A Totipotent "All-In-One" Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment.
Adv Mater
; 35(2): e2207330, 2023 Jan.
Article
em En
| MEDLINE
| ID: mdl-36259590
ABSTRACT
Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti-tumor immunity, which can be achieved by using multiple-agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct "all-in-one" totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high-content peptide library is designed. By using the "3D-molecular-evolution" screening strategy, an efficient and totipotent "all-in-one" peptide (TAP) is obtained, which possesses the abilities of self-assembling, blocking the PD-1/PD-L1 axis, inhibiting Rbm38-eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient-derived xenografts, PD-L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody-based drugs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antígeno B7-H1
/
Neoplasias
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Adv Mater
Assunto da revista:
BIOFISICA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article