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: 9984632
• 负责人: GAIL E. SONENSHEIN
• 金额: $ 0.21万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9984632
• 关键词: Address; Affect; Angiogenic Factor; Antibodies; Antibody Therapy; Binding; Biological Assay; Breast; Breast Cancer Patient; Breast Cancer cell line; Caring; Cell Line; Cell Surface Proteins; Cells; Cessation of life; Chimera organism; Chromogranin A; Cisplatin; Clinic; Clinical; Complementarity Determining Regions; Data; Development; Disintegrin Domain; Disintegrins; Dissociation; Distant Metastasis; Dose; Drug or chemical Tissue Distribution; Ensure; Evolution; Freezing; Frequencies; Funding; Generations; Grant; Growth; Human; Hybridomas; IgG1; IgG2; Immune; Immunohistochemistry; Inflammatory; Innovation Corps; Integrins; Knockout Mice; Lead; Legal patent; Light; Lung; MDA MB 231; Malignant Neoplasms; Mammary Gland Parenchyma; Maps; Membrane; Messenger RNA; Metalloproteases; Metastatic Neoplasm to the Bone; Metastatic malignant neoplasm to brain; Modeling; Modification; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Neuroendocrine Cell; Oncologist; Operative Surgical Procedures; Paclitaxel; Pancreas; Patient-Focused Outcomes; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Precision therapeutics; Preparation; Primary Neoplasm; Product R; Proteins; Radiation; Recurrence; Regimen; Relapse; Research; Risk; Safety; Sampling; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Stomach; Surface; Symptoms; Testing; Tissues; Treatment Protocols; Tumor-Derived; United States National Institutes of Health; Universities; Variant; Work; Xenograft Model; aggressive therapy; base; cancer care; cancer cell; cell type; chemotherapy; commercialization; cross reactivity; cytokine; cytokine release syndrome; effective intervention; effective therapy; efficacy testing; extracellular; gastrointestinal; human tissue; humanized mouse; immunogenicity; improved; in vivo; inhibiting antibody; inhibitor/antagonist; lead candidate; malignant breast neoplasm; novel; off-patent; programs; research and development; response; safety study; safety testing; side effect; standard of care; stem; targeted treatment; therapeutic target; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth

Triple-negative breast cancers (TNBCs) account for ~25% of breast cancer deaths and lack targeted therapies. We identified the non-essential, cell surface protein ADAM8 as an important target on TNBC. ADAM8 is present in 34% of primary TNBCs, and 48% of all breast cancer patient-derived metastases, but absent in normal breast tissues. High ADAM8 mRNA levels correlate with poor patient outcome. The ADAM8 Metalloproteinase (MP) and Disintegrin (DI) domains drive tumor growth and metastasis through release of pro-angiogenic factors and activation of β1-integrin on cancer cells, respectively. A research-only anti-ADAM8 mouse monoclonal antibody (mAb) that inhibits the MP and DI domains decreased TNBC tumor growth and metastasis, validating ADAM8 as a therapeutic target. A PCT patent application (US14/37857) was filed May 13, 2014 by Drs. Sonenshein, Mineva and Romagnoli, and Tufts University, with claims to target the ADAM8 MP + DI domains (dual antagonist antibody) for treatment of breast and other ADAM8-driven cancers (e.g., gastric, lung, pancreatic). In October 2014, Adecto Pharmaceuticals, Inc. (AP) was founded by the 3 inventors to develop ADAM8 antibody-based therapies for aggressive cancers. Successful completion of the aims of our Phase I STTR has led to: i) generation of anti-human ADAM8 mouse mAbs (termed ADPs) that inhibit both the MP and DI domains, and ii) identification of two lead candidates (ADP2/ADP13) that decrease growth and dissemination of TNBC cell line-derived (CLD) tumors and improve mouse survival. We propose ADAM8 dual antagonist antibody therapy will become a new component of TNBC care. Through discussions with oncologists, we identified recurrent brain metastasis-free TNBC as our first indication and a combination of humanized ADP (hADP) + Standard-of-Care (SoC) chemotherapy (CT) as the treatment regimen. Preliminary results with ADP13 + Nab-Paclitaxel (N-PAC) demonstrate robust reduction in tumor regrowth compared to N- PAC alone in support of this approach. Immunohistochemistry of 30 normal human tissues detected ADAM8 primarily in gastrointestinal neuroendocrine cells (NECs) and occasionally in stomach and lung inflammatory immune cells. This limited expression pattern suggests targeting ADAM8 carries a low risk of side effects. Our 3 aims are to: (1) Identify the most effective SoC CT (e.g., N-PAC/Cisplatin) + ADP combination using CLD and patient-derived xenograft models; (2) Generate humanized (hADP2/hADP13) variants by CDR grafting, identify a functional lead for each in cell-based assays and confirm activity in humanized mice; (3) Perform early safety studies (determine effects of ADAM8 inhibition on primary PBMCs and NECs; confirm hADP lack of immunogenicity & tissue cross-reactivity). These studies will identify a lead hADP with early safety data and an entry path to the clinic. Guidance from GLP & GMP consultants will ensure AP is ready to transition to IND studies and allow us to attract investors/strategic partners and Phase 2b funding for continued development and commercialization of a novel treatment for TNBC patients, who currently lack targeted therapies.

三阴性乳腺癌(TNBCs)约占乳腺癌死亡的25%，缺乏针对性的治疗。 我们确定非必需的细胞表面蛋白ADAM8是TNBC的一个重要靶点。ADAM8是 在34%的原发TNBC和48%的乳腺癌患者来源的转移中存在，但在 正常的乳腺组织。ADAM8mRNA水平高与患者预后差相关。ADAM8 金属蛋白酶(MP)和去整合素(DI)结构域通过释放 促血管生成因子和β-1-整合素对癌细胞的激活。一种仅供研究的抗ADAM8 抑制MP和DI结构域的鼠单抗可抑制TNBC肿瘤的生长和 转移，验证ADAM8作为治疗靶点。PCT专利申请(US14/37857)已于5月提交 2014年13日，由Sonenshein博士、Mineva博士和Romagnoli博士以及塔夫茨大学提出，声称目标是ADAM8 MP+DI结构域(双重拮抗剂抗体)用于治疗乳腺癌和其他ADAM8驱动的癌症(例如， 胃、肺、胰腺)。2014年10月，Adecto制药公司(AP)由这三位发明家创立 开发基于ADAM8抗体的侵袭性癌症治疗方法。圆满完成我们的目标 第一阶段STTR导致：i)产生抗人ADAM8小鼠单抗(称为ADPs)，抑制两种 MP和DI结构域，以及ii)确定两个主要候选者(ADP2/ADP13)，它们会降低增长和 转移TNBC细胞系来源的(CLD)肿瘤并提高小鼠的存活率。我们建议ADAM8 DUAL 拮抗剂抗体治疗将成为TNBC护理的新组成部分。通过与 肿瘤学家，我们确定复发的无脑转移的TNBC是我们的第一个适应症，并结合了 人源化ADP(HADP)+标准护理(SOC)化疗(CT)为治疗方案。初步 结果显示，与N-PAC相比，ADP13+NAB-紫杉醇(N-PAC)显著降低了肿瘤的再生长。 只有政府账目委员会一人支持这种做法。30例正常人组织中ADAM8的免疫组织化学检测 主要见于胃肠神经内分泌细胞(NECs)，偶尔见于胃和肺炎性细胞 免疫细胞。这种有限的表达模式表明，靶向ADAM8的副作用风险很低。我们的 3个目标是：(1)使用CLD确定最有效的SoC CT(例如，N-PAC/顺铂)+ADP组合 和患者来源的异种移植模型；(2)通过CDR移植产生人源化(hADP2/hADP13)变异体， 在基于细胞的分析中确定每一个的功能先导，并确认人源化小鼠的活动；(3)执行 早期安全性研究(确定ADAM8抑制对原代PBMC和NECs的影响；确认hADP缺乏 免疫原性和组织交叉反应性)。这些研究将确定具有早期安全数据的领先hADP和 通往诊所的入口小路。GLP和GMP顾问的指导将确保AP准备好过渡到IND 研究并允许我们吸引投资者/战略合作伙伴和第二阶段资金，以实现持续发展 以及将一种新的治疗方法商业化，用于目前缺乏靶向治疗的TNBC患者。