Eliminating B Cell Precursor Acute Lymphoblastic Leukemia by Targeting the Uniquely Specific Pre-B Cell Receptor

通过靶向独特的特异性前 B 细胞受体消除 B 细胞前体急性淋巴细胞白血病

• 批准号: 10374764
• 负责人: Larry W. Tjoelker
• 金额: $ 25.41万
• 依托单位: PASCAL BIOSCIENCES US, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374764
• 关键词: Adult; Alkylating Agents; Antibodies; Antibody-drug conjugates; Applications Grants; Avidity; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; B-cell precursor acute lymphoblastic leukemia cell; Biological Assay; Cell Line; Cells; Childhood Leukemia; Clinical; Cytotoxic agent; DNA; Data; Development; Disease remission; Drug Kinetics; Engineering; Goals; Heavy-Chain Immunoglobulins; Human; Immune system; Immunity; Immunocompromised Host; Immunoglobulins; In Vitro; Infection; Lead; Leukemic Cell; Link; Malignant Neoplasms; Mature B-Lymphocyte; Messenger RNA; Microtubules; Monoclonal Antibodies; Morals; Mus; Normal tissue morphology; Patients; Penetrance; Plasma Cells; Program Development; Property; Proteins; Refractory; Relapse; Research; Safety; Sampling; Signaling Molecule; Stains; Testing; Therapeutic; Tissues; Toxic effect; Work; adverse outcome; anticancer activity; arm; base; cancer cell; chemotherapy; combat; crosslink; drug development; efficacy testing; experimental study; humanized antibody; in vivo; in vivo Model; innovation; leukemia; mutant; novel therapeutic intervention; patient derived xenograft model; patient stratification; polypeptide; pre-B cell receptor; protein expression; pyrrolobenzodiazepine; surrogate light chain; targeted treatment; therapeutic target

ABSTRACT B cell precursor acute lymphoblastic leukemia (BCP-ALL), a malignancy that arises from mutant pre-B cells, is the most common childhood leukemia but also occurs in adults. While effective in up to 90% of patients, current chemo- and targeted therapies for BCP-ALL temporarily destroy the humoral (antibody-producing) arm of the immune system and cause toxicities with long term consequences. The goal of this R21 grant proposal is to engage in conceptual research regarding the utility of the pre-B cell receptor (pre-BCR) as a unique therapeutic target for the treatment of BCP-ALL. The pre-BCR comprises an immunoglobulin (Ig) heavy chain and a surrogate light chain (SLC) together with the signaling molecules Ig alpha and Ig beta. The SLC is composed of two noncovalently-linked polypeptides, VpreB and l5. In normal tissues, the pre-BCR is expressed only in pre- B cells but not in more mature B cells nor in any other tissues. Importantly, our preliminary data suggest that VpreB and l5 are expressed in >90% of BCP-ALL. We therefore generated high avidity monoclonal antibodies (mAbs) specific for VpreB and l5 and found that the mAbs are internalized into BCP-ALL cells expressing the pre-BCR. Internalization is an important prerequisite for the antibody component of an antibody-drug conjugate (ADC). Our central hypothesis is that attacking BCP-ALL with an ADC specific for VpreB or l5 will eliminate the leukemia cells while sparing the mature humoral immune system to combat infection. Our goal is to obtain proof- of-concept data that first, confirms internalization of VpreB mAbs in several BCP-ALL cell lines and allows selection of a single, most efficiently internalizing lead mAb (Specific Aim 1); second, show at the protein level the widespread expression of the pre-BCR in 35 BCP-ALL patient leukemia samples (Specific Aim 2); and third, demonstrate the ability of our lead VpreB ADC to kill established and patient-derived BCP-ALL cell lines in vitro, ex vivo, and in a patient-derived xenograft model (Specific Aim 3). We hope that this research will support the development of a new BCP-ALL therapeutic that will safely eliminate leukemia cells while sparing the humoral immune system and ultimately supplanting chemotherapy so that patients can achieve full remission without short- or long-term adverse consequences.

抽象的 B细胞前体急性淋巴细胞白血病（BCP-ALL）是一种由突变前B细胞引起的恶性肿瘤 最常见的童年白血病，但也发生在成年人中。虽然最多有90％的患者有效 BCP的化学疗法和靶向疗法 - 所有人都会暂时破坏该部门的体液（抗体产生）臂 免疫系统并引起长期后果的毒性。该R21赠款提案的目标是 从事有关前B细胞受体（BER-BCR）作为独特治疗的效用的概念研究 BCP ALL治疗的目标。前BCR包括一个免疫球蛋白（IG）重链和A 替代光链（SLC）以及信号分子Igα和Igβ。 SLC由 两个非共交连接的多肽VPREB和L5。在正常组织中，前BCR仅在前表达 B细胞，但不在更成熟的B细胞中或在任何其他组织中。重要的是，我们的初步数据表明 VPREB和L5在BCP-ALL> 90％以> 90％表示。因此，我们产生了高流行单克隆抗体 （mAb）对VPREB和L5的特异性 前BCR。内部化是抗体 - 药物结合物的抗体成分的重要先决条件 （ADC）。我们的中心假设是，使用特定于VPREB或L5的ADC攻击BCP将消除 白血病细胞在保留成熟的体液免疫系统以对抗感染。我们的目标是获得证明 - 概念数据的数据首先证实了在几个BCP all细胞系中VPREB mAb的内在化，并允许 选择单个，最有效地内化铅mab（特定目标1）；第二，在蛋白质水平上显示 BCP所有患者白血病样本中BCR的广泛表达（特定AIM 2）；第三， 证明我们铅VPREB ADC在体外杀死已建立和患者的BCP所有细胞系的能力， 离体和患者衍生的异种移植模型（特定目标3）。我们希望这项研究将支持 开发新的BCP所有治疗性，该治疗方法将安全消除白血病细胞，同时避免体液 免疫系统并最终取代化学疗法，以便患者可以完全缓解而无需 短期或长期不利后果。