li-Key/Melanoma MHC Class II Vaccines

描述（由申请人提供）：mhc呈递肽疫苗是黑色素瘤最有前途的实验性疗法之一。然而，在临床试验中，启动ctl的MHC I类肽缺乏显著的抗肿瘤作用。与MHC II类肽共同免疫可显著增强CTL效力，增强抗体的产生并提供记忆。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。抗原表达科学家发现，将免疫调节的li-Key片段偶联到MHC II类表位的n端，II类表位肽呈递的效力是仅表位肽的200倍。我们对免疫小鼠的研究表明，通过ELISPOT检测，li-Key/MHC II杂交体对Th1细胞的增强作用为4-6倍。体外li-Key/HER-21/neu（MHC II表位）杂交体能有效刺激乳腺癌患者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，用于我们的合作者，纪念斯隆凯特琳癌症中心（MSKCC）的Jedd Wolchok博士的临床试验。他将使用这些MHC II类杂交体增强CTL和对先前使用的酪氨酸酶和gp100 hla - a2限制性CTL表位肽疫苗的临床反应。在这里，我们将确定MHC II类表位的最佳序列，以纳入新的杂交体，最佳间隔长度，剂量/剂量和小鼠免疫反应参数。在体外使用人类细胞进行研究的同时，MSKCC的MigueI-Angel Perales博士将证实我们的结构-活性发现。一个GMP批次的最佳肽在小鼠和兔子中的毒理学研究将完成我们对该SBIR的临床前研究，支持Memorial Sloan-Kettering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.