Non-superagonist CD28-based dual-signal T cell engager targeting

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Bispecific T cell engagers show promise but face challenges like T cell anergy from single-signal activation.
• CD28 co-stimulation enhances T cell functionality and antitumor efficacy, with non-superagonistic approaches minimizing toxicity.
• Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1) is a promising cancer-testis antigen target for immunotherapy.

Purpose of the Study:

• To develop a dual-signal T-cell engager strategy targeting KK-LC-1 using CD28 co-stimulation.
• To evaluate the antitumor efficacy of KK-LC-1-targeted T cell engagers, alone and in combination therapies.

Main Methods:

• Engineered two T cell engagers (KK-LC-1×CD3 and KK-LC-1×CD28) using phage display technology for KK-LC-1 and CD28 targets.
• Verified binding activity and evaluated biological activities and antitumor efficacy in vitro and in vivo.

Main Results:

• Engineered KK-LC-1×CD3 and KK-LC-1×CD28 engagers showed high binding affinity.
• Co-administration of engagers augmented T cell activation and antitumor efficacy compared to monotherapy.
• Combination therapy suppressed tumor growth, enhanced intratumoral CD8+ and CD4+ T cell infiltration, and extended median survival.

Conclusions:

• Validated the feasibility of KK-LC-1-targeted dual-signal T-cell engager strategy for solid tumors.
• Demonstrated synergistic enhancement of antitumor efficacy when combined with PD-1×CTLA-4 bispecific antibodies in preclinical studies.