开发EDP001,一种靶向CD19和BCMA的四价T细胞衔接器,用于治疗B细胞淋巴瘤

Background: The current therapeutic landscape for B-cell lymphoma, while much advanced, still faces significant limitations primarily related to treatment resistance, toxicity and accessibility. This study describes a novel tetra-specific antibody, EDP001, that binds CD3, BCMA, and CD19 with two distinct epitopes. The biparatopic CD19 design greatly enhances antigen avidity, while the inclusion of BCMA enables dual-antigen targeting and further increases its efficacy. EDP001 is designed to maximize tumor cell killing, mitigate antigen escape, and sustain low cytokine secretion. Thus, EDP001 holds a great potential for the better treatment of various B cell malignancies. Methods: Multiple rounds of screening and characterization of antibody candidates were performed by comprehensive evaluation including binding affinity, specificity and functional analysis. Specific target-killing activity was examined using multiple B cell lines expressing CD19 and/or BCMA. Cytotoxicity against primary B cells from different donors were also examined. In vivo B-cell depletion and anti-tumor efficacy were tested in hCD34+ reconstituted mice and a panel of B-cell malignant murine models, respectively. Results: EDP001 exhibited high affinity for BCMA while demonstrating low affinity for CD3, as intended by design. Notably, its biparatopic anti-CD19 domains conferred an approximately 100-fold higher binding affinity for CD19 than clinically validated CD19/CD3 bispecific antibodies. EDP001 potently lysed target tumor cells expressing CD19, BCMA, or both antigens, outperforming CD3×CD19 or CD3×BCMA bispecific antibodies. In addition, it induced significantly more potent cytotoxicity against primary B cells from both healthy donors and SLE patients, with minimal cytokine release. In vivo studies showed that EDP001 mediated profound and sustained B-cell depletion in hCD34+ reconstituted mice and demonstrated superior anti-tumor activity across multiple B-cell malignant models with varying expression levels of CD19 or BCMA (e.g., Raji, NCI-H929, Jeko-1, WSU-DLCL2, NALM6-BCMA), surpassing CD3×CD19 and CD3×BCMA bispecific antibodies in all the animal models tested. Conclusion: EDP001 is the first reported tetravalent TCE targeting CD19 and BCMA. The unique molecular design of EDP001 enables a deep depletion of primary B cells as well as various lymphoma lines in preclinical studies. EDP001 may represent a promising off-the-shelf therapeutics with a superior efficacy for the treatment of variety of B-cell lymphomas.