Molecular basis of PD-1 blockade by dostarlimab, the FDA-approved antibody for cancer immunotherapy.
Biochem Biophys Res Commun
; 599: 31-37, 2022 04 09.
Article
em En
| MEDLINE
| ID: mdl-35168061
ABSTRACT
Targeting of programmed cell death 1 (PD-1) with monoclonal antibodies to block the interaction with its ligand PD-L1 has been successful in immunotherapy of multiple types of cancer, and their mechanism involves the restoration of the T-cell immune response. April 2021, the US FDA approved dostarlimab, a therapeutic antibody against PD-1, for the treatment of endometrial cancer. Here, we report the crystal structure of the extracellular domain of PD-1 in complex with the dostarlimab Fab at the resolution of 1.53 Å. Although the interaction between PD-1 and dostarlimab involves mainly the residues within the heavy chain of dostarlimab, the steric occlusion of PD-L1 binding is primarily contributed by the light chain. Dostarlimab induces conformational rearrangements of the BC, C'D and FG loops of PD-1 to achieve a high affinity. Significantly, the residue R86 within the C'D loop of PD-1 plays a critical role for dostarlimab binding by occupying the concave surface on the heavy chain via multiple interactions. This high-resolution structure can provide helpful information for designing improved anti-PD-1 biologics or effective combination strategies for cancer immunotherapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos Fab das Imunoglobulinas
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Anticorpos Monoclonais Humanizados
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Receptor de Morte Celular Programada 1
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Inibidores de Checkpoint Imunológico
Limite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2022
Tipo de documento:
Article
País de publicação:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA