An engineered IgM antibody targeting CD20 has enhanced complement-dependent cytotoxicity compared with an IgG.

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology Pub Date : 2025-09-14 DOI:10.1016/j.exphem.2025.105250

Kevin C Hart, Paul R Hinton, Marigold Manlusoc, Kevin B Carlin, Samuel Schneider, Maya F Kotturi, Ramesh Baliga, Bruce A Keyt

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引用次数: 0

Abstract

Complement-dependent cytotoxicity (CDC) is one of the main mechanisms of action for approved therapeutic anti-CD20 immunoglobulin (Ig) G antibodies, including rituximab, ofatumumab, and ocrelizumab, in the treatment of B-cell lymphoma patients. However, resistance to these therapies inevitably develops in patients, and thus novel antibody approaches are needed. Here, we described the CDC activity of an anti-CD20 IgM in comparison to an anti-CD20 IgG. We applied live-cell imaging and kinetic analysis to measure CDC activity in real time. Through this imaging platform, we demonstrated that an IgM antibody exhibited more potent and faster target cell killing through CDC compared with an IgG antibody. Additionally, an IgM antibody was more effective at killing target cells with low antigen density, in low levels of complement, and in the presence of high complement inhibitor expression. An anti-CD20 IgM also showed superior CDC against ex vivo tumor samples from a patient with B-cell lymphoma. These preclinical studies demonstrated the potential of an anti-CD20 IgM-based therapeutic antibody having superior CDC in B-cell lymphoma compared with a traditional IgG antibody.

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与IgG相比，靶向CD20的工程IgM抗体具有增强的补体依赖性细胞毒性。

补体依赖性细胞毒性（CDC）是批准的治疗性抗cd20 IgG抗体（包括利妥昔单抗、ofatumumab和ocrelizumab）治疗B细胞淋巴瘤患者的主要作用机制之一。然而，患者不可避免地会对这些疗法产生耐药性，因此需要新的抗体方法。在这里，我们描述了抗cd20 IgM的CDC活性与抗cd20 IgG的比较。我们应用活细胞成像和动力学分析来实时测量CDC的活性。通过这个成像平台，我们证明了IgM抗体比IgG抗体更有效、更快地通过CDC杀死靶细胞。此外，IgM抗体在低抗原密度、低补体水平和高补体抑制剂表达的情况下更有效地杀死靶细胞。抗cd20 IgM对离体B细胞淋巴瘤患者肿瘤样本也显示出优越的CDC。这些临床前研究表明，与传统的IgG抗体相比，基于抗cd20 igm的治疗性抗体在B细胞淋巴瘤中具有更好的CDC。摘要：补体依赖性细胞毒性（CDC）是已批准的抗cd20 IgG抗体治疗B细胞淋巴瘤的主要作用机制之一。然而，患者不可避免地会对这些疗法产生耐药性，因此需要新的抗体方法。在这里，我们描述了抗cd20 IgM的CDC活性与抗cd20 IgG的比较。在低抗原密度、低补体水平和高补体抑制剂表达的情况下，IgM抗体更有效地杀死肿瘤细胞。这些临床前研究表明，与传统的IgG抗体相比，基于igm的抗cd20治疗性抗体具有更好的CDC活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental hematology 医学-血液学

CiteScore

5.30

自引率

0.00%

发文量

审稿时长

58 days

期刊介绍： Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.