Bypassing the immunosuppressive effects of CA125/MUC16 via re-engineered rituximab (NAV-006) to improve its antitumor activity in vivo.

Q2 Medicine

Antibody Therapeutics Pub Date : 2025-04-24 eCollection Date: 2025-07-01 DOI:10.1093/abt/tbaf008

Luigi Grasso, Bradford J Kline, Nicholas C Nicolaides

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Abstract

The monoclonal antibody rituximab functions through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) and is used to treat non-Hodgkin's lymphoma. Elevated serum CA125/MUC16 levels, present in some follicular lymphoma patients, have been shown to correlate with reduced efficacy of rituximab. Previous studies revealed that CA125/MUC16 binds to rituximab, diminishing its CDC and ADCC. A rituximab variant, NAV-006, was engineered to counteract CA125/MUC16's immunosuppressive effects. NAV-006 demonstrated enhanced CDC and ADCC activities and was unaffected by CA125/MUC16. In the present study, NAV-006 showed improved in vivo antitumor activity compared to rituximab in a human lymphoma model with reconstituted CA125/MUC16. Additionally, CA125/MUC16 bound to newer antibody-based lymphoma treatment agents, including obinutuzumab and tafasitamab, suppressing their immune effector functions. Bispecific antibodies mosunetuzumab and glofitamab also exhibited reduced cytotoxicity in the presence of CA125/MUC16. These findings suggest that NAV-006 could improve therapeutic efficacy in B-cell lymphomas, particularly in patients with elevated CA125/MUC16 levels.

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通过重组利妥昔单抗（NAV-006）绕过CA125/MUC16的免疫抑制作用，提高其体内抗肿瘤活性。

单克隆抗体利妥昔单抗通过补体依赖性细胞毒性（CDC）和抗体依赖性细胞毒性（ADCC）发挥作用，用于治疗非霍奇金淋巴瘤。一些滤泡性淋巴瘤患者血清CA125/MUC16水平升高已被证明与利妥昔单抗疗效降低相关。先前的研究表明，CA125/MUC16与利妥昔单抗结合，降低其CDC和ADCC。设计了一种利妥昔单抗变体NAV-006来抵消CA125/MUC16的免疫抑制作用。NAV-006表现出增强的CDC和ADCC活性，并且不受CA125/MUC16的影响。在本研究中，与利妥昔单抗相比，NAV-006在重组CA125/MUC16的人淋巴瘤模型中显示出更高的体内抗肿瘤活性。此外，CA125/MUC16结合新的基于抗体的淋巴瘤治疗药物，包括obinutuzumab和tafasitamab，抑制其免疫效应功能。双特异性抗体mosunetuzumab和glofitamab在CA125/MUC16存在下也表现出降低的细胞毒性。这些发现表明，NAV-006可以提高b细胞淋巴瘤的治疗效果，特别是对CA125/MUC16水平升高的患者。

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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