Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.
Cancer Immunol Res
; 12(6): 719-730, 2024 Jun 04.
Article
in En
| MEDLINE
| ID: mdl-38558120
ABSTRACT
Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
CD3 Complex
/
Intracellular Signaling Peptides and Proteins
/
Tumor Necrosis Factor Receptor Superfamily, Member 9
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Small Cell Lung Carcinoma
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Lung Neoplasms
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Membrane Proteins
Limits:
Animals
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Female
/
Humans
Language:
En
Journal:
Cancer Immunol Res
/
Cancer immunology res. (Online)
/
Cancer immunology research (Online)
Year:
2024
Type:
Article
Affiliation country:
Japan