BAFF-based trifunctional T-cell engagers trigger robust tumor immunity against B-cell malignancies

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• T-cell engagers (TCEs) are advanced protein-engineered therapeutics with significant clinical success in B-cell malignancies.
• Multispecific TCEs offer a strategy to overcome tumor heterogeneity and antigen escape, but format design remains a challenge.

Purpose of the Study:

• To engineer and evaluate various BAFF-based T-cell engager formats targeting BAFF receptors (BAFFR, BCMA, TACI) for B-cell malignancies.
• To identify an optimal construct for enhanced T-cell mediated cytotoxicity and tumor eradication.

Main Methods:

• Engineered BAFF-based TCEs with different formats, incorporating anti-CD3 Fab or IgG domains fused with BAFF ligands.
• Varied constructs in valency and included long-acting elements like Fc domains or albumin binding domain consensus sequence (ABDCon).
• Assessed cytotoxicity and tumor burden control in B-cell malignancy models.

Main Results:

• Fc domain inclusion did not improve tumor eradication; valency and spatial configuration significantly impacted cytotoxicity.
• The trifunctional TriBAFF/CD3/ABDCon construct, with an anti-CD3 Fab backbone and BAFF/ABDCon fusions, proved optimal.
• TriBAFF/CD3/ABDCon demonstrated superior tumor control and tolerability in B-cell malignancy models compared to blinatumomab and BAFF-based CAR-T cells.

Conclusions:

• Natural ligands can be effectively utilized as antibody-targeting modules in T-cell engager design.
• The TriBAFF/CD3/ABDCon format provides a promising next-generation multispecific TCE for improved treatment of B-cell malignancies and potentially other cancers.