Development of a Companion Diagnostic Assay for Detection of ADAM8-Positive Cancers

开发用于检测 ADAM8 阳性癌症的伴随诊断测定法

• 批准号: 10545124
• 负责人: GAIL E. SONENSHEIN
• 金额: $ 100万
• 依托单位: ADECTO PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545124
• 关键词: Abraxane; Age; Age-Years; American Society of Clinical Oncology; Antibodies; Antibody Therapy; Biological Assay; Biological Markers; Biopsy; Breast; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; CLIA certified; Cancer Etiology; Cell Line; Cell Surface Proteins; Cessation of life; Clinical; Clinical Trials; Colon Carcinoma; Companions; Contractor; Cox Proportional Hazards Models; Detection; Development; Diagnostic; Disease; Endocrine; Epidermal Growth Factor Receptor; Extracellular Domain; Female; Funding; Future; Growth; Guidelines; Hormone Receptor; Human; Image Analysis; Immunohistochemistry; Incidence; Lead; Malignant Neoplasms; Malignant neoplasm of liver; Manuals; Monitor; Monoclonal Antibodies; Mus; NOD/SCID mouse; Normal tissue morphology; Oncology; Pathologist; Pathology; Patient-Focused Outcomes; Patients; Performance; Pharmacologic Substance; Phase; Population; Predictive Value; Predictive Value of Tests; Prognosis; Progressive Disease; Protocols documentation; Race; Regimen; Reproducibility; Research; Risk; Risk Factors; Running; Sample Size; Sampling; Scheme; Small Business Innovation Research Grant; Specificity; Stains; Stress; System; Testing; Time; Tissue Preservation; Tumor Volume; Tumor-Derived; Validation; Woman; Work; antagonist; base; cancer subtypes; chemotherapy; clinical prognostic; companion diagnostics; detection assay; digital; digital imaging; effective therapy; follow-up; high risk; immunogenicity; improved; improved outcome; lead candidate; malignant breast neoplasm; malignant stomach neoplasm; mouse model; novel; patient derived xenograft model; predictive test; prognostic; prognostic indicator; prognostic value; research clinical testing; response; sample fixation; standard of care; targeted treatment; therapeutically effective; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth

Breast cancer (BrCa) leads to ~685,000 deaths in women yearly worldwide (WHO). While patients with Hormone Receptor (HR) and Human Epidermal Growth Factor Receptor-2 (HER2)-driven cancers (HR+ and/or HER2+) have benefited from endocrine and HER2-targeted therapies, they still account for the majority of deaths. The HR and HER2 negative (HR-/HER2-) subtype, also known as Triple-negative breast cancer (TNBC), is the most aggressive and even more challenging to treat, leading to ~25% of deaths, despite a much lower incidence. More effective therapies are urgently needed. We identified the cell surface protein ADAM8 as an independent marker of poor BrCa patient outcome and a driver of tumor growth and spread. Using ADAM8-positive (ADAM8+) TNBC mouse models, we showed antibody (Ab)-based targeting of ADAM8 is an effective therapeutic (Tx) strategy [1]. Preliminary immunohistochemistry (IHC) of primary TNBCs revealed only a subset are ADAM8+ (17/50 or 34%), suggesting a diagnostic (Dx) will be needed to identify patients who can benefit from targeted therapy. We launched Adecto Pharmaceuticals to develop Dx and Tx products to improve the outcome of patients with ADAM8+ cancers. ADP2, our top Tx Ab, reduces pre-existing TNBC growth and spread, improves survival, and enhances response to standard-of-care chemotherapy. ADP2 was successfully humanized, and a lead candidate (AD100) selected ahead of IND-enabling studies. AD100 regimens could dramatically improve BrCa treatment. Here, we propose to develop an IHC-based Dx for ADAM8+ cancers as a companion to AD100 or a standalone prognostic for identification of patients at high risk of progressive disease. Currently, there is no Dx for detection of these tumors. Using a panel of highly specific anti-ADAM8 monoclonal Abs (mAbs) and Phase 1 SBIR funds, we (i) optimized IHC conditions and identified ADP2 as lead Dx Ab; (ii) developed a breast staining/scoring control cell line microarray (CCM) with 3 lines expressing low, medium or high ADAM8, and analyzed patient-derived xenograft samples; (iii) validated IHC assay and CCM, and established an ADAM8 scoring system, in primary BrCa samples (which completed all proposed aims). Consistent with earlier findings, ADP2 IHC showed 36.1% of TNBCs (22/61) were ADAM8+, and unexpectedly 32.8% of non-TNBC BrCas (115/351). A 10-year age-adjusted analysis of the HR+/HER2- subtype, with largest sample size, revealed ADAM8 score associated with poor survival, providing early support for a prognostic use of this assay. In this Direct to Phase 2 application, we propose to: 1) refine the ADP2 assay to permit accurate characterization of ADAM8 in any BrCa sample within ASCO/CAP guidelines; 2) verify ADAM8 positivity rates and study the prognostic value of the assay in BrCa; 3) test the predictive value of the assay for AD100 response using TNBC and HR+/HER2- mouse models; 4) complete CLIA validation of the assay by a clinical Dx contractor. Successful completion of the proposed aims will result in an ADAM8 IHC assay with CLIA standard operating protocols ready for testing in future clinical trials.

乳腺癌 (BrCa) 每年导致全球约 685,000 名女性死亡 (WHO)。当荷尔蒙患者 受体 (HR) 和人表皮生长因子受体 2 (HER2) 驱动的癌症（HR+ 和/或 HER2+） 尽管受益于内分泌和 HER2 靶向治疗，但他们仍然占死亡人数的大多数。这 HR 和 HER2 阴性 (HR-/HER2-) 亚型，也称为三阴性乳腺癌 (TNBC)，是最常见的乳腺癌。 尽管发病率低得多，但攻击性且治疗更具挑战性，导致约 25% 的死亡。 迫切需要更有效的治疗方法。我们确定细胞表面蛋白 ADAM8 是一个独立的 BrCa 患者预后不良的标志，也是肿瘤生长和扩散的驱动因素。使用 ADAM8 阳性 (ADAM8+) TNBC 小鼠模型，我们证明基于抗体 (Ab) 的 ADAM8 靶向是一种有效的治疗 (Tx) 策略[1]。原发性 TNBC 的初步免疫组织化学 (IHC) 显示只有一个子集为 ADAM8+ （17/50 或 34%），表明需要进行诊断 (Dx) 来确定可以从靶向治疗中受益的患者 治疗。我们成立了 Adecto Pharmaceuticals 来开发 Dx 和 Tx 产品，以改善治疗结果 ADAM8+ 癌症患者。 ADP2 是我们的顶级 Tx Ab，可减少先前存在的 TNBC 生长和传播，改善 生存，并增强对标准护理化疗的反应。 ADP2 成功人源化， 在 IND 启用研究之前选择主要候选药物 (AD100)。 AD100方案可以显着改善 BrCa 治疗。在这里，我们建议开发一种基于 IHC 的 ADAM8+ 癌症 Dx，作为 AD100 的伴侣 或用于识别进展性疾病高风险患者的独立预后。目前，没有 Dx 用于检测这些肿瘤。使用一组高度特异性的抗 ADAM8 单克隆抗体 (mAb) 和 在 SBIR 资助的第 1 阶段，我们 (i) 优化了 IHC 条件并确定 ADP2 作为领先的 Dx Ab； (ii) 乳房发育 染色/评分对照细胞系微阵列 (CCM)，具有 3 个表达低、中或高 ADAM8 的细胞系，以及 分析患者来源的异种移植样本； (iii) 验证 IHC 检测和 CCM，并建立 ADAM8 评分系统，在初级 BrCa 样本中（完成了所有提出的目标）。与早期的发现一致， ADP2 IHC 显示 36.1% 的 TNBC (22/61) 为 ADAM8+，出乎意料的是，32.8% 的非 TNBC BrCas (115/351)。对 HR+/HER2- 亚型进行的 10 年年龄调整分析（样本量最大）显示 ADAM8 评分与较差的生存率相关，为该检测的预后应用提供早期支持。在这个 针对第 2 阶段应用，我们建议：1) 完善 ADP2 测定，以准确表征 ASCO/CAP 指南内任何 BrCa 样本中的 ADAM8； 2) 验证 ADAM8 阳性率并研究 BrCa 检测的预后价值； 3) 使用 TNBC 测试 AD100 反应测定的预测价值 和 HR+/HER2- 小鼠模型； 4) 由临床 Dx 承包商完成检测的 CLIA 验证。成功的 完成拟议的目标将导致使用 CLIA 标准操作协议进行 ADAM8 IHC 检测 为未来的临床试验做好准备。