li-Key/Melanoma MHC Class II Vaccines

li-Key/黑色素瘤 MHC II 类疫苗

• 批准号: 6691543
• 负责人: MINZHEN XU
• 金额: $ 44.41万
• 依托单位: ANTIGEN EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691543
• 关键词: MHC class II antigen; active immunization; biotechnology; chimeric proteins; clinical research; dosage; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; human subject; interferon alpha; interleukin 5; laboratory mouse; laboratory rabbit; melanoma; monophenol monooxygenase; neoplasm /cancer vaccine; synthetic vaccines; vaccine development

DESCRIPTION (provided by applicant): MHC-presented peptide vaccines are one of the most promising experimental therapies for melanoma. However, MHC class I peptides that prime CTLs lack dramatic anti-tumor effect in clinical trials. Co-immunization with MHC class II peptides substantially enhances CTL potency, augments antibody development and provides memory. A drawback to this approach is that MHC class II epitope bind poorly, therefore they are weak immunogens. Antigen Express scientists found that coupling the li-Key segment of the immunoregulatory li-protein to the N-terminus of a MHC class II epitope enhances the potency of class II epitope peptide presentation 200 times more than the epitope-only peptide. Our studies in immunized mice demonstrate 4-6 fold enhancement of Th1 cells by with li-Key/MHC II hybrid as measured by ELISPOT. In vitro li-Key/HER-21/neu(MHC II epitope) hybrids potently stimulate peripheral blood or draining lymph node lymphocytes from breast cancer patients. Applying these methods to melanoma, we will define the most potent HLA-DR-restricted li-Key/tyrosinase(MHC II) and li-key/gpl00(MHC II) hybrids for a clinical trial by our collaborator, Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center (MSKCC). He will use these MHC class II hybrids to potentiate CTL and clinical responses to previously used tyrosinase and gp100 HLA-A2-restricted CTL epitope peptide vaccines. Here we will define the optimal sequence of MHC class II epitopes for incorporation in new hybrids, optimal spacer length, and dose/dosage and immune response parameters in mice. In parallel with studies using human cells in vitro, Dr. MigueI-Angel Perales from MSKCC will confirm our structure-activity findings. Toxicology studies in mice and rabbits of one GMP batch of the optimal peptide(s) will complete our preclinical studies of this SBIR, supporting a clinical trial at Memorial Sloan-Kettering.

描述（由申请人提供）：MHC 呈递的肽疫苗是最有前途的黑色素瘤实验疗法之一。然而，启动 CTL 的 MHC I 类肽在临床试验中缺乏显着的抗肿瘤作用。与 MHC II 类肽联合免疫可显着增强 CTL 效力、增强抗体发育并提供记忆。这种方法的缺点是 MHC II 类表位结合不良，因此它们是弱免疫原。 Antigen Express 科学家发现，将免疫调节 li 蛋白的 li-Key 片段与 MHC II 类表位的 N 末端偶联，可增强 II 类表位肽呈递的效力，比仅表位的肽高 200 倍。我们对免疫小鼠的研究表明，通过 ELISPOT 测量，使用 li-Key/MHC II 杂交体可使 Th1 细胞增强 4-6 倍。体外 li-Key/HER-21/neu（MHC II 表位）杂合体可有效刺激乳腺癌患者的外周血或引流淋巴结淋巴细胞。将这些方法应用于黑色素瘤，我们将定义最有效的 HLA-DR 限制性 li-Key/酪氨酸酶 (MHC II) 和 li-key/gpl00(MHC II) 杂交体，供我们的合作者纪念斯隆凯特琳癌症中心 (MSKCC) 的 Jedd Wolchok 博士进行临床试验。他将使用这些 MHC II 类杂交体来增强对先前使用的酪氨酸酶和 gp100 HLA-A2 限制性 CTL 表位肽疫苗的 CTL 和临床反应。在这里，我们将定义用于掺入新杂交体的 MHC II 类表位的最佳序列、最佳间隔长度以及小鼠的剂量/剂量和免疫反应参数。在使用人体细胞进行体外研究的同时，MSKCC 的 MigueI-Angel Perales 博士将证实我们的结构-活性研究结果。对一批 GMP 最佳肽在小鼠和兔子中进行的毒理学研究将完成我们对该 SBIR 的临床前研究，为纪念斯隆-凯特琳癌症中心的临床试验提供支持。