Promoting immunity against acute myeloid leukemia through Fc effector-optimized antibody inhibitory of MICA/B shedding

通过 Fc 效应子优化抗体抑制 MICA/B 脱落，增强对急性髓系白血病的免疫力

• 批准号: 10585146
• 负责人: Lucas Ferrari de Andrade
• 金额: $ 49.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-06 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585146
• 关键词: Academia; Acute Myelocytic Leukemia; Address; Affinity; Antibodies; Antigens; Binding; Biological Assay; Biology; Blood; Bone Marrow; Bypass; CD34 gene; Cell Line; Cells; Cellular Immunity; Cellular Stress; Clinical; Clinical Trials; Collaborations; Cytotoxic T-Lymphocytes; Dichloromethylene Diphosphonate; Drug Combinations; Effector Cell; Engraftment; Epigenetic Process; Extracellular Domain; Fc Receptor; Fc domain; Goals; Grant; HDAC4 gene; Hematopoietic Neoplasms; Hematopoietic stem cells; Histone Deacetylase Inhibitor; Human; IgG1; Immune; Immunity; Immunocompetent; Immunologic Surveillance; Immunotherapeutic agent; Immunotherapy; Leukemic Cell; Lymphocyte; Macrophage; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane Proteins; Messenger RNA; Metalloproteases; Modeling; Monoclonal Antibodies; Mus; Mutation; Natural Killer Cells; Outcome; Pathway interactions; Patients; Pattern; Phagocytosis; Phagocytosis Induction; Pharmacologic Substance; Phase; Phase I Clinical Trials; Point Mutation; Post-Translational Protein Processing; Pre-Clinical Model; Protein Disulfide Isomerase; Proteins; Publishing; Regimen; Series; Signal Transduction; Solid Neoplasm; Structure; Surface; T-Lymphocyte; Testing; Time; Translating; Treatment Efficacy; Universities; acute myeloid leukemia cell; analog; antileukemic activity; cancer cell; cancer type; cytotoxic; experimental group; experimental study; human model; humanized mouse; immunogenicity; in vivo; in vivo Model; inhibiting antibody; leukemia; leukemic stem cell; mRNA Expression; monocyte; mouse model; novel; pre-clinical; protein expression; receptor; response; synergism

SUMMARY Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. Malignant transformation triggers expression of surface proteins that serve as “danger signals”, such as MICA and MICB (MICA/B) that are commonly expressed by leukemia cells in response to cellular stress pathways. Natural killer (NK) cells and cytotoxic T lymphocytes recognize MICA/B with the NKG2D receptor, which in turn induces cytotoxic functions against leukemia cells. However, they often escape recognition by shedding MICA/B via an intriguing post-translational modification called proteolytic cleavage. In previous and revolutionary study, we developed a series of MICA/B-targeted monoclonal antibodies that inhibit the shedding of MICA/B by blocking the extracellular domain that undergoes an unfolding by disulfide isomerase, which enables subsequent cleavage by metalloproteases. One of them was further characterized, and it promotes NK cell-mediated immunity against solid tumors by dual signaling of NKG2D and Fc receptors. Recently, we discovered that the antibody also promotes macrophage-driven immunity in AML models, by enabling antibody-dependent phagocytosis of leukemia cells in the blood and bone marrow. In this setting, MICA/B serve as “leukemia antigens” for Fc receptor-driven immunity, although contributions by NKG2D, NK cells, and T cells were also detected. Now we developed a new version of this antibody, with three point mutations in the Fc domain to increase the binding affinity to all three Fc activating receptors while maintaining low affinity to the Fc inhibitory receptor. This new version is humanized and induces potent NK cell effector functions against human AML cells, compared to the humanized wild type version. We also established mouse models of human Fc receptor biology and both murine and human AML models, to establish the anti-leukemia activity of our now enhanced molecule in vivo. Furthermore, we propose a mechanism-driven drug combination regimen, whereby a histone deacetylase inhibitor (romidepsin) induces human leukemia cells to express MICA/B mRNAs that are then translated to MICA/B proteins, which are followed by stabilization on cellular surface by our antibody that inhibits the shedding. We propose that immunotherapy for AML can be achieved via this drug combination, which increases the innate immunogenicity of leukemia cells. For these reasons, our studies will generate important information about how to induce protective immunity against AML. Antibody-mediated inhibition of MICA/B shedding is a new immunotherapeutic opportunity pioneered by us and now validated independently by multiple pharmaceutical companies, one of which has recently began phase-I clinical trial testing an antibody analog to ours, but the wild type version, in patients with advanced solid tumors. Therefore, our studies will generate compelling rationale to test MICA/B-targeted antibodies in AML trials, by pharmaceutical companies, ourselves in academia, or both by working in collaboration.

概括 急性髓系白血病（AML）是一种克隆性造血干细胞和祖细胞恶性肿瘤，其特征为 不良的临床结果会引发“危险”的表面蛋白的表达。 信号”，例如白血病细胞通常表达的 MICA 和 MICB (MICA/B)，以响应 细胞应激途径。自然杀伤 (NK) 细胞和细胞毒性 T 淋巴细胞通过 NKG2D 识别 MICA/B。 受体，进而诱导针对白血病细胞的细胞毒性功能，然而，它们经常逃脱。 通过一种有趣的翻译后修饰（称为蛋白水解切割）脱落 MICA/B 来识别。 在之前的革命性研究中，我们开发了一系列 MICA/B 靶向单克隆抗体，可抑制 通过阻断二硫键异构酶解折叠的胞外结构域来脱落 MICA/B， 这使得随后能够被金属蛋白酶切割，并且进一步表征了其中之一。 通过 NKG2D 和 Fc 受体的双重信号传导促进 NK 细胞介导的针对实体瘤的免疫。 最近，我们发现该抗体还可以通过以下方式促进 AML 模型中巨噬细胞驱动的免疫： 在这种情况下，能够实现血液和骨髓中白血病细胞的抗体依赖性吞噬作用。 尽管 NKG2D、NK 做出了贡献，但 MICA/B 作为 Fc 受体驱动免疫的“白血病抗原” 现在我们开发了这个抗体的新版本，有三个点。 Fc 结构域中的突变可增加与所有三种 Fc 激活受体的结合亲和力，同时保持 与 Fc 抑制性受体的亲和力低，这种新版本是人源化的，可诱导有效的 NK 细胞效应。 与人源化野生型版本相比，我们还建立了针对人类 AML 细胞的功能。 人类 Fc 受体生物学模型以及小鼠和人类 AML 模型，以建立抗白血病药物 我们现在增强的分子的体内活性此外，我们提出了一种机制驱动的药物组合。 因此，组蛋白脱乙酰酶抑制剂（罗米地辛）诱导人白血病细胞表达 MICA/B 然后 mRNA 被翻译成 MICA/B 蛋白，然后通过以下方式稳定在细胞表面： 我们提出抑制脱落的抗体可以通过这种药物实现 AML 的免疫治疗。 由于这些原因，我们的研究将增加白血病细胞的先天免疫原性。 生成有关如何诱导针对抗体介导的保护性免疫的重要信息。 抑制 MICA/B 脱落是我们首创并现已验证的一种新的免疫治疗机会 多家药企独立研发，其中一家近期已开始I期临床试验 在患有晚期实体瘤的患者中测试我们的抗体类似物，但野生型版本，因此， 我们的研究将为制药公司在 AML 试验中测试 MICA/B 靶向抗体提供令人信服的理由 公司、我们自己在学术界，或者两者合作。