eIg-based bispecific T-cell engagers targeting EGFR: Format matters

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Bispecific antibodies, particularly T-cell engagers (TCEs), are promising cancer therapeutics.
• TCEs redirect T-cells to tumor cells via dual antigen targeting (e.g., tumor antigen and CD3).
• The molecular format and valency of TCEs can significantly influence their therapeutic activity.

Purpose of the Study:

• To investigate how different molecular formats of bispecific TCEs targeting EGFR and CD3 affect their efficacy.
• To evaluate the impact of Fc region presence, EGFR valency, and binding site arrangement on TCE function.

Main Methods:

• Generation of 11 distinct bispecific TCE formats using the eIg platform, varying in Fc region inclusion and EGFR/CD3 binding site configuration (1+1 or 2+1).
• Analysis of TCE binding to target and T-cells.
• Assessment of T-cell-mediated tumor cell killing, cytokine release, and T-cell proliferation.

Main Results:

• Bivalent binding to EGFR significantly enhanced TCE binding affinity and tumor cell killing.
• The specific molecular composition and arrangement of the CD3-binding arm modulated target cell killing, cytokine release, and T-cell proliferation.
• Different TCE formats exhibited varying levels of potency, highlighting format-dependent activity.

Conclusions:

• Screening a diverse panel of bispecific TCE formats is crucial for identifying optimal candidates.
• The molecular format of TCEs is a critical determinant of their therapeutic potency and T-cell activation profile.