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Published on: May 6, 2019
Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy
Hirofumi Mikami1, Shu Feng2, Yutaka Matsuda3
1Research Division, Chugai Pharmaceutical, Yokohama, Kanagawa, Japan.
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.
Insights
A novel trispecific antibody targeting DLL3 shows promise for small-cell lung cancer (SCLC). This engineered antibody enhances T-cell responses and tumor control, offering a potential new therapy for patients resistant to immune checkpoint inhibitors.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options.
- Immune checkpoint inhibitors (ICIs) have shown restricted efficacy in SCLC.
- Existing bispecific T-cell engagers offer therapeutic potential but not all SCLC patients respond.
Purpose of the Study:
- To enhance the efficacy of T-cell engagers for SCLC by integrating CD137 costimulatory signals.
- To engineer a DLL3-targeted trispecific antibody incorporating CD3/CD137 dual-specific binding.
- To prevent systemic T-cell activation through controlled CD3 and CD137 engagement.
Main Methods:
- Generation of a CD3/CD137 dual-specific Fab fragment.
- Engineering of a DLL3-targeted trispecific antibody (DLL3 trispecific).
- Evaluation of tumor growth control and intratumoral T-cell infiltration in preclinical models.
Main Results:
- The DLL3 trispecific antibody demonstrated superior tumor growth inhibition compared to conventional bispecific T-cell engagers.
- A significant increase in intratumoral T cells was observed with the DLL3 trispecific antibody.
- The engineered antibody effectively induced concurrent CD137 costimulation.
Conclusions:
- DLL3 trispecific antibody represents a promising therapeutic strategy for SCLC.
- Concurrent CD137 costimulation enhances the efficacy of T-cell engagers in SCLC.
- This approach may overcome resistance to current immunotherapies in SCLC.
