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Structural insights into the unique pH-responsive characteristics of the anti-TIGIT therapeutic antibody Ociperlimab.
- Source :
-
Structure (London, England : 1993) [Structure] 2024 May 02; Vol. 32 (5), pp. 550-561.e5. Date of Electronic Publication: 2024 Mar 08. - Publication Year :
- 2024
-
Abstract
- TIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab&#95;Fab and Tiragolumab&#95;Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103 <subscript>HCDR3</subscript> and HIS76 <subscript>TIGIT</subscript> explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment.<br />Competing Interests: Declaration of interests J. Sun, L.X., J.Z., X.C., K.L., and J. Song are inventors on a patent application related to this work filed by BeiGene (Beijing) Co., Ltd (PCT international patent application no. PCT/CN2018/125375, filed on 29 Dec 2018; PCT international patent application no. PCT/CN2023/107563, filed on 14 July 2023).<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Subjects :
- Hydrogen-Ion Concentration
Humans
Crystallography, X-Ray
Antibodies, Monoclonal chemistry
Binding Sites
Antibodies, Monoclonal, Humanized chemistry
Antibodies, Monoclonal, Humanized pharmacology
Antibodies, Monoclonal, Humanized immunology
Models, Molecular
Receptors, Immunologic metabolism
Receptors, Immunologic chemistry
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 1878-4186
- Volume :
- 32
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Structure (London, England : 1993)
- Publication Type :
- Academic Journal
- Accession number :
- 38460520
- Full Text :
- https://doi.org/10.1016/j.str.2024.02.009