# CXCR4 Inhibition Enhances the Efficacy of CD19 Monoclonal Antibody-Mediated Extermination of B-Cell Lymphoma

## TL;DR

Blocking CXCR4 improves the effectiveness of CD19 antibody treatments for B-cell lymphomas like DLBCL and Waldenström Macroglobulinemia.

## Contribution

The study introduces a synergistic approach combining CD19 monoclonal antibodies and CXCR4 inhibition to enhance lymphoma treatment.

## Key findings

- CD19 is crucial for B-cell lymphoma survival and CXCL12-induced migration.
- CXCR4 inhibition with EPI-X4 derivative JM#21 enhances ADCC and reduces migration.
- Combining CD19 mAbs with CXCR4 inhibitors improves therapeutic outcomes in lymphoma models.

## Abstract

CD19 and CXCR4 are pivotal regulators of B-cell activation and migration, respectively. Specifically, CXCR4 signaling critically influences the dissemination of various malignant B cells through constitutive activation and aberrant expression. This study explores the interaction between CD19 and CXCR4 signaling in the context of B-cell lymphomas, particularly focusing on diffuse large B-cell lymphoma (DLBCL) and Waldenström Macroglobulinemia (WM). We assessed the roles of CD19 in survival and CXCL12-induced migration by using knockout (KO) cells of DLBCL and WM origin alongside evaluating the impact of CD19 monoclonal antibodies (mAbs) on antibody-dependent cell-mediated cytotoxicity (ADCC). Our results highlight that CD19 is important for survival and CXCL12-induced migration, and mAbs variably increase CXCL12-induced migration and enhance ADCC. Additionally, we demonstrate that the endogenous peptide inhibitor of the CXCR4 (EPI-X4) derivative JM#21 effectively inhibits CD19-mediated migration enhancement and promotes ADCC, thereby augmenting the therapeutic efficacy of CD19 mAb-based immunotherapy in lymphoma models. Our study underscores the potential of targeting both CD19 and CXCR4 to refine therapeutic strategies for treating B-cell malignancies, suggesting a synergistic approach could improve clinical outcomes in WM treatment.