DM1-Monoclonal Antibody Conjugates

描述(由申请人提供)：这项研究计划的直接目的是开发一种经济的方法来生产美丹素DM1，用于随后与单抗(MAb)的偶联。这类药物正在进行临床前开发，作为癌细胞靶向的抗肿瘤药物。目前，DM1的生产是从发酵产物阿司匹林P3(AP3)半合成，成本超过10,000美元/克。将DM1的成本降低到约1,000美元/克是可行的，并将鼓励更广泛的探索，将其作为单抗结合物用于癌症治疗。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法将AP3转化为阿司匹林P0(APO)。(2)探索合成DM1最有效、最经济的化学方法，避免DM1中N-酰基-N-甲基-L-丙氨酸部分的手性中心外消旋。(3)通过过量表达正向调控AP3生物合成基因表达的asm18基因，建立AP3高产菌株。我们研究的长期目标是开发一种大规模的工艺，以实际成本生产临床试验和癌症治疗所需的DM1。 建议的商业应用： 这项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DM1，当它与肿瘤细胞特异性单抗(MAb)结合时，在癌症治疗中显示出显著的效果。DM1-mAb结合物正在制药行业进行临床前开发，很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满足临床前和临床开发的需要，成本远远低于目前作为这种细胞毒素唯一来源的DM1合成。

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.