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.

科学文摘