Antibody targeting of ADAM8 for treatment of triple-negative breast cancer

ADAM8 抗体靶向治疗三阴性乳腺癌

• 批准号: 9353930
• 负责人: GAIL E. SONENSHEIN
• 金额: $ 6.35万
• 依托单位: ADECTO PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353930
• 关键词: Accounting; Adverse effects; Advisory Committees; Affinity; Angiogenic Factor; Animal Cancer Model; Animal Model; Antibodies; Antibody Therapy; Benchmarking; Binding; Biological Assay; Biology; Blood; Blood Vessels; Brain; Breast; Breast Cancer Cell; Breast Cancer Patient; Budgets; Businesses; Caring; Cell Adhesion; Cell Line; Cell Surface Proteins; Cells; Cessation of life; Clinic; Cloning; Data; Development; Disease; Disintegrin Domain; Disintegrins; Endothelium; Enzyme-Linked Immunosorbent Assay; Epitopes; Estrogen Receptor Status; Financial compensation; Goals; Growth; Human; Hybridomas; Immunoglobulin G; In Vitro; Injection of therapeutic agent; Integral Membrane Protein; Integrins; Legal patent; Licensing; Luciferases; Lung; MDA MB 231; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Messenger RNA; Metalloproteases; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Monoclonal Antibodies; Multivariate Analysis; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Palpable; Pancreatic Adenocarcinoma; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phase; Phenotype; Pilot Projects; Preclinical Testing; Proteins; Publishing; Quality of life; Radiation; Reagent; Recombinants; Relapse; Research Contracts; Small Business Technology Transfer Research; Surface; Testing; Therapeutic; Time; Tumor Burden; Tumor-Derived; Universities; Work; angiogenesis; base; cancer cell; chemotherapy; cross reactivity; density; effective intervention; effective therapy; implantation; improved; in vitro Assay; in vivo; knock-down; lymph nodes; malignant breast neoplasm; migration; monoclonal antibody production; mortality; mouse model; outcome forecast; pre-clinical; promoter; research and development; residence; screening; standard of care; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

Triple-negative breast cancers (TNBCs) account for ~25% of breast cancer deaths and lack targeted therapies. Drs. Sonenshein, Mineva and Romagnoli and their co-workers recently identified the non-essential, cell surface protein ADAM8 (A Disintegrin And Metalloprotease 8) as a pivotal promoter of breast tumor growth and metastasis, and validated it as a target of antibody therapy for TNBC. ADAM8 mRNA was highly expressed in TNBCs, and its level correlated with poor patient outcome. ADAM8 protein was present in 34% of primary TNBCs, and half of all breast cancer patient-derived metastases, but absent in adjacent normal breast tissues. Orthotopic tumors from ADAM8 knockdown TNBC cells grew only to a palpable size and generated very few circulating tumor cells and brain metastases. The Metalloproteinase (MP) and Disintegrin (DI) domains of ADAM8 were critical in tumor growth and dissemination through release of pro-angiogenic factors and activation of β1-integrin on cancer cells, respectively. Treatment with a reagent grade commercial anti-ADAM8 mouse monoclonal antibody (mAb) MAB1031 (R&D), with in vitro antagonist activity against both the MP and DI domains, reduced primary TNBC tumor burden by 70% at 1.5 mg/kg vs control isotype-matched IgG2B in an orthotopic model when started at the time of cell implantation. MAB1031 also profoundly reduced dissemination of pre-existing tumors to the brain and lungs, providing proof-of-concept that a dual antagonist mAb can be prepared and that both domains are accessible to antibody-based therapy in vivo. Thus, we hypothesize that ADAM8 antibody-based treatment constitutes an effective therapy for TNBC patients expressing this transmembrane protein. A PCT patent application PCT/US14/37857 was filed May 13, 2014 by Drs. Sonenshein, Mineva and Romagnoli, and Tufts University, with claims including the targeting of ADAM8 MP and DI domains for treatment of breast and other ADAM8-driven cancers, including pancreatic adenocarcinomas. In October 2014, Adecto Pharmaceuticals, Inc (AP) was founded by the three inventors with the goal of developing ADAM8-specific antibodies for the treatment of TNBC and metastatic breast cancer as the initial indications. In this Phase 1 STTR application, AP will work closely with the Sonenshein lab (SL) to prepare mouse mAbs specific for human ADAM8 that inhibit both its MP and DI domains and perform pilot preclinical testing in mice. The specific aims are to: (1) Isolate a panel of mAbs specific for HuADAM8 with MP and DI domain antagonist activity; (2) Identify the most effective antagonist mAbs using cell based assays; (3) Perform pilot in vivo testing of the ability of the two most effective ADAM8 antagonist mAbs to inhibit growth and metastatic dissemination of pre-existing luciferase-tagged MDA-MB-231 cell-derived tumors. We propose that ADAM8 antibody-based therapy has the potential to revolutionize the treatment of TNBC patients, and reduce the mortality associated with metastatic breast cancer and thus will become a new component of care for TNBC.

三阴性乳腺癌（TNBC）约占乳腺癌死亡人数的25%，并且缺乏靶向治疗。 Drs. Sonenshein，Mineva和Romagnoli及其同事最近发现了非必需的细胞表面 蛋白质ADAM 8（一种去整合素和金属蛋白酶8）作为乳腺肿瘤生长的关键促进剂， 转移，并验证其作为TNBC的抗体治疗的靶点。ADAM 8 mRNA在正常对照组和正常对照组中均呈高表达。 TNBCs及其水平与患者预后不良相关。ADAM 8蛋白在34%的原发性 TNBC和所有乳腺癌患者来源的转移的一半，但在相邻的正常乳腺组织中不存在。 来自ADAM 8敲除TNBC细胞的原位肿瘤仅生长至可触及的大小，并且产生非常少的肿瘤。 循环肿瘤细胞和脑转移。的金属蛋白酶（MP）和去整合素（DI）结构域， ADAM 8通过释放促血管生成因子在肿瘤生长和扩散中起关键作用， β1-整合素在癌细胞上的活化。用试剂级市售抗ADAM 8治疗 小鼠单克隆抗体（mAb）MAB 1031（R&D），具有抗MP和 DI结构域，在1.5 mg/kg下与对照同种型匹配的IgG 2B相比，使原发性TNBC肿瘤负荷降低70%， 在细胞植入时开始的原位模型。MAB 1031也大大降低了 预先存在的肿瘤扩散到大脑和肺部，提供了双重拮抗剂 可以制备mAb，并且两个结构域都可用于体内基于抗体的治疗。因此我们 假设基于ADAM 8抗体的治疗构成TNBC患者的有效疗法 表达这种跨膜蛋白。PCT专利申请PCT/US 14/37857于2014年5月13日由 Drs. Sonenshein，Mineva和Romagnoli以及塔夫茨大学，声称包括针对ADAM 8 MP和DI结构域用于治疗乳腺癌和其他ADAM 8驱动的癌症，包括胰腺癌 腺癌2014年10月，Adecto Pharmaceuticals，Inc（AP）由三位发明人创立， 开发用于治疗TNBC和转移性乳腺癌的ADAM 8特异性抗体的目标， 最初的迹象。在第一阶段的STTR应用中，AP将与Sonenshein实验室（SL）密切合作， 制备特异于人ADAM 8的小鼠mAb，其抑制其MP和DI结构域，并进行试验性研究。 在小鼠中进行临床前试验。具体目的是：（1）用MP分离一组对HuADAM 8特异的mAb 和DI结构域拮抗剂活性;（2）使用基于细胞的测定鉴定最有效的拮抗剂mAb;（3） 对两种最有效的ADAM 8拮抗剂mAb抑制生长的能力进行初步体内测试 和预先存在的经转移酶标记的MDA-MB-231细胞来源的肿瘤的转移性播散。我们提出 基于ADAM 8抗体的疗法有可能彻底改变TNBC患者的治疗， 降低与转移性乳腺癌相关的死亡率，因此将成为护理的新组成部分 关于TNBC