Piccione Emily C, Juarez Silvia, Liu Jie, Tseng Serena, Ryan Christine E, Narayanan Cyndhavi, Wang Lijuan, Weiskopf Kipp, Majeti Ravindra
a Department of Medicine; Division of Hematology, Cancer Institute; and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford , CA , USA.
MAbs. 2015;7(5):946-56. doi: 10.1080/19420862.2015.1062192.
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.
阻断抗吞噬信号CD47的药物可与促吞噬抗肿瘤抗原抗体协同作用，有效消除肿瘤。虽然CD47在癌细胞上过度表达，但其在许多正常组织中的表达可能会形成一个“抗原库”，从而降低CD47阻断剂的治疗效果。在此，我们报道了双特异性抗体（BsAbs）的研发，该抗体共同靶向CD47和CD20（非霍奇金淋巴瘤（NHL）的治疗靶点），相对于亲本抗体，其对CD47的亲和力降低，但对CD20仍保持强结合力。这些特性有助于BsAbs选择性结合肿瘤细胞，从而引发吞噬作用。用BsAbs治疗人源化NHL小鼠可减轻淋巴瘤负担并延长生存期，同时重现抗CD47和抗CD20联合治疗的协同疗效。这些发现证明了以肿瘤相关抗原靶向CD47的BsAb作为诱导肿瘤细胞选择性吞噬并重现联合抗体治疗协同作用的可行策略的原理。这种方法可能广泛应用于癌症治疗，为现有抗体疗法添加CD47阻断成分。
