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.

科学摘要 急性髓系白血病 (AML) 包括一组具有遗传和临床异质性的疾病 侵袭性血液恶性肿瘤。尽管 AML 的分子表征取得了进展，但大多数 患者会因疾病复发并死亡，这表明迫切需要新的治疗方法。 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 新颖的目标。我们使用来自不同白血病亚型的母细胞白血病细胞进行蛋白质组学研究，发现 假定的治疗靶标 HSPA1L，在 AML 和其他血液学细胞表面表达 恶性肿瘤，但不影响除男性生殖系统以外的正常组织。我们验证了这个表达 通过流式细胞术和共聚焦分析来确定目标。我们的假设是免疫疗法的目标是 表面蛋白 HSPA1L 的特定表位可以选择性地消除靶标表达的 AML，同时 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 针对 HSPA1L 的单克隆抗体，通过 ELISA 选择阳性克隆并验证 AML 中的细胞表面靶标结合 细胞。在本提案中，我们将描述 AML 和 AML 干/祖细胞中 HSPA1L 的表达模式 细胞；并通过测试抗体，将首次生产的单克隆抗体用于治疗应用 单独使用、抗体-药物缀合物或作为免疫参与的靶向耗竭效应器功能在体外和体内使用 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) 或吸引效应细胞（例如 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 MAb 与 auristatin 结合。 HSPA1L 在 AML 和 AML 干/祖细胞中的表达模式 将研究正常骨髓细胞和造血干细胞。 在目标 2 中，我们将测试选定的先导 HSPA1L MAb 在有或没有缀合作为 ADC 的情况下的功效。 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) 体内 NSG 小鼠的 AML 模型。 我们组建了一支多方面的团队，由经验丰富的研究人员组成，他们在单克隆抗体方面拥有深厚的背景 生成和测试、蛋白质组学和靶点发现、成人和成人新药的临床前评估 儿科白血病体外和体内模型，以及成人和儿科急性白血病的临床转化。如果 成功后，这个多研究者项目将为未来的靶点临床开发产生新型抗体 表达将在临床试验中单独或与标准化疗联合进行测试的白血病。