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) 是一种由突变的前 B 细胞引起的恶性肿瘤， 最常见的儿童白血病，但也发生在成人中。虽然目前对高达 90% 的患者有效， BCP-ALL 的化疗和靶向治疗暂时破坏了 BCP-ALL 的体液（产生抗体）臂 免疫系统并引起具有长期后果的毒性。此 R21 拨款提案的目标是 参与有关前 B 细胞受体 (pre-BCR) 作为独特治疗方法的实用性的概念研究 BCP-ALL 的治疗目标。前 BCR 包含免疫球蛋白 (Ig) 重链和 替代轻链 (SLC) 以及信号分子 Ig α 和 Ig β。 SLC 的组成包括 两个非共价连接的多肽，VpreB 和l5。在正常组织中，前 BCR 仅在前 B 细胞，但不存在于更成熟的 B 细胞或任何其他组织中。重要的是，我们的初步数据表明 VpreB 和 l5 在 >90% 的 BCP-ALL 中表达。因此，我们产生了高亲合力单克隆抗体 (mAb) 特异性针对 VpreB 和 l5，并发现 mAb 内化到表达 BCR 之前。内化是抗体-药物缀合物的抗体成分的重要先决条件 （ADC）。我们的中心假设是，使用针对 VpreB 或 l5 的 ADC 攻击 BCP-ALL 将消除 白血病细胞，同时保留成熟的体液免疫系统来对抗感染。我们的目标是获得证据—— 概念数据首先证实了 VpreB mAb 在几种 BCP-ALL 细胞系中的内化，并允许 选择单一、最有效内化先导单克隆抗体（具体目标 1）；二、在蛋白质水平上表现 前 BCR 在 35 个 BCP-ALL 患者白血病样本中广泛表达（具体目标 2）；第三， 证明我们的领先 VpreB ADC 在体外杀死已建立的和患者来源的 BCP-ALL 细胞系的能力， 体外和患者来源的异种移植模型（具体目标 3）。我们希望这项研究能够支持 开发一种新的 BCP-ALL 疗法，可以安全地消除白血病细胞，同时不损害体液 免疫系统并最终取代化疗，使患者无需化疗即可获得完全缓解 短期或长期的不良后果。