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: 10625516
• 负责人: Marina Y Konopleva
• 金额: $ 18.56万
• 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/10625516
• 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; Engraftment; 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; Macrophage; 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; antileukemic activity; cancer cell; cancer/testis antigen; candidate selection; chemotherapy; clinical development; clinical translation; cytotoxicity; efficacy evaluation; efficacy testing; experience; in vitro Assay; in vivo; in vivo Model; in vivo evaluation; leukemia; leukemia treatment; leukemic stem cell; 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; 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.

科学摘要 急性髓样白血病（AML）包括一组遗传和临床异质的群体 侵略性血液学恶性肿瘤。尽管AML的分子表征取得了进步，但大多数 患者将复发并死于疾病，表明迫切需要采用新型治疗方法。 最近，基于抗体的疗法已成为白血病治疗的有效工具，但仍需要 新目标。我们使用来自不同白血病亚型的BLAST白血病细胞的蛋白质组学研究已经鉴定 假定的治疗靶标HSPA1L，如在AML和其他血液学的细胞表面表达 恶性肿瘤，但除了男性生殖系统外，还要保留正常组织。我们验证了这一点的表达 通过流式细胞仪和共聚焦分析进行目标。我们的假设是免疫治疗方法的靶向方法 表面蛋白HSPA1L的特定表位可以选择性地消除表达目标的AML，而 避免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 （mAb）针对HSPA1L，通过ELISA选择阳性克隆并验证了AML中的细胞表面靶标结合 细胞。在此提案中，我们将表征AML和AML茎/祖细胞中HSPA1L的表达模式 细胞；并通过测试抗体利用首次生产的单克隆抗体来治疗应用 单独使用抗体 - 药物结合物或使用体外和IN中的免疫接合靶向耗尽效应函数 体内白血病模型。 在AIM 1中，我们将表征选定的候选抗体，以探索单独使用它们的可行性， 取决于细胞毒性（CDC）或使效应细胞（例如NK和巨噬细胞）触发补体 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mabs结合到auristatin。 AML中HSPA1L的表达模式和AML茎/祖先 将研究细胞以及正常的骨髓细胞和造血干细胞。 在AIM 2中，我们将测试所选铅HSPA1L mAb的功效，无论是否有或不作为ADC 使用SCID小鼠和患者衍生的异种移植物（PDX）中的生物发光标记的AML细胞系模型的体内体内 NSG小鼠中的AML模型。 我们组建了一个由经验丰富的调查员组成的多面团队 生成和测试，蛋白质组学和靶向发现，成人和 体外和体内模型的小儿白血病，以及成人和小儿急性白血病的临床翻译。如果 成功的，这个多入侵器项目将生成新的抗体，以实现目标的未来临床发展。 表达白血病，将在临床试验中，单独或与标准化疗结合进行测试。