Development of T-cell engagers selective for cells co-expressing two antigens

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• T cell-engaging antibodies (TCEs) show promise in treating hematological cancers but face challenges in solid tumors due to toxicities from normal tissue antigen expression.
• Targeting dual tumor-associated antigens, Ly6E and B7-H4, offers a strategy to improve specificity in breast cancer, where these antigens are co-expressed on about 50% of tumors.
• Existing bispecific TCEs targeting single antigens risk on-target, off-tumor toxicities, as demonstrated by severe adverse effects in murine models with B7-H4 targeting.

Purpose of the Study:

• To develop novel trispecific antibodies for dual-antigen targeting (Ly6E and B7-H4) to enhance T cell-mediated cancer cell death.
• To investigate the impact of dual-antigen binding and domain placement on the efficacy and safety of TCEs.
• To overcome the on-target toxicities associated with traditional bispecific TCEs in solid malignancies.

Main Methods:

• Design and characterization of trispecific antibodies co-targeting Ly6E, B7-H4, and CD3.
• In vitro assessment of tumor cell killing by trispecific TCEs, evaluating the influence of binding domain affinity and placement.
• In vivo efficacy and tolerability studies in xenograft models using dual-antigen targeted T cell engagers (DAT-TCEs).

Main Results:

• In vitro tumor cell killing efficacy correlated with the placement of the higher-affinity B7-H4 binding domain, with minimal additional benefit from Ly6E binding.
• Trispecific TCEs demonstrated tumor growth inhibition in xenograft models.
• The designed trispecific TCEs showed improved tolerability compared to bispecific TCEs, avoiding severe adverse effects observed previously.

Conclusions:

• Dual-antigen targeting using appropriately designed trispecific TCEs can significantly improve the safety and efficacy of cancer immunotherapy.
• This strategy holds potential for expanding the therapeutic window and applicability of TCEs to a broader range of solid tumors.
• The findings support the development of dual-antigen targeted T cell engagers (DAT-TCEs) as a promising therapeutic modality.