CLINICAL UTILITY OF MONOCLONAL ANTIBODIES AND RECOMBINANT IMMUNOGLOBULIN FORMS

单克隆抗体和重组免疫球蛋白形式的临床应用

• 批准号: 5200920
• 负责人: J SCHLOM
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5200920
• 关键词: antitumor antibody; breast neoplasms; carcinoembryonal antigen; carcinoma; disease /disorder model; gastrointestinal neoplasms; human tissue; immunoconjugates; immunoglobulins; interferons; laboratory mouse; monoclonal antibody; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; ovary neoplasms; pharmacokinetics; prostate neoplasms; radiopharmacology; radiotracer; recombinant proteins; tissue /cell culture; tumor antigens

Monoclonal Antibodies (MAbs) and their consequent recombinant immunoglobulin (Ig) forms are being developed and characterized for use in both therapeutic and diagnostic applications for a range of human cancers. Therapeutic applications involve the use of MAbs or recombinant Ig forms conjugated to radionuclides, drugs or prodrugs. In vivo diagnostic applications involve the use of radiolabeled Ig forms for use in gamma scanning or intraoperatively with a gamma detecting probe, i.e., radioimmuno-guided surgery (RIGS). The MAbs developed are principally reactive against two pancarcinoma antigens. They are (a) carcinoembryonic antigen (CEA), which is found in gastrointestinal, pancreatic, breast, and non-small cell lung cancer, and (b) TAG-72, which is found on the majority of the following carcinoma types: gastrointestinal, pancreatic, breast, ovarian, endometrial, prostate, and non-small cell lung. The first anti-TAG-72 MAb developed was B72.3. 111In-labeled B72.3 is the first and still only MAb to be approved by the FDA for in vivo use in cancer. It has been approved for the oncologic imaging for both colorectal cancer and ovarian cancer. A series of higher affinity anti-TAG-72 antibodies have now been developed. The prototype of these is MAb CC49. Collaborative Phase I and Phase II clinical trials to determine the therapeutic efficacy of radiolabeled murine CC49 are currently ongoing in breast , prostate, gastrointestinal and ovarian cancers, with and without the use of recombinant interferon to upregulate TAG-72 expression. Some objective clinical responses have now been observed in ovarian, breast, and prostate cancer protocols employing CC49. A Phase III clinical trial employing radiolabeled CC49 and RIGS is currently underway and is demonstrating the ability of this procedure to define occult lesions in approximately 25 % of GI surgery. Emphasis is now being placed on the biological characterization of recombinant Ig forms. These include single-chain Fv molecules, CDR grafted humanized forms, and domain deleted Ig forms. Studies are ongoing in experimental models to define metabolic patterns, pharmacokinetic properties, and tumor targeting ability of these various recombinant Ig forms to optimize therapeutic efficacy and minimize toxicity and host immune responses.

单克隆抗体（MAb）及其后续重组 免疫球蛋白（IG）形式正在开发和表征， 用于治疗和诊断应用， 人类癌症 治疗应用涉及使用MAb或 与放射性核素、药物或前药缀合的重组IG形式。 体内诊断应用涉及使用放射性标记的IG 用于伽马扫描或术中伽马扫描的表格 检测探针，即，放射免疫引导手术（RIGS）。 的mab 主要对两种泛癌抗原反应。 它们是（a）癌胚抗原（CEA），其存在于 胃肠癌、胰腺癌、乳腺癌和非小细胞肺癌， 和（B）TAG-72，其在以下大多数中发现 癌类型：胃肠癌，胰腺癌，乳腺癌，卵巢癌， 子宫内膜、前列腺和非小细胞肺。 第一个抗TAG-72 开发的MAb为B72.3。 111 In标记的B72.3是第一个 只有单克隆抗体被FDA批准用于癌症的体内使用。 它有 已被批准用于结直肠癌和 卵巢癌 一系列高亲和力抗TAG-72抗体 现在已经开发出来了。 这些的原型是MAb CC 49。 合作的I期和II期临床试验，以确定 放射性标记的鼠CC 49的治疗效果目前正在进行中 在乳腺癌、前列腺癌、胃肠癌和卵巢癌中， 不使用重组干扰素上调TAG-72 表情 现在已经观察到一些客观的临床反应 在卵巢癌、乳腺癌和前列腺癌方案中使用CC 49。 一 使用放射性标记的CC 49和RIGS的III期临床试验是 目前正在进行中，并正在证明这一程序的能力 在大约25%的胃肠道手术中确定隐匿性病变。 现在的重点是生物学特性， 重组IG形成。 这些包括单链Fv分子、CDR 移植的人源化形式和结构域缺失的IG形式。 研究是 正在实验模型中定义代谢模式， 药物代谢动力学特性和这些药物的肿瘤靶向能力 各种重组IG形式以优化治疗功效， 最大限度地减少毒性和宿主免疫反应。