Novel antibody-drug conjugates targeting T-cell lymphoma

靶向 T 细胞淋巴瘤的新型抗体-药物偶联物

• 批准号: 10386723
• 负责人: John P. Miller
• 金额: $ 24.65万
• 依托单位: ASYLIA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386723
• 关键词: Acids; Affinity; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; Antineoplastic Agents; Apoptotic; Attention; B-Lymphocytes; Binding; Biotinylation; Breast Cancer cell line; Camptothecin; Cathepsins; Cell Line; Cell Lineage; Cell Maturation; Cell Surface Proteins; Cell model; Cell surface; Cells; Characteristics; Clinic; Clinical; Conjugating Agent; Cutaneous; Cutaneous T-cell lymphoma; Data; Deacetylase; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Drug toxicity; Exhibits; Failure; Feedback; Generations; Goals; Heat shock proteins; Heat-Shock Proteins 70; Hematologic Neoplasms; Heterogeneity; Human; Hypoxia; Immunotherapeutic agent; Investigational Drugs; Lead; Link; Literature; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Modeling; Molecular Chaperones; Monoclonal Antibodies; Multiple Myeloma; Mus; Mutation; Neoplasms; Normal tissue morphology; Patient-Focused Outcomes; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Preparation; Property; Proteome; Proteomics; Refractory; Regimen; Relapse; Resistance; Schedule; Series; Solid Neoplasm; Specificity; Surface; Surface Antigens; T-Cell Lymphoma; TNFRSF8 gene; Therapeutic; Therapeutic antibodies; Toxic effect; Toxicology; Tumor Antigens; Tumor Cell Line; Work; Xenograft procedure; anti-cancer; base; biological adaptation to stress; biomarker-driven; cancer cell; cell transformation; clinical translation; clinically relevant; cytotoxic; drug candidate; drug distribution; efficacy study; experience; experimental study; genome editing; human monoclonal antibodies; immunogenic cell death; improved outcome; in vivo; in vivo Model; inhibitor; novel; novel therapeutics; overexpression; patient derived xenograft model; peripheral blood; potential biomarker; pre-clinical; protein folding; pyrrolobenzodiazepine; research clinical testing; resistance mechanism; success; synergism; triple-negative invasive breast carcinoma; tumor; uptake

Abstract: T-cell lymphomas have remained treatment-challenging, not least because of their remarkable heterogeneity. The lab of Robert Orlovsky (co-founder of Asylia) analyzed the membrane proteome of peripheral and cutaneous T-cell lymphoma and discovered that surface Heat shock protein (csHSP)-70 as being consistently overexpressed. While HSP70 is well established as an intracellular stress-response chaperone, its localization to the cell surface in cancer, is gaining increased attention. Considering the recent clinical successes of antibody-drug conjugates and the exceptionally high and selective overexpression of cell surface HSP70 in T-cell lymphoma, we summarize that csHSP70 presents as an exceptionally attractive target for antibody drug conjugates (ADC) for the treatment of this malignancy. We have generated a high affinity monoclonal antibody (clone 239-87) specifically recognizing cell-surface HSP70. In preliminary data, we have generated an ADC of mAb 239-87 with MMAE, which specifically bound csHSP70 on T-cell NHL cell lines but did not bind normal peripheral blood-derived cells. Linked to MMAE, the 239-87-MMAE ADC showed cytotoxic activity against both peripheral and cutaneous T-cell lymphoma lines cell lines with comparable, or greater potency than the leading clinical ADC, brentuximab vedotin. We now propose a series of critical experiments to accelerate the clinical translation of 239-87 ADCs for the treatment of T-cell lymphoma. In aim 1, we will humanize mAb 239-87 and optimize the drug-like characteristics of the current murine clone. We will study binding of the leads to soluble HSP70, and to csHSP70 in wild-type and genome edited cell models to verify that they retain csHSP70 affinity and specificity. In specific aim 2, we will convert clone 239-87 mAb into an ADC. We will first synthesize a panel of ADCs based on the optimal lead antibody molecule linked to MMAE, a maytansine, a camptothecin, and a pyrrolobenzodiazepine with cathepsin- and acid-cleavable linkers and compare their efficacy against T-cell lymphoma cell lines. Next, we will genetically modulate csHSP70 and perform internalization and quantitative flow studies to determine the minimum csHSP70 expression needed to see anti-cancer efficacy. Finally, we will verify the potential for synergy between our ADCs and agents that enhance csHSP70, such as histione deacetylase inhibitors. In Aim 3, we will validate the activity of clone 239-87 ADCs using in vivo tumor cell line-derived models. Next, we will validate the activity of selected best performers in more physiologically relevant patient-derived xenograft (PDX) models. Finally, we will perform pharmacokinetic studies in these PDXs to begin to understand potential drug distribution and toxicity parameters. Taken together, these studies will provide a proof-of-concept that HSP70-targeted ADCs have the necessary efficacy and pharmacologic properties for development as attractive drug candidates and allow us to move forward with investigational new drug-enabling toxicology studies in preparation for phase I clinical testing.

摘要：T细胞淋巴瘤一直保持治疗挑战，尤其是因为它们的显着性 异质性。罗伯特·奥洛夫斯基（Robert Orlovsky）（庇护的联合创始人）的实验室分析了周围的膜蛋白质组 皮肤T细胞淋巴瘤，并发现表面热休克蛋白（CSHSP）-70为 一贯过表达。虽然HSP70被很好地确定为细胞内应力 - 响应伴侣，但 癌症中细胞表面的定位正在增加注意力。考虑到最近的临床成功 抗体 - 药物结合物以及细胞表面HSP70中极高和选择性的过表达 T细胞淋巴瘤，我们总结说CSHSP70作为抗体药物的极具吸引力的靶标的 偶联（ADC）治疗这种恶性肿瘤。我们产生了高亲和力单克隆抗体 （克隆239-87）专门识别细胞表面HSP70。在初步数据中，我们生成了一个ADC MAB 239-87与MMAE，该MMAE特别结合CSHSP70在T细胞NHL细胞系上，但不结合正常 外周血衍生细胞。与MMAE有关，239-87-MMAE ADC表现出对这两者的细胞毒性活性 外周和皮肤T细胞淋巴瘤线细胞系具有可比或更大的效力 临床ADC，Brentuximab vedotin。 现在，我们提出了一系列关键实验，以加速239-87 ADC的临床翻译 T细胞淋巴瘤的治疗。在AIM 1中，我们将人性化mAb 239-87并优化类似药物的样子 当前鼠克隆的特征。我们将研究铅与可溶性HSP70的结合，以及与CSHSP70的结合 在野生型和基因组中，编辑了细胞模型，以验证它们保留CSHSP70亲和力和特异性。具体 AIM 2，我们将将克隆239-87 mab转换为ADC。我们将首先根据 最佳铅抗体分子与MMAE，Maytansine，camptothecin和吡咯苯甲二氮杂有关 与组织蛋白酶和可裂解的连接器一起，并将其功效与T细胞淋巴瘤细胞系进行比较。下一个， 我们将基因调节CSHSP70并进行内部化和定量流研究，以确定 最小CSHSP70表达需要看到抗癌功效。最后，我们将验证协同作用的潜力 在我们的ADC和增强CSHSP70的药物之间，例如Histione脱乙酰基酶抑制剂。在AIM 3中，我们将 使用体内肿瘤细胞系衍生的模型来验证克隆239-87 ADC的活性。接下来，我们将验证 精选的最佳性能者在更相关的患者衍生异种移植（PDX）模型中的活性。 最后，我们将在这些PDX中进行药代动力学研究，以开始了解潜在的药物分布 和毒性参数。 综上所述，这些研究将提供概念验看，表明HSP70靶向的ADC具有 作为有吸引力的候选药物的开发的必要功效和药理学特性，使我们能够 通过研究新的药物毒理学研究，以准备I期临床测试。