Defining the novel cancer testis antigen HSPA1L as immunotherapeutic target in AML

将新型癌症睾丸抗原 HSPA1L 定义为 AML 的免疫治疗靶点

• 批准号: 10433726
• 负责人: Marina Y Konopleva
• 金额: $ 22.72万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433726
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Adverse effects; Affect; Aftercare; Allogenic; Antibodies; Antibody Therapy; Antibody-drug conjugates; Apoptosis; Binding; Blast Cell; Blood Cells; Bone Marrow; Bone Marrow Cells; Brain; CD34 gene; Cell Line; Cell Surface Proteins; Cell surface; Cells; Characteristics; Chemotherapy-Oncologic Procedure; Child; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Clinical; Clinical Trials; Complement; Complement-Dependent Cytotoxicity; Confocal Microscopy; Disease; Dose; Effector Cell; Elderly; Enzyme-Linked Immunosorbent Assay; Epididymis; Epitopes; Experimental Models; Flow Cytometry; Future; Generations; Gland; Heat-Shock Proteins 70; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; IL3RA gene; Immune; Immune response; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; In Vitro; Induction of Apoptosis; Infant; Label; Lead; Leukemic Cell; Male Genital Organs; Membrane Proteins; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Molecular Target; Monoclonal Antibodies; Mouse Strains; Mus; Myelogenous; Natural Killer Cells; Normal tissue morphology; Pathway interactions; Patients; Pattern; Phagocytosis; Pharmaceutical Preparations; Preparation; Prognosis; Proteins; Proteomics; Randomized; Reagent; Recombinants; Relapse; Research Personnel; SCID Mice; Sampling; Schedule; Spleen; Stem cell transplant; Surface; Tail; Testing; Testis; Therapeutic Monoclonal Antibodies; Time; Transplantation; Tumor Burden; Validation; Veins; Western Blotting; acute myeloid leukemia cell; adult leukemia; antibody-dependent cell cytotoxicity; base; cancer cell; cancer testis antigen; chemotherapy; clinical development; clinical translation; cytotoxicity; efficacy testing; experience; in vitro Assay; in vivo; in vivo Model; in vivo evaluation; leukemia; macrophage; male; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; older patient; overexpression; patient derived xenograft model; pediatric acute leukemia; peripheral blood; pre-clinical; pre-clinical assessment; precursor cell; response; sex; spermadhesin; stem; stem cells; therapeutic target; tool; young adult

SCIENTIFIC ABSTRACT Acute myeloid leukemia (AML) comprises a genetically and clinically heterogeneous group of aggressive hematological malignancies. Despite advances in molecular characterization of AML, the majority of patients will relapse and die of their disease, indicating the urgent need for novel therapeutic approaches. Recently, antibody-based therapeutics have emerged as an effective tool in leukemia therapy but still in need of novel targets. Our proteomic studies using blast leukemia cells from different leukemia subtypes, have identified a putative therapeutic target HSPA1L, as being expressed on the cell surface of AML and other hematologic malignancies, but sparing normal tissues except for male reproductive system. We validated expression of this target by flow cytometry and confocal analyses. Our hypothesis is that immune therapy approaches targeting specific epitopes of the surface protein HSPA1L can selectively eliminate target-expressing AML while avoiding immune-related adverse effects. Importantly, we have already generated monoclonal antibodies (MAbs) against HSPA1L, selected positive clones by ELISA and validated cell surface target binding in AML cells. In this proposal, we will characterize expression patterns of HSPA1L in AML and AML stem/progenitor cells; and utilize first-time produced monoclonal antibodies for therapeutic applications, by testing antibodies alone, antibody-drug conjugates or as immune engaged targeted depletion effector function using in vitro and in vivo leukemia models. In Aim 1, we will characterize selected candidate antibodies exploring the feasibility of using them alone, to trigger complement depending cytotoxicity (CDC) or engage effector cells, such as NK and macrophages to trigger antibody dependent cell cytotoxicity or phagocytosis (ADCC or ADCP); or as antibody-drug conjugates (ADC) by conjugating MAbs to auristatin. The expression patterns of HSPA1L in AML, and AML stem/progenitor cells and in normal bone marrow cells and hematopoietic stem cells will be studied. In Aim 2, we will test the efficacy of the selected lead HSPA1L MAbs with or without conjugation as ADCs in vivo in bioluminescent-labeled AML cell line models using SCID mice, and in patient-derived xenograft (PDX) AML models in NSG mice. We have assembled a multi-faceted team of highly experienced investigators with deep background in MAbs generation and testing, proteomics and target discovery, pre-clinical assessment of novel agents in adult and pediatric leukemias in vitro and in vivo models, and clinical translation in adult and pediatric acute leukemias. If successful, this multi-investigator project will generate novel antibodies for future clinical development in target- expressing leukemias that will be tested in clinical trials, alone or in combination with standard chemotherapy.

科学抽象 急性髓性白血病（AML）包括一组遗传和临床异质性的白血病， 恶性血液病尽管AML的分子表征取得了进展，但大多数 患者会复发并死于疾病，这表明迫切需要新的治疗方法。 最近，基于抗体的治疗已经成为白血病治疗中的有效工具，但仍然需要 新的目标我们使用不同白血病亚型的白血病母细胞进行蛋白质组学研究， 假定的治疗靶点HSPA 1 L，如在AML和其他血液系统疾病的细胞表面上表达的， 恶性肿瘤，但保留除男性生殖系统外的正常组织。我们验证了这一表达 通过流式细胞术和共聚焦分析靶向。我们的假设是，免疫治疗方法靶向 表面蛋白HSPA 1 L的特异性表位可以选择性地消除靶表达AML， 避免与免疫相关的不良反应。重要的是，我们已经产生了单克隆抗体， 针对HSPA 1 L的单克隆抗体，通过ELISA选择阳性克隆，并验证AML中的细胞表面靶点结合 细胞在本研究中，我们将描述HSPA 1 L在AML和AML干/祖细胞中的表达模式， 细胞;并利用首次生产的单克隆抗体用于治疗应用，通过测试抗体 单独、抗体-药物缀合物或作为免疫参与的靶向耗竭效应子功能， 体内白血病模型。 在目标1中，我们将表征选定的候选抗体，探索单独使用它们的可行性，以 触发补体依赖性细胞毒性（CDC）或接合效应细胞，如NK和巨噬细胞， 触发抗体依赖性细胞毒性或吞噬作用（ADCC或ADCP）;或作为抗体-药物缀合物 (ADC)通过将单克隆抗体与澳瑞他汀缀合。HSPA 1 L在急性髓性白血病及其干/祖细胞中的表达 将研究正常骨髓细胞和造血干细胞中的细胞毒性。 在目的2中，我们将测试具有或不具有缀合物的所选前导HSPA 1 L MAb作为ADC在以下中的功效： 在使用SCID小鼠的生物发光标记的AML细胞系模型和患者来源的异种移植物（PDX）中的体内 NSG小鼠中的AML模型。 我们已经组建了一个多方面的团队，由经验丰富的研究人员组成，具有深厚的MAb背景 生成和测试，蛋白质组学和目标发现，成人和 体外和体内模型中的儿科白血病，以及成人和儿科急性白血病的临床转化。如果 成功，这个多研究者项目将产生新的抗体，用于未来的靶向临床开发， 表达白血病，将在临床试验中测试，单独或与标准化疗组合。