DM1-Monoclonal Antibody Conjugates

DM1-单克隆抗体偶联物

• 批准号: 6549145
• 负责人: CHARLES R HUTCHINSON
• 金额: $ 10万
• 依托单位: KOSAN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549145
• 关键词: antineoplastic antibiotics; antitumor antibody; chemical synthesis; cytotoxicity; gene expression; high performance liquid chromatography; immunoconjugates; method development; microtubules; molecular cloning; monoclonal antibody; neoplasm /cancer immunology; polyketide synthase; polymerase chain reaction; racemization; regulatory gene; transfection /expression vector; tubulin

DESCRIPTION (provided by applicant): The immediate aim of this research proposal is to develop an economic method to produce the maytansinoid DM1 for subsequent conjugation to monoclonal antibodies (mAb). Drugs of this type are undergoing preclinical development as cancer cell targeted antitumor drugs. DM1 currently is produced by semisynthesis from the fermentation product, ansamitocin P3 (AP3), at a cost exceeding $10,000/gram. Reduction in the cost of DM1 to approx. $1,000/gram is feasible and would encourage broader exploration of its use as a mAb conjugate in cancer treatment. In Phase I work, we will pursue the following specific aims: (1) Explore and discover more efficient and economic chemical or enzymatic methods for conversion of AP3 to ansamitocin P0 (APO). (2) Explore and discover the most efficient and economic chemical method for the synthesis of DM1 from APO that avoids racemization of the chiral center in the N-acyl-N-methyl-L-alanine moiety of DM1. (3) Create an AP3 overproducing strain by overexpression of the asm18 gene that positively controls expression of AP3 biosynthesis genes. The long term goal of our research is to develop a large scale process for manufacturing the amount of DM1 needed for clinical trials and cancer treatment at a practical cost. PROPOSED COMMERCIAL APPLICATIONS: The research will provide an economic means to produce large amounts of the semisynthetic cytotoxin, DM1, that when conjugated to tumor cell specific monoclonal antibodies (mAb), has shown remarkable efficacy in cancer therapy. DM1-mAb conjugates are undergoing preclinical development in the pharmaceutical industry and are likely to enter clinical trials within the next two years. Therefore, a successful outcome of our research would meet the needs for preclinical and clinical development at a far lower cost than the current DM1 synthesis that is the only source of this cytotoxin.

描述（由申请人提供）：该研究建议的直接目的是开发一种经济方法，以生产Maytansinoid DM1，以随后与单克隆抗体（MAB）结合。这种类型的药物正在经历临床前发育，作为癌细胞靶向抗肿瘤药物。 DM1目前是由发酵产品Ansamitocin P3（AP3）的半合成生产的，成本超过10,000美元/克。 DM1的成本降低至大约。 $ 1,000/克是可行的，将鼓励更广泛地探索其用作癌症治疗中的mAb偶联物。在第一阶段的工作中，我们将追求以下特定目的：（1）探索并发现将AP3转化为Ansamitocin P0（APO）的更有效，经济化学或酶促方法。 （2）探索并发现了APO合成DM1的最有效，最经济的化学方法，该方法避免了DM1的N-酰基N-甲基-L-丙氨酸部分中手性中心的种族化。 （3）通过过度表达ASM18基因，从而产生AP3过度产生菌株，该基因积极控制AP3生物合成基因的表达。我们研究的长期目标是开发一个大规模的过程，以实用成本制造临床试验和癌症治疗所需的DM1量。 拟议的商业应用： 这项研究将提供一种经济手段，以产生大量的半合成细胞毒素DM1，即当与肿瘤细胞特异性单克隆抗体（MAB）结合时，在癌症治疗中表现出了显着的效力。 DM1-MAB结合物正在制药行业正在进行临床前开发，并可能在未来两年内进行临床试验。因此，我们研究的成功结果将满足临床前和临床发育的需求，其成本要低得多，而当前的DM1合成是该细胞毒素的唯一来源。