An Anti-BCMA Affibody Affinity Protein for Therapeutic and Diagnostic Use in Multiple Myeloma

TL;DR

Researchers developed a small, non-antibody protein called 1-E6 that binds to BCMA, a target in multiple myeloma, showing potential for use in therapies and diagnostics.

Contribution

The study introduces a novel anti-BCMA affibody with low nM affinity and high stability as an alternative to antibodies.

Findings

Clone 1-E6 demonstrated low nM affinity to BCMA and high thermal stability.

1-E6 interfered with BCMA binding to its natural ligand APRIL and the antibody belantamab, indicating overlapping epitopes.

A fluorescent 1-E6 homodimer specifically bound to BCMA+ MM.1s cells in flow cytometry and microscopy.

Abstract

B Cell Maturation Antigen (BCMA) has gained considerable attention as a target in directed therapies for multiple myeloma (MM) treatment, via immunoglobulin-based bispecific T cell engagers or CAR T cell strategies. We describe the development of alternative, non-immunoglobulin BCMA-recognising affinity proteins, based on the small (58 aa) three-helix bundle affibody scaffold. A first selection campaign using a naïve affibody phage library resulted in the isolation of several BCMA-binding clones with different kinetic profiles. One clone showing the slowest dissociation kinetics was chosen as the template for the construction of two second-generation libraries. Characterization of output clones from selections using these libraries led to the identification of clone 1-E6, which demonstrated low nM affinity to BCMA and high thermal stability. Biosensor experiments showed that 1-E6 interfered with the binding of BCMA to both its natural ligand APRIL and to the clinically evaluated anti-BCMA monoclonal antibody belantamab, suggesting overlapping epitopes. A fluorescently labelled head-to-tail homodimer construct of 1-E6 showed specific binding to the BCMA+ MM.1s cell line in both flow cytometry and fluorescence microscopy. Taken together, the results suggest that the small anti-BCMA affibody 1-E6 could be an interesting alternative to antibody-based affinity units in the development of BCMA-targeted therapies and diagnostics.

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