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）：本研究提案的直接目的是开发一种经济的方法来生产美登木素DM 1，用于随后与单克隆抗体（mAb）偶联。这种类型的药物正在进行临床前开发，作为癌细胞靶向抗肿瘤药物。DM 1目前是通过发酵产物安丝菌素P3（AP 3）半合成生产的，成本超过10，000美元/克。DM 1的成本降低至约10，000美元/克。1,000美元/克是可行的，并将鼓励更广泛地探索其作为mAb缀合物在癌症治疗中的用途。在第一阶段的工作中，我们将追求以下具体目标：（1）探索和发现更有效和经济的化学或酶促方法将AP 3转化为安丝菌素P0（APO）。(2)探索和发现由APO合成DM 1的最有效和最经济的化学方法，避免DM 1的N-酰基-N-甲基-L-丙氨酸部分的手性中心的外消旋化。(3)通过过表达阳性控制AP 3生物合成基因表达的asm 18基因创建AP 3高产菌株。我们研究的长期目标是开发一种大规模的方法，以实际成本生产临床试验和癌症治疗所需的DM 1。 拟议的商业应用： 该研究将提供一种经济的方法来生产大量的半合成细胞毒素DM 1，当与肿瘤细胞特异性单克隆抗体（mAb）结合时，DM 1在癌症治疗中显示出显着的疗效。DM 1-mAb偶联物正在制药行业进行临床前开发，并可能在未来两年内进入临床试验。因此，我们研究的成功结果将以比目前DM 1合成（该细胞毒素的唯一来源）低得多的成本满足临床前和临床开发的需求。