The cluster of differentiation 38 (CD38) is a well validated target for treating multiple myeloma (MM). Although anti-CD38 monoclonal antibodies have demonstrated outstanding initial responses in patients with multiple myeloma, nearly all patients eventually develop resistance and relapse. In addition, currently approved CD38 targeting therapies have failed to show monotherapy efficacy in lymphomas, where CD38 expression is present but at lower levels. To effectively target CD38 on tumor cells, we generated an ADCC enhanced bispecific CD38 x ICAM-1 antibody, VP301. This bispecific antibody targets unique epitopes on CD38 and ICAM-1 on tumor cells with reduced red blood cell binding compared to the benchmark CD38 antibody daratumumab. VP301 demonstrated potent ADCC and ADCP activities on a selected set of myeloma and lymphoma cell lines even those with low CD38 expression. In an ex vivo drug sensitivity assay, we observed responses to VP301 in multiple myeloma primary samples from relapsed/refractory patients. Moreover, VP301 demonstrated potent tumor inhibition activities in in vivo myeloma and lymphoma models. Interestingly, combination of VP301 with the immunomodulatory drug, lenalidomide, led to synergistic anti-tumor growth activity in an in vivo efficacy study. In conclusion, the CD38 x ICAM-1 bispecific antibody VP301 demonstrated promising efficacy and specificity toward CD38+ and ICAM-1+ tumor cells and represents a novel approach for treating multiple myeloma and lymphoma.

中文翻译：

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CD38 x ICAM-1 双特异性抗体是治疗多发性骨髓瘤和淋巴瘤的新方法

分化簇 38 (CD38) 是经过充分验证的治疗多发性骨髓瘤 (MM) 的靶标。尽管抗CD38单克隆抗体在多发性骨髓瘤患者中表现出出色的初始反应，但几乎所有患者最终都会产生耐药性并复发。此外，目前批准的 CD38 靶向疗法未能显示出对淋巴瘤的单一疗法疗效，淋巴瘤中存在 CD38 表达，但水平较低。为了有效靶向肿瘤细胞上的 CD38，我们生成了 ADCC 增强型双特异性 CD38 x ICAM-1 抗体 VP301。这种双特异性抗体靶向肿瘤细胞上 CD38 和 ICAM-1 上的独特表位，与基准 CD38 抗体 daratumumab 相比，红细胞结合减少。VP301 对一组选定的骨髓瘤和淋巴瘤细胞系（甚至 CD38 表达低的细胞系）表现出有效的 ADCC 和 ADCP 活性。在离体药物敏感性测定中，我们观察了来自复发/难治性患者的多发性骨髓瘤原发样本中对 VP301 的反应。此外，VP301 在体内骨髓瘤和淋巴瘤模型中表现出有效的肿瘤抑制活性。有趣的是，在体内功效研究中，VP301 与免疫调节药物来那度胺的组合产生了协同抗肿瘤生长活性。总之，CD38 x ICAM-1 双特异性抗体 VP301 对 CD38+ 和 ICAM-1+ 肿瘤细胞表现出良好的疗效和特异性，代表了一种治疗多发性骨髓瘤和淋巴瘤的新方法。