The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcγRIIIa on immune effector cells. The NVS32b mAbs selectively target CD32b+ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32b+ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc–binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b+ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32b+ malignant cells.

中文翻译：

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开发具有增强 Fc 功能的抗 CD32b 抗体用于治疗 B 细胞和浆细胞恶性肿瘤

唯一的抑制性 Fcγ 受体 CD32b (FcγRIIb) 在 B 细胞和浆细胞发育及其恶性对应物上表达。已知恶性 B 细胞上的 CD32b 表达提供了一种对利妥昔单抗的抗性机制，可以用 CD32b 阻断抗体来改善。因此，CD32b 代表了一种有吸引力的肿瘤抗原，可用于单克隆抗体 (mAb) 靶向。为此，开发了两种抗 CD32b mAb，NVS32b1 和 NVS32b2。它们的互补决定区 (CDR) 以高特异性和亲和力结合 CD32b Fc 结合域，而 Fc 区被无岩藻糖基化以增强免疫效应细胞上 FcγRIIIa 的激活。NVS32b mAb 选择性靶向 CD32b+ 恶性细胞和健康 B 细胞，但不靶向骨髓细胞。它们通过抗体依赖性细胞毒性和吞噬作用（ADCC 和 ADCP）以及补体依赖性细胞毒性 (CDC) 介导调理 CD32b+ 细胞的有效杀伤。此外，NVS32b CDR 阻断 CD32b Fc 结合域，从而最大限度地减少 CD32b 介导的对治疗性 mAb 的耐药性，包括利妥昔单抗、obinutuzumab 和 daratumumab。NVS32b mAb 表现出强大的体内 CD32b+ 异种移植物抗肿瘤活性和免疫调节活性，包括将巨噬细胞募集到肿瘤和增强树突细胞成熟以响应免疫复合物。最后，使用来自 B 细胞慢性淋巴细胞白血病 (CLL) 和多发性骨髓瘤患者的样本证实了 NVS32b mAb 对 CD32b+ 原发性恶性 B 细胞和浆细胞的活性。