Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia.
Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia.
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DOI：
10.1158/1535-7163.mct-17-1095
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发表时间：
2018-08
影响因子：
5.7
通讯作者：
Ferlin WG
中科院分区：
文献类型：
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作者：
Buatois V;Johnson Z;Salgado-Pires S;Papaioannou A;Hatterer E;Chauchet X;Richard F;Barba L;Daubeuf B;Cons L;Broyer L;D'Asaro M;Matthes T;LeGallou S;Fest T;Tarte K;Clarke Hinojosa RK;Genescà Ferrer E;Ribera JM;Dey A;Bailey K;Fielding AK;Eissenberg L;Ritchey J;Rettig M;DiPersio JF;Kosco-Vilbois MH;Masternak K;Fischer N;Shang L;Ferlin WG
CD 47是一种普遍表达的先天免疫检查点受体，作为一种通用的“不要吃我”吞噬信号，通常被血液和实体癌上调以逃避免疫监视。CD 47靶向模式的发展受到靶点普遍表达的阻碍，通常导致快速药物消除和血液毒性，包括贫血。为了克服这些不利因素，我们开发了一种完全人双特异性抗体NI-1701，其设计用于选择性地共结合B细胞上的CD 47和CD 19。NI-1701表现出良好的消除动力学，对非人灵长类动物单次或多次给药后对血液学参数无有害影响。NI-1701在异种移植小鼠模型中诱导有效的体外和体内活性，以杀死过多的B细胞恶性肿瘤中的癌细胞并控制肿瘤生长。NI-1701提供最大肿瘤生长抑制的机制依赖于B细胞上的CD 47/CD 19的共接合，诱导靶细胞的有效抗体依赖性细胞吞噬作用。NI-1701诱导的免疫缺陷NOD/SCID小鼠肿瘤生长控制比抗CD 20靶向抗体利妥昔单抗更有效。有趣的是，当肿瘤植入小鼠共同施用NI-1701和利妥昔单抗时，观察到协同效应，导致一些动物中显著改善的肿瘤生长抑制和消退。我们在本文中描述了一种新的双特异性抗体方法，其旨在使B细胞变得更容易被吞噬和消除，从而为患有对抗-CD 20靶向治疗难治/耐药的B细胞恶性肿瘤的患者提供替代或辅助治疗选择。
CD47, a ubiquitously expressed innate immune checkpoint receptor that serves as a universal “don’t eat me” signal of phagocytosis, is often up-regulated by hematological and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to co-engage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematological parameters following single or multiple administrations to non-human primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the co-engagement of CD47/CD19 on B cells inducing potent antibody dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were co-administered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B cell malignancies refractory/resistant to anti-CD20 targeted therapy.