and effectiveness, could provide a reference for the development of antitumor drugs.

Footnotes

    • Received November 5, 2020.
    • Accepted June 11, 2021.
  • ↵1 These authors contributed equally.

  • The work was supported by grants from the National Natural Sciences Foundation of China [No. 31771010, No. 81700122, No. 81773755].

  • https://doi.org/10.1124/molpharm.120.000202.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 100 (3)
Molecular Pharmacology
Vol. 100, Issue 3
1 Sep 2021
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Research ArticleArticle

An SIRPα Variant, FD164, with Balanced Safety and Effectiveness

Zhihong Wang, Naijing Hu, Xinying Li, Haitao Wang, Caiping Ren, Chunxia Qiao, Guojiang Chen, Jing Wang, Liuzhong Zhou, Jiaguo Wu, Dingmu Zhang, Jiannan Feng, Beifen Shen, Hui Peng and Longlong Luo
Molecular Pharmacology September 1, 2021, 100 (3) 193-202; DOI: https://doi.org/10.1124/molpharm.120.000202

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Research ArticleArticle

An SIRPα Variant, FD164, with Balanced Safety and Effectiveness

Zhihong Wang, Naijing Hu, Xinying Li, Haitao Wang, Caiping Ren, Chunxia Qiao, Guojiang Chen, Jing Wang, Liuzhong Zhou, Jiaguo Wu, Dingmu Zhang, Jiannan Feng, Beifen Shen, Hui Peng and Longlong Luo
Molecular Pharmacology September 1, 2021, 100 (3) 193-202; DOI: https://doi.org/10.1124/molpharm.120.000202
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