抗体药物偶联物 (ADC) 合成中部分还原和偶联反应的动力学研究,Organic Process Research & Development

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抗体药物偶联物 (ADC) 合成中部分还原和偶联反应的动力学研究
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-10-20 , DOI: 10.1021/acs.oprd.3c00264
Subramanya Nayak ₁ , Steven M. Richter ₁

Affiliation

部分还原抗体的天然链间二硫键，并通过接头将所得半胱氨酸硫醇基团与有效的小分子治疗剂共价缀合，从而产生抗体-药物缀合物 (ADC) 的异质混合物。由于这些缀合物在抗体的不同位置连接有不同数量的药物接头分子，因此这种混合物具有不一致的药理学特性、稳定性和治疗指数 (TI)。为了更好地了解导致各种药物与抗体比率 (DAR) 的 ADC 合成过程，进行了部分还原和缀合反应的动力学研究。研究发现，与缀合反应相比，所研究的部分还原反应速度较慢，并且是 ADC 合成过程中的限速步骤。此外，据观察，一旦重链-重链上的一个二硫键被还原剂断裂，抗体重链-重链上剩余的二硫键优选被还原。这导致位置异构体的还原率存在显着差异，这些位置异构体具有相同数量的还原半胱氨酸硫醇，但位置不同。这在部分还原反应期间产生了广泛的产物分布。开发动力学模型是为了预测各种工艺参数对产物分布的影响，并应用于确定 ADC 工艺的有利设计空间，以最大限度地提高所需 DAR 物质的产量，并提供评估其他合成条件和结果的工具。优化目标。

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Kinetic Studies of the Partial Reduction and Conjugation Reactions in an Antibody-Drug Conjugate (ADC) Synthesis

Partially reducing native interchain disulfide bonds of antibodies and covalently conjugating the resulting cysteine thiol groups to potent small-molecule therapeutic agents via linkers result in a heterogeneous mixture of antibody-drug conjugates (ADCs). Since these conjugates have a varying number of drug-linker molecules attached at different positions of antibodies, this mixture has nonuniform pharmacological properties, stability, and therapeutic index (TI). To develop a better understanding of the ADC synthesis process that results in various drug-to-antibody ratios (DAR), kinetic studies of partial reduction and conjugation reactions were performed. It was found that the partial reduction reactions studied are slow, in comparison to the conjugation reactions, and are the rate-limiting steps in the ADC synthesis processes. Furthermore, it was observed that once one disulfide bond on the heavy–heavy chains is broken by the reducing agent, the remaining disulfide bonds on the heavy–heavy chains of an antibody are preferably reduced. This resulted in significant differences in the reduction rates of positional isomers, which have the same number of reduced cysteine thiols but at different positions. This gives rise to a wide product distribution during the partial reduction reactions. Kinetic models are developed to predict the impact of various process parameters on the distribution of products and are applied to identify the favorable design space for the ADC processes to maximize the yield of desired DAR species as well as offer a tool to evaluate other synthesis conditions and optimization objectives.

更新日期：2023-10-20

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