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

三阴性乳腺癌（TNBC）占乳腺癌死亡的约25%，缺乏靶向治疗。 我们将非必需的细胞表面蛋白ADAM 8确定为TNBC的重要靶点。ADAM 8是 存在于34%的原发性TNBC和48%的所有乳腺癌患者来源的转移灶中，但在 正常乳腺组织。高ADAM 8 mRNA水平与患者预后不良相关。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β1-整联蛋白在癌细胞上的活化。一种仅用于研究的抗ADAM 8抗体 抑制MP和DI结构域的小鼠单克隆抗体（mAb）降低TNBC肿瘤生长， 转移，验证ADAM 8作为治疗靶点。PCT专利申请（US 14/37857）于2010年5月提交。 2014年13月13日，Sonenshein博士、Mineva博士和Romagnoli博士以及塔夫茨大学声称针对ADAM 8 MP + DI结构域（双重拮抗剂抗体）用于治疗乳腺癌和其他ADAM 8驱动的癌症（例如， 胃、肺、胰腺）。2014年10月，Adecto Pharmaceuticals，Inc. (AP)是由三位发明家 开发针对侵袭性癌症的基于ADAM 8抗体的疗法。成功完成我们的目标 I期STTR已经导致：i）产生抗人ADAM 8小鼠mAb（称为ADP），其抑制ADAM 8和ADAM 8两者。 MP和DI结构域，和ii）鉴定降低生长和增殖的两种先导候选物（ADP 2/ADP 13）。 TNBC细胞系来源的（CLD）肿瘤的扩散和改善小鼠存活。我们建议ADAM 8双 拮抗剂抗体疗法将成为TNBC护理的新组成部分。通过与 肿瘤学家，我们确定复发性无脑转移TNBC作为我们的第一个适应症， 人源化ADP（hADP）+标准护理（SoC）化疗（CT）作为治疗方案。初步 使用ADP 13 + Nab-紫杉醇（N-PAC）的结果表明，与N-紫杉醇相比， 只有PAC支持这一做法。30例正常人体组织中ADAM 8的免疫组化检测 主要存在于胃肠神经内分泌细胞（NEC）中，偶尔存在于胃和肺炎症细胞中， 免疫细胞这种有限的表达模式表明，靶向ADAM 8的副作用风险较低。我们 3个目标是：（1）确定最有效的SoC CT（例如，N-PAC/顺铂）+ ADP组合，使用CLD 和患者来源的异种移植模型;（2）通过CDR移植产生人源化（hADP 2/hADP 13）变体， 在基于细胞测定中鉴定每种的功能性先导物，并在人源化小鼠中确认活性;（3）进行 早期安全性研究（确定ADAM 8抑制对原代PBMC和NEC的影响;证实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性数据的先导hADP， 诊所的入口GLP和GMP顾问的指导将确保AP准备好过渡到IND 研究，使我们能够吸引投资者/战略合作伙伴和2b期资金，以继续发展 以及目前缺乏靶向治疗的TNBC患者的新型治疗的商业化。

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.