Abstract A034: Unlocking BCMA in aggressive lymphomas: A native receptor-targeted peptide for theranostic applications
Elisabetta Pingitore, Khushboo Fatima, Selena Mimmi, Valentina Crapella, Anna Maria Zimbo, Antonio Lupia, Alessia Onali, Domenico Maisano, Francesco Bertoni, Alessandra Scagliola, Federica Melle, Maria Carmela Vegliante, Doriana Gramegna, Michele Guida, Sabino Ciavarella, Enrico IaccinoAbstract
Background
Plasmablastic lymphoma (PBL) and related Diffuse Large B-cell Lymphoma (DLBCL) variants with plasmablastic differentiation are aggressive malignancies characterized by high BCMA (TNFRSF17) expression, yet BCMA-targeted therapies remain largely unexplored in this setting despite poor outcomes with standard approaches. These tumors frequently present with extramedullary disease, poor vascularity, and profound immunosuppression – features that reduce the efficacy of Fc-dependent biologics and underscore the need for Fc-independent targeting approaches.
Aim
We aimed to identify small BCMA-binding peptide ligands (≈1–5 kDa) for theranostic applications in plasmablastic lymphomas. Our strategy focused on targeting the native BCMA receptor on intact tumor cells to preserve its physiological conformation, including its cysteine-rich ectodomain and membrane-associated lipid environment, which is critical for genuine epitope recognition and binding interactions.
Methods
We performed phage display screening to identify BCMA-binding peptides using large combinatorial peptide libraries displayed on M13 phage, through three iterative rounds of positive selection on BCMA-positive NCI-H929 cells and negative selection on induced BCMA-negative NCI-H929 cells. We subsequently performed in silico characterization of the binding mechanisms of selected peptides, including protein-peptide docking analyses using the HADDOCK server and binding free energy estimation with the PRODIGY tool.
Results
We identified three peptide scaffolds capable of binding BCMA in its native form on BCMA-positive cells. Peptide pBCMA_7 was selected because of its clonal prevalence and its binding affinity toward BCMA-positive tumor cells. Docking and free energy studies suggest a configuration in which the peptide associates with a surface-accessible region of BCMA, forming extensive interactions through both backbone and side-chain atoms. Molecular dynamics simulations further indicate a stable and consistent binding mode within an exposed pocket of the receptor. Notably, pBCMA_7 exhibited strong binding (-11.2 kcal/mol) across a range of plasmablastic lymphoma cell lines (DB, Pfeiffer, SU-DHL-2, U-2932, Karpas 422) as well as multiple myeloma cell lines (NCI-H929, U266 and IM9).
Conclusion
We report the identification of BCMA-binding peptide ligands with demonstrated activity in plasmablastic lymphomas and related large B-cell lymphomas with plasmablastic differentiation. These peptide scaffolds constitute a versatile theranostic toolkit supporting Fc-independent patient stratification, therapy monitoring and delivery of imaging and therapeutic agents. By establishing phage display against native receptors as a tractable strategy for ligand discovery in an unexplored oncological setting, this work opens a wide therapeutic space for BCMA-directed precision targeting in aggressive lymphomas.
Citation Format:
Elisabetta Pingitore, Khushboo Fatima, Selena Mimmi, Valentina Crapella, Anna Maria Zimbo, Antonio Lupia, Alessia Onali, Domenico Maisano, Francesco Bertoni, Alessandra Scagliola, Federica Melle, Maria Carmela Vegliante, Doriana Gramegna, Michele Guida, Sabino Ciavarella, Enrico Iaccino. Unlocking BCMA in aggressive lymphomas: A native receptor-targeted peptide for theranostic applications [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A034.