Multiple myeloma (MM) is an incurable malignancy of plasma cells and the second most common hematologic malignancy in the United States. Although antibodies in clinical cancer therapy are generally of the IgG class, antibodies of the IgE class have attractive properties as cancer therapeutics, such as their high affinity for Fc receptors (FcεRs), the low serum levels of endogenous IgE allowing for less competition for FcR occupancy, and the lack of inhibitory FcRs. Importantly, the FcεRs are expressed on immune cells that elicit antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and/or antigen presentation such as mast cells, eosinophils, macrophages, and dendritic cells. We now report the development of a fully human IgE targeting human CD38 as a potential MM therapy. We targeted CD38 given its high and uniform expression on MM cells. The novel anti-CD38 IgE, expressed in mammalian cells, is properly assembled and secreted, exhibits the correct molecular weight, binds antigen and the high affinity FcεRI, and induces degranulation of FcεRI expressing cells in vitro and also in vivo in transgenic BALB/c mice expressing human FcεRIα. Moreover, the anti-CD38 IgE induces ADCC and ADCP mediated by monocytes/macrophages against human MM cells (MM.1S). Importantly, the anti-CD38 IgE also prolongs survival in a preclinical disseminated xenograft mouse model using SCID-Beige mice and human MM.1S cells when administered with human peripheral blood mononuclear cells (PBMCs) as a source of monocyte effector cells. Our results suggest that anti-CD38 IgE may be effective in humans bearing MM and other malignancies expressing CD38.
多发性骨髓瘤是一种无法治愈的浆细胞恶性肿瘤，在美国是第二常见的血液系统恶性肿瘤。尽管临床癌症治疗中使用的抗体通常属于IgG类别，但IgE类抗体作为癌症治疗手段具有引人注目的特性，例如其对Fc受体（FcεRs）的高亲和力、内源性IgE血清水平较低从而减少对FcR占位的竞争，以及缺乏抑制性FcRs。重要的是，FcεRs表达于能引发抗体依赖性细胞介导的细胞毒性（ADCC）、抗体依赖性细胞介导的吞噬作用（ADCP）和/或抗原呈递的免疫细胞上，如肥大细胞、嗜酸性粒细胞、巨噬细胞和树突状细胞。本研究报道了一种靶向人CD38的全人源IgE的研发，作为多发性骨髓瘤的潜在疗法。选择CD38作为靶点是因为其在多发性骨髓瘤细胞上高且均匀表达。这种在哺乳动物细胞中表达的新型抗CD38 IgE能够正确组装和分泌，具有正确的分子量，能结合抗原和高亲和力FcεRI，并在体外及表达人FcεRIα的转基因BALB/c小鼠体内诱导表达FcεRI的细胞脱颗粒。此外，抗CD38 IgE能诱导单核细胞/巨噬细胞介导的针对人多发性骨髓瘤细胞（MM.1S）的ADCC和ADCP。重要的是，在使用SCID-Beige小鼠和人MM.1S细胞的临床前播散性异种移植小鼠模型中，当与人外周血单个核细胞（作为单核效应细胞的来源）共同给药时，抗CD38 IgE还能延长生存期。我们的研究结果表明，抗CD38 IgE可能对患有多发性骨髓瘤及其他表达CD38的恶性肿瘤的患者有效。
A Fully Human IgE Specific for CD38 as a Potential Therapy for Multiple Myeloma
肿瘤(癌症)患者之家