Remodeling of the Tumor Microenvironment by a Chemokine/Anti-PD-L1 Nanobody Fusion Protein.
Mol Pharm
; 16(6): 2838-2844, 2019 06 03.
Article
em En
| MEDLINE
| ID: mdl-31013423
An optimal response to immune checkpoint blockade requires the presence of effector cells in the tumor microenvironment. We designed a PD-L1-targeted delivery strategy for chemokines, key molecules that drive leukocyte trafficking, to the tumor microenvironment, as a means of attracting the relevant leukocyte populations. This strategy combines a PD-L1-blocking single-domain antibody fragment (nanobody or VHH), a charge-engineered chemokine CCL21, and its subsequent characterization in a microfluidic device that resembles the tumor microenvironment. We show that the PD-L1-blocking VHH is a reliable fusion partner for the preparation of a functional chemokine fusion. Engineering the surface charge of CCL21 reduced its nonspecific binding to glycosaminoglycans, a property of chemokines that complicates their targeted delivery. Using a microfluidic assay, we show that it is possible to deliver a chemokine-VHH fusion to a PD-L1-positive environment and recruit effector cells.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quimiocinas
/
Microambiente Tumoral
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Pharm
Assunto da revista:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos