Celldex Therapeutics, Inc., Phillipsburg, NJ, USA.
Clin Cancer Res. 2012 Jul 15;18(14):3812-21. doi: 10.1158/1078-0432.CCR-11-3308. Epub 2012 May 15.
The TNF receptor superfamily member CD27 is best known for its important role in T-cell immunity but is also recognized as a cell-surface marker on a number of B- and T-cell malignancies. In this article, we describe a novel human monoclonal antibody (mAb) specific for CD27 with properties that suggest a potential utility against malignancies that express CD27.
The fully human mAb 1F5 was generated using human Ig transgenic mice and characterized by analytical and functional assays in vitro. Severe combined immunodeficient (SCID) mice inoculated with human CD27-expressing lymphoma cells were administered 1F5 to investigate direct antitumor effects. A pilot study of 1F5 was conducted in non-human primates to assess toxicity.
1F5 binds with high affinity and specificity to human and macaque CD27 and competes with ligand binding. 1F5 activates T cells only in combination with T-cell receptor stimulation and does not induce proliferation of primary CD27-expressing tumor cells. 1F5 significantly enhanced the survival of SCID mice bearing Raji or Daudi tumors, which may be mediated through direct effector mechanisms such as antibody-dependent cellular cytotoxicity. Importantly, administration of up to 10 mg/kg of 1F5 to cynomolgus monkeys was well tolerated without evidence of significant toxicity or depletion of circulating lymphocytes.
Collectively, the data suggest that the human mAb 1F5, which has recently entered clinical development under the name CDX-1127, may provide direct antitumor activity against CD27-expressing lymphoma or leukemia, independent of its potential to enhance immunity through its agonistic properties.
TNF 受体超家族成员 CD27 最为人所知的是其在 T 细胞免疫中的重要作用，但它也被认为是许多 B 细胞和 T 细胞恶性肿瘤的表面标志物。在本文中，我们描述了一种新型的人源单克隆抗体（mAb）1F5，它针对 CD27，具有潜在的针对表达 CD27 的恶性肿瘤的应用潜力。
使用人 Ig 转基因小鼠生成完全人源 mAb 1F5，并通过体外分析和功能测定进行表征。用表达人 CD27 的淋巴瘤细胞接种严重联合免疫缺陷（SCID）小鼠，以研究 1F5 的直接抗肿瘤作用。在非人类灵长类动物中进行了 1F5 的初步研究，以评估毒性。
1F5 与人源和食蟹猴 CD27 具有高亲和力和特异性结合，并与配体结合竞争。1F5 仅在与 T 细胞受体刺激联合时激活 T 细胞，并且不会诱导原代表达 CD27 的肿瘤细胞增殖。1F5 显著增强了携带 Raji 或 Daudi 肿瘤的 SCID 小鼠的存活，这可能通过抗体依赖性细胞毒性等直接效应机制介导。重要的是，给食蟹猴施用高达 10mg/kg 的 1F5 是耐受良好的，没有明显毒性或循环淋巴细胞耗竭的证据。
总的来说，数据表明，最近以 CDX-1127 为名进入临床开发的人源 mAb 1F5 可能提供针对表达 CD27 的淋巴瘤或白血病的直接抗肿瘤活性，而与其通过激动特性增强免疫的潜力无关。
