li-Key/Melanoma MHC Class II Vaccines

描述(申请人提供)：MHC提出的多肽疫苗是治疗黑色素瘤最有前途的实验疗法之一。然而，启动CTL的MHC-I类多肽在临床试验中缺乏显著的抗肿瘤作用。与MHC第二类多肽联合免疫可显著增强CTL效力，增强抗体发展并提供记忆。这种方法的一个缺点是MHC II类表位结合很差，因此它们是弱免疫原。抗原快递的科学家发现，将免疫调节蛋白的li-key片段与MHC第二类表位的N-末端偶联，比仅有表位的多肽提高了第二类表位多肽的效力200倍。我们在免疫小鼠中的研究表明，根据ELISPOT的测量，Li-Key/MHC II杂交物使Th1细胞增强了4-6倍。在体外，Li-key/Her-21/neu(MHC II表位)杂交物能够有效地刺激乳腺癌患者的外周血或引流的淋巴淋巴细胞。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)杂交细胞，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类杂交物来增强CTL和临床对以前使用的酪氨酸酶和gp100人类白细胞抗原A2限制的CTL表位疫苗的反应。在这里，我们将定义MHC II类表位的最佳序列，以用于新的杂交种，最佳间隔区长度，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，来自MSKCC的MigueI-Angel Perales博士将证实我们的结构活性发现。在小鼠和兔子身上进行的一批最佳多肽(S)的毒理学研究将完成我们对这种SBIR的临床前研究，支持在斯隆-凯特林纪念医院进行的临床试验。

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.