Targeting Metastatic Breast Cancer with Human Antibodies

描述（由申请人提供）： 今天先进的技术可以发现非常早期的乳腺肿瘤。然而，目前乳腺癌的预后标准并不能准确地表明肿瘤的侵袭性，是否已经开始扩散，以及应该选择哪些治疗方案来实现每个病例的最佳结果。乳腺癌转移到肺、肝、骨和脑涉及肿瘤细胞通过血流传播，体外和体内研究表明，人乳腺癌细胞的转移性亚群以组成性激活的功能形式表达粘附受体，整合素α v β 3。这种受体使细胞能够结合血小板并在血液流动过程中停滞，如在循环中发现的那样，它还支持侵入性肿瘤细胞的迁移和存活。长期目标是靶向转移性乳腺癌细胞的功能标志物，例如活化的整合素ava3，用于早期检测、预防和抑制转移性疾病。我们使用抗体噬菌体展示技术和消减淘选策略对人乳腺癌细胞模型的低转移性与高转移性变体分离人单链Fv（scFv）抗体，其通过靶向整合素ava3的活化构象来识别转移性乳腺癌细胞。这些抗体具有配体模拟特性和抑制功能，其干扰小鼠模型中人乳腺癌细胞的肺定殖，并且它们抑制现有的转移性疾病。这项工作的目标是测试针对活化的ava3和转移性乳腺癌细胞的其他新标志物的人scFv可以被优化为1的假设。报告转移性疾病，2.检测具有转移倾向的细胞，和3.抑制乳腺癌转移。scFv将通过化学和分子工程进行修饰，以增强其对于每个预期应用的活性。成像系统将使用标记的scFv抗体来跟踪循环中的转移细胞并识别微转移病灶。新的免疫结合物含有小，高毒性化合物将测试其对转移性乳腺癌的影响。如果成功，这项工作将有助于改善目前的抗癌治疗。

DESCRIPTION (provided by applicant): Today's advancing technologies can detect very early breast tumors. However, current prognostic criteria for breast cancer do not accurately indicate how aggressive a tumor is, whether it has already begun to spread, and which treatment options should be chosen to achieve the best possible outcome in each individual case. Breast cancer metastasis to the lungs, liver, bone and brain involves tumor cell dissemination via the blood stream, and studies, in vitro and in vivo, showed that a metastatic subset of human breast cancer cells expresses an adhesion receptor, the integrin alphavbeta3, in a constitutively activated functional form. This receptor enables the cells to bind platelets and arrest during blood flow, as found in the circulation, and it also supports invasive tumor cell migration and survival. The long-term objective is to target functional markers of metastatic breast cancer cells, such as the activated integrin ava3, for early detection, prevention and inhibition of metastatic disease. We used antibody phage display technology and a subtractive panning strategy on poorly versus highly metastatic variants of a human breast cancer cell model to isolate human single chain Fv (scFv) antibodies that identify metastatic breast cancer cells by targeting the activated conformation of integrin ava3. These antibodies have ligand mimetic properties and inhibitory functions that interfere with lung colonization by human breast cancer cells in a mouse model, and they inhibit existing metastatic disease. The goal of this work is to test the hypothesis that human scFvs against activated ava3, and other novel markers of metastatic breast cancer cells can be optimized to 1. report metastatic disease, 2. detect cells with a metastatic propensity, and 3. inhibit breast cancer metastasis. The scFvs will be modified by chemical and molecular engineering to enhance their activity for each intended application. Imaging systems will use tagged scFv antibodies to track metastatic cells in the circulation and to identify micro-metastatic lesions. Novel immunoconjugates containing small, highly toxic compounds will be tested for their effects on metastatic breast cancer. If successful, this work will contribute to an improvement of current anti-cancer treatment.