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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.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2021 Sep; Vol. 100 (3), pp. 193-202. Date of Electronic Publication: 2021 Jul 27. - Publication Year :
- 2021
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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 (SIRP α ) may provide new options for cancer treatment. Using computer-aided targeted epitope mammalian cell-displayed antibody library, we screened and obtained an engineered SIRP α variant fragment crystallizable fusion protein, FD164, with higher CD47-binding activity than wild-type SIRP α Compared with wild-type SIRP α , 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 N <superscript>45</superscript> , E <superscript>47</superscript> , <superscript>52</superscript> TEVYVK <superscript>58</superscript> , K <superscript>60</superscript> , <superscript>115</superscript> EVTELTRE <superscript>122</superscript> , and E <superscript>124</superscript> residues of CD47 are important for SIRP α or FD164 recognition. Briefly, we obtained a high-affinity SIRP α 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.<br /> (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized adverse effects
Antibodies, Monoclonal, Humanized therapeutic use
Antigens, Differentiation adverse effects
Antigens, Differentiation chemistry
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Burkitt Lymphoma drug therapy
Burkitt Lymphoma immunology
Burkitt Lymphoma pathology
CD47 Antigen chemistry
CHO Cells
Cell Line
Cricetulus
Drug Design
Epitopes chemistry
Epitopes genetics
Epitopes immunology
Hemagglutination drug effects
Immunotherapy
Mice, SCID
Models, Molecular
Phagocytosis drug effects
Phagocytosis immunology
Receptors, Immunologic chemistry
Recombinant Fusion Proteins adverse effects
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins immunology
Rituximab therapeutic use
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Mice
Antigens, Differentiation genetics
Antigens, Differentiation immunology
CD47 Antigen immunology
Receptors, Immunologic genetics
Receptors, Immunologic immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0111
- Volume :
- 100
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 34315811
- Full Text :
- https://doi.org/10.1124/molpharm.120.000202