One size does not fit all: navigating the multi-dimensional space to optimize T-cell engaging protein therapeutics.
MAbs
; 13(1): 1871171, 2021.
Article
em En
| MEDLINE
| ID: mdl-33557687
ABSTRACT
T-cell engaging biologics is a class of novel and promising immune-oncology compounds that leverage the immune system to eradicate cancer. Here, we compared and contrasted a bispecific diabody-Fc format, which displays a relatively short antigen-binding arm distance, with our bispecific IgG platform. By generating diverse panels of antigen-expressing cells where B cell maturation antigen is either tethered to the cell membrane or located to the juxtamembrane region and masked by elongated structural spacer units, we presented a systematic approach to investigate the role of antigen epitope location and molecular formats in immunological synapse formation and cytotoxicity. We demonstrated that diabody-Fc is more potent for antigen epitopes located in the membrane distal region, while bispecific IgG is more efficient for membrane-proximal epitopes. Additionally, we explored other parameters, including receptor density, antigen-binding affinity, and kinetics. Our results show that molecular format and antigen epitope location, which jointly determine the intermembrane distance between target cells and T cells, allow decoupling of cytotoxicity and cytokine release, while antigen-binding affinities appear to be positively correlated with both readouts. Our work offers new insight that could potentially lead to a wider therapeutic window for T-cell engaging biologics in general.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
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Imunoglobulina G
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Receptores de Antígenos de Linfócitos T
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Linfócitos T
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Engenharia de Proteínas
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Anticorpos Biespecíficos
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Antígeno de Maturação de Linfócitos B
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Epitopos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article