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 急性髓样白血病（AML）是克隆造血茎和祖细胞恶性肿瘤，其特征是 临床结果不佳。恶性转化会触发表面蛋白的表达 信号”，例如白血病细胞通常表达的云母和MICB（云母） 细胞应力途径。天然杀手（NK）细胞和细胞毒性T淋巴细胞识别NKG2D识别云母 接收器又诱导针对白血病细胞的细胞毒性功能。但是，他们经常逃脱 通过引人入胜的翻译后修饰（称为蛋白水解裂解）识别云母/B。在 以前和革命性的研究，我们开发了一系列限制的云母/b靶向单克隆抗体 通过阻止经历二硫键异构酶展开的细胞外域来脱落云母/B 这可以通过金属蛋白酶进行后续裂解。其中之一是进一步的特征， 通过NKG2D和FC受体的双重信号传导促进NK细胞介导的对实体瘤的免疫力。 最近，我们发现抗体还通过 使血液和骨髓中白血病细胞的抗体依赖性吞噬作用。在这种情况下， 云母/B充当FC接收器驱动免疫的“白血病抗原”，尽管NKG2D，NK 还检测到细胞和T细胞。现在，我们开发了一种新版本的这种抗体，有三点 FC结构域中的突变以增加与所有三个FC激活受体的结合亲和力，同时保持 对FC抑制受体的亲和力低。该新版本是人性化的，并诱导潜在的NK细胞效应器 与人源化野生型版本相比，针对人AML细胞的功能。我们还建立了鼠标 人类FC受体生物学的模型以及鼠和人类AML模型，以建立抗白血病 我们现在在体内增强的分子的活性。此外，我们提出了一种机构驱动的药物组合 疗法，组蛋白脱乙酰基酶抑制剂（romidepsin）诱导人白血病细胞表达云母/B 然后将mRNA转化为云母/B蛋白，随后通过 我们的抗体会抑制脱落。我们建议可以通过这种药物来实现AML的免疫疗法 组合增加了白血病细胞的先天免疫原性。由于这些原因，我们的研究将 生成有关如何诱导AML保护性免疫的重要信息。抗体介导的 抑制云母/B脱落是我们开创的新的免疫治疗机会，现在已验证 由多家制药公司独立，其中一家最近开始了I期临床试验 在患有晚期实体瘤的患者中测试与我们的抗体类似物，但野生型版本。所以， 我们的研究将产生令人信服的基本原理，以测试AML试验中的云母/B靶向抗体 公司，我们在学术界或通过合作工作的公司。