CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies
CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies
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DOI：
10.1182/blood-2017-09-807610
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发表时间：
2018-02-08
期刊：
影响因子：
20.3
通讯作者：
Press, Oliver W.
中科院分区：
文献类型：
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作者：
Green, Damian J.;O'Steen, Shyril;Press, Oliver W.
前靶向放射免疫治疗(PRIT)已显示出针对肿瘤抗原的显著疗效，但免疫原性和内源性生物素阻断可能限制临床转译。我们描述了一种治疗多发性骨髓瘤(MM)和其他B细胞恶性肿瘤的新的PRIT方法，为此，我们开发了一种抗CD38双特异性融合蛋白，它可以消除内源性生物素干扰和免疫原性成分。在多发性骨髓瘤和非霍奇金淋巴瘤(NHL)的异种移植模型中，CD38-双特异性构建物显示出良好的血液清除和肿瘤靶向性。剂量学计算表明，Y-90注射剂量为43.8GY/毫克尿，肝脏肿瘤与正常器官剂量比为7：1，肺和肾脏为15：1。在治疗研究中，在MM和NHL异种移植模型中，CD38-双特异性Prit在第12天导致100%完全缓解，最终在最佳剂量下治愈了80%的小鼠。在直接比较中，CD38双特异性被证明与链霉亲和素(SA)生物素为基础的CD38-SA Prit的疗效相同或更好。每种方法在测试的最高辐射剂量(1200亩Ci)下至少治愈了75%的小鼠，而在600和1000亩Ci剂量下，双特异性Ci方法的表现优于SA方法，总体治愈小鼠的比例增加了35%(P<；.004)。双特异性Prit的高效率，加上其降低的免疫原性和内源性生物素干扰的风险，使CD38双特异性成为临床翻译的一个有吸引力的候选基因。关键的是，CD38Prit可能有利于无反应、高风险疾病的患者，因为难治性疾病通常保持对辐射的敏感性。我们推测PRIT不仅可以延长生存期，而且有可能治愈MM和治疗难治的NHL患者。
Pretargeted radioimmunotherapy (PRIT) has demonstrated remarkable efficacy targeting tumor antigens, but immunogenicity and endogenous biotin blocking may limit clinical translation. We describe a new PRIT approach for the treatment of multiple myeloma (MM) and other B-cell malignancies, for which we developed an anti-CD38-bispecific fusion protein that eliminates endogenous biotin interference and immunogenic elements. In murine xenograft models of MM and non-Hodgkin lymphoma (NHL), the CD38-bispecific construct demonstrated excellent blood clearance and tumor targeting. Dosimetry calculations showed a tumor-absorbed dose of 43.8 Gy per millicurie injected dose of Y-90, with tumor-to-normal organ dose ratios of 7:1 for liver and 15:1 for lung and kidney. In therapy studies, CD38-bispecific PRIT resulted in 100% complete remissions by day 12 in MM and NHL xenograft models, ultimately curing 80% of mice at optimal doses. In direct comparisons, efficacy of the CD38 bispecific proved equal or superior to streptavidin (SA)-biotin- based CD38-SA PRIT. Each approach cured at least 75% of mice at the highest radiation dose tested (1200 mu Ci), whereas at 600- and 1000-mu Ci doses, the bispecific outperformed the SA approach, curing 35% more mice overall (P < .004). The high efficacy of bispecific PRIT, combined with its reduced risk of immunogenicity and endogenous biotin interference, make the CD38 bispecific an attractive candidate for clinical translation. Critically, CD38 PRIT may benefit patients with unresponsive, high-risk disease because refractory disease typically retains radiation sensitivity. We posit that PRIT might not only prolong survival, but possibly cure MM and treatment-refractory NHL patients.