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Introduction While anti-CD20 antibodies like obinutuzumab (OBI) have improved clinical outcomes, B-cell malignancies remain a significant therapeutic challenge. OBI induces direct cell death (DCD) and augments antibody-dependent cellular cytotoxicity (ADCC), but the molecular mechanisms involved in DCD remain unclear. This study aims to bridge this knowledge gap and develop enhanced treatment modalities. Methods We employed an antibody–APEX2 proximity labeling platform to identify novel regulators of OBI-induced DCD. Mechanistic studies were conducted to evaluate lysosomal membrane permeabilization (LMP). Furthermore, we developed a new class of bioengineered antibody-lectin fusion proteins, termed "concabodies," and evaluated their efficacy through in vitro assays and ex vivo experiments using peripheral blood mononuclear cells (PBMCs) from patients with chronic lymphocytic leukemia (CLL). Results Myelin protein zero-like 1 (MPZL1) was identified as a novel regulator of OBI-induced DCD, modulating LMP as a key characteristic. We found that concanavalin A (Con A) also triggers LMP and DCD via MPZL1-mediated internalization. The developed concabodies exhibited significantly enhanced DCD and ADCC while concurrently reducing the non-specific toxicity of free Con A. Notably, this enhanced cytotoxicity was maintained even in cells expressing a dominant-negative MPZL1 Y241F mutant, and the concabodies efficiently depleted malignant B cells in CLL patient samples. Discussion Taken together, this work establishes MPZL1 as a crucial molecular target for antibody-induced DCD and presents concabodies as a mechanistically rational and clinically relevant approach to improve the efficacy of anti-CD20 immunotherapy in B-cell malignancies.
Choi et al. (Wed,) studied this question.