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

ADAM8 抗体靶向治疗三阴性乳腺癌

基本信息

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
项目类别：
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

项目摘要

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（TNBC）占乳腺癌死亡的约25％，缺乏靶向疗法。我们将非必需的细胞表面蛋白ADAM8鉴定为TNBC的重要靶标。 Adam8是 34％的原发性TNBC和所有乳腺癌患者衍生转移的48％，但不存在正常的乳腺组织。高ADAM8 mRNA水平与差的患者结局相关。 ADAM8 金属蛋白酶（MP）和分解蛋白（DI）结构域通过释放来驱动肿瘤生长和转移促血管生成因子和β1-整合蛋白在癌细胞上的激活。仅研究的抗ADAM8 抑制MP和DI结构域的小鼠单克隆抗体（MAB）降低了TNBC肿瘤的生长和转移，将ADAM8验证为治疗靶标。 5月提交了PCT专利申请（US14/37857） 13，2014 by Drs。 Sonenshein，Mineva和Romagnoli和Tufts University，声称针对ADAM8 MP + DI结构域（双重拮抗剂抗体）用于治疗乳房和其他ADAM8驱动的癌症（例如，胃，肺，胰腺）。 2014年10月，Adecto Pharmaceuticals，Inc。（AP）由3个发明者创立开发用于侵袭性癌症的基于ADAM8抗体的疗法。成功完成我们的目标 I期STTR导致：I）产生抗人ADAM8小鼠mab（称为ADP） MP和DI域，以及II）识别两个降低生长和 TNBC细胞系衍生（CLD）肿瘤的传播并改善小鼠的存活率。我们提出ADAM8双重拮抗剂抗体疗法将成为TNBC护理的新组成部分。通过讨论肿瘤学家，我们确定了复发性脑转移无TNBC是我们的第一个迹象和组合人源化ADP（HADP） +护理标准（SOC）化学疗法（CT）作为治疗方案。初步的与N-相比仅PAC支持这种方法。检测到ADAM8的30种正常人体组织的免疫组织化学胃肠道神经内分泌细胞（NECS）的主要，偶尔在失速和肺部炎症中免疫细胞。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目的是：（1）使用CLD确定最有效的SOC CT（例如N-PAC/顺铂） + ADP组合和患者衍生的特电模型；（2）通过CDR嫁接生成人性化（HADP2/HADP13）变体确定每个在基于细胞的测定中的功能铅，并确认人性化小鼠的活性；（3）执行早期安全研究（确定ADAM8抑制对主要PBMC和NEC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铅HADP，并且通往诊所的入口路径。 GLP和GMP顾问的指导将确保AP准备过渡到IND 研究并允许我们吸引投资者/战略合作伙伴和2B阶段资金进行持续发展以及目前缺乏靶向疗法的TNBC患者的新型治疗方法的商业化。