A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia
A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia
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DOI：
10.1182/bloodadvances.2019001188
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发表时间：
2020-03-10
期刊：
影响因子：
7.5
通讯作者：
Gaudet, Francois
中科院分区：
文献类型：
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作者：
Nair-Gupta, Priyanka;Diem, Michael;Gaudet, Francois
CD33在90%的急性髓系白血病(AML)患者中表达，其胞外部分由V结构域和C2结构域组成。最近的一项研究表明，单核苷酸多态性 (SNP) rs12459419 (C > T) 会导致包含 V 结构域的 CD33 表达减少，并限制 V 结构域结合的抗 CD33 抗体的功效。我们开发了 JNJ-67571244，一种新型人源双特异性抗体，能够结合 CD33 的 C2 结构域和 CD3，诱导 T 细胞募集和 CD33(+) 肿瘤细胞的细胞毒性，而与 SNP 基因型状态无关。 JNJ-67571244 特异性结合表达 CD33 的靶细胞，并在体外诱导 CD33(+) AML 细胞系的细胞毒性以及 T 细胞激活和细胞因子释放。 JNJ-67571244还在已建立的人类AML播散性和皮下小鼠模型中表现出统计学上显着的体内抗肿瘤活性。此外，该抗体可消除 AML 患者血液样本中的 CD33(+) 母细胞，同时激活 T 细胞。 JNJ-67571244 还与食蟹猴 CD33 和 CD3 发生交叉反应，在食蟹猴中给予 JNJ-67571244 会导致 T 细胞激活、短暂的细胞因子释放和 CD33(+) 白细胞群的持续减少。 JNJ-67571244 在食蟹猴中具有良好的耐受性，剂量高达 30 mg/kg。最后，无论 SNP 基因型状态如何，JNJ-67571244 都能介导细胞系和初级样品的有效细胞毒性，这表明与其他 V 结合抗体相比具有潜在的治疗益处。 JNJ-67571244目前正处于针对复发/难治性AML和高危骨髓增生异常综合征患者的1期临床试验中。
CD33 is expressed in 90% of patients with acute myeloid leukemia (AML), and its extracellular portion consists of a V domain and a C2 domain. A recent study showed that a single nucleotide polymorphism (SNP), rs12459419 (C > T), results in the reduced expression of V domain-containing CD33 and limited efficacy of V domain-binding anti-CD33 antibodies. We developed JNJ-67571244, a novel human bispecific antibody capable of binding to the C2 domain of CD33 and to CD3, to induce T-cell recruitment and CD33(+) tumor cell cytotoxicity independently of their SNP genotype status. JNJ-67571244 specifically binds to CD33-expressing target cells and induces cytotoxicity of CD33(+) AML cell lines in vitro along with T-cell activation and cytokine release. JNJ-67571244 also exhibited statistically significant antitumor activity in vivo in established disseminated and subcutaneous mouse models of human AML. Furthermore, this antibody depletes CD33(+) blasts in AML patient blood samples with concurrent T-cell activation. JNJ-67571244 also cross-reacts with cynomolgus monkey CD33 and CD3, and dosing of JNJ-67571244 in cynomolgus monkeys resulted in T-cell activation, transient cytokine release, and sustained reduction in CD33(+) leukocyte populations. JNJ-67571244 was well tolerated in cynomolgus monkeys up to 30 mg/kg. Lastly, JNJ-67571244 mediated efficient cytotoxicity of cell lines and primary samples regardless of their SNP genotype status, suggesting a potential therapeutic benefit over other V-binding antibodies. JNJ-67571244 is currently in phase 1 clinical trials in patients with relapsed/refractory AML and high-risk myelodysplastic syndrome.