mRNA Delivery of a Bispecific Single-Domain Antibody to Polarize Tumor-Associated Macrophages and Synergize Immunotherapy against Liver Malignancies.
Adv Mater
; 33(23): e2007603, 2021 Jun.
Article
em En
| MEDLINE
| ID: mdl-33945178
ABSTRACT
Liver malignancies are among the tumor types that are resistant to immune checkpoint inhibition therapy. Tumor-associated macrophages (TAMs) are highly enriched and play a major role in inducing immunosuppression in liver malignancies. Herein, CCL2 and CCL5 are screened as two major chemokines responsible for attracting TAM infiltration and inducing their polarization toward cancer-promoting M2-phenotype. To reverse this immunosuppressive process, an innovative single-domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) with high potency and specificity is directly evolved. mRNA encoding BisCCL2/5i is encapsulated in a clinically approved lipid nanoparticle platform, resulting in a liver-homing biomaterial that allows transient yet efficient expression of BisCCL2/5i in the diseased organ in a multiple dosage manner. This BisCCL2/5i mRNA nanoplatform significantly induces the polarization of TAMs toward the antitumoral M1 phenotype and reduces immunosuppression in the tumor microenvironment. The combination of BisCCL2/5i with PD-1 ligand inhibitor (PD-Li) achieves long-term survival in mouse models of primary liver cancer and liver metastasis of colorectal and pancreatic cancers. The work provides an effective bispecific targeting strategy that could broaden the PD-Li therapy to multiple types of malignancies in the human liver.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Anticorpos de Domínio Único
/
Macrófagos Associados a Tumor
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Adv Mater
Assunto da revista:
BIOFISICA
/
QUIMICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos