A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells
A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells
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DOI：
10.1080/19420862.2015.1062192
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发表时间：
2015-09-03
期刊：
影响因子：
5.3
通讯作者：
Majeti, Ravindra
中科院分区：
文献类型：
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作者：
Piccione, Emily C.;Juarez, Silvia;Majeti, Ravindra
阻断抗吞噬信号CD47的试剂可以与促吞噬抗肿瘤抗原抗体协同作用以有效地消除肿瘤。虽然CD47在癌细胞上过表达，但它在许多正常组织中的表达可能会产生“抗原库”，从而使CD47阻断剂的治疗效果最小化。在这里，我们报告了共靶向CD47和CD20的双特异性抗体（BsAb）的开发，所述双特异性抗体是非霍奇金淋巴瘤（NHL）的治疗靶标，其相对于亲本抗体对CD47具有降低的亲和力，但保留与CD20的强结合。这些特征促进BsAb与肿瘤细胞的选择性结合，导致吞噬作用。用BsAb治疗人NHL移植小鼠降低了淋巴瘤负荷并延长了存活期，同时重现了抗CD47和抗CD20联合治疗的协同功效。这些发现作为BsAb靶向具有肿瘤相关抗原的CD47作为诱导肿瘤细胞的选择性吞噬作用并概括组合抗体疗法的协同作用的可行策略的原理证明。这种方法可以广泛应用于癌症，以在现有的抗体疗法中添加CD47阻断成分。
Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.