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）每年在全球妇女（WHO）导致约685,000人死亡。而激素的患者 受体（HR）和人表皮生长因子受体-2（HER2）驱动的癌症（HR+和/或HER2+） 他们从内分泌和靶向HER2靶向疗法中受益，他们仍然占死亡人数的大部分。这 HR和HER2阴性（HR-/HER2-）亚型，也称为三阴性乳腺癌（TNBC），是最多的 尽管发病率要低得多，但攻击性，甚至更具挑战性的治疗，导致死亡人数约为25％。 迫切需要更有效的疗法。我们将细胞表面蛋白ADAM8鉴定为独立 BRCA患者预后不良的标志和肿瘤生长和扩散的驱动力。使用ADAM8阳性（ADAM8+） TNBC小鼠模型，我们显示出基于ADAM8的抗体（AB）靶向是有效的治疗（TX） 策略[1]。初级TNBC的初步免疫组织化学（IHC）显示，只有一个子集是ADAM8+ （17/50或34％），建议将需要进行诊断（DX）来识别可以从有针对性的患者中受益的患者 治疗。我们推出了Adecto Pharmaceuticals来开发DX和TX产品，以改善 患有ADAM8+癌症的患者。 ADP2，我们的顶级TX AB，减少了先前存在的TNBC增长和扩散，可改善 生存，并增强对护理标准化疗的反应。 ADP2成功人性化，一个 铅候选人（AD100）在辅助研究之前选择。 AD100方案可以显着改善 BRCA治疗。在这里，我们建议为ADAM8+癌症开发基于IHC的DX作为AD100的伴侣 或独立的预后，用于鉴定患有高度疾病风险的患者。目前，没有 DX用于检测这些肿瘤。使用一组高度特异的抗ADAM8单克隆ABS（mAb）和 第1阶段SBIR基金，我们（i）优化了IHC条件，并将ADP2识别为铅DX AB； （ii）乳房发展 染色/评分控制细胞系微阵列（CCM），具有3条线表达低，中或高ADAM8，并且 分析的患者衍生异种移植样品； （iii）验证了IHC分析和CCM，并建立了ADAM8 评分系统，在主要BRCA样品中（完成了所有提议的目标）。与早期发现一致 ADP2 IHC显示36.1％的TNBC（22/61）为ADAM8+，意外的是32.8％的非TNBC BRCAS （115/351）。样本量最大的HR+/HER2-亚型的10岁调整分析显示 ADAM8分数与差的生存率相关，为预后使用该测定法提供了早期支持。在这个 直接到第2阶段应用，我们建议：1）完善ADP2分析以允许准确表征 ADAM8在ASCO/CAP指南中的任何BRCA样本中； 2）验证ADAM8阳性率并研究 BRCA分析的预后价值； 3）使用TNBC测试AD100响应的测定的预测值 和HR+/HER2-鼠标模型； 4）临床DX承包商对测定法的完全CLIA验证。成功的 拟议的目标的完成将导致通过CLIA标准操作协议进行ADAM8 IHC分析 准备在以后的临床试验中进行测试。