Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki-Ku, Kawasaki-Shi, Kanagawa 210-8681, Japan.
Ajinomoto Bio-Pharma Services, 11040 Roselle Street, San Diego, California 92121, United States.
Mol Pharm. 2021 Nov 1;18(11):4058-4066. doi: 10.1021/acs.molpharmaceut.1c00473. Epub 2021 Sep 27.
To overcome a lack of selectivity during the chemical modification of native non-engineered antibodies, we have developed a technology platform termed "AJICAP" for the site-specific chemical conjugation of antibodies through the use of a class of IgG Fc-affinity reagents. To date, a limited number of antibody-drug conjugates (ADCs) have been synthesized via this approach, and no toxicological study was reported. Herein, we describe the compatibility and robustness of AJICAP technology, which enabled the synthesis of a wide variety of ADCs. A stability assessment of a thiol-modified antibody synthesized by AJICAP technology indicated no appreciable increase in aggregation or decomposition upon prolonged storage, indicating that the unexpectedly stable thiol intermediate has a great potential intermediate for payload or linker screening or large-scale manufacturing. Payload conjugation with this stable thiol intermediate generated several AJICAP-ADCs. xenograft studies indicated that the AJICAP-ADCs displayed significant tumor inhibition comparable to benchmark ADC Kadcyla. Furthermore, a rat pharmacokinetic analysis and toxicology study indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index, compared with stochastic conjugation technology. This is the first report of the therapeutic index estimation of site-specific ADCs produced by utilizing Fc affinity reagent conjugation. The described site-specific conjugation technology is a powerful platform to enable next-generation ADCs through reduced heterogeneity and enhanced therapeutic index.
为了克服在天然非工程化抗体的化学修饰过程中缺乏选择性的问题，我们开发了一种称为“AJICAP”的技术平台，用于通过使用一类 IgG Fc 亲和力试剂来实现抗体的定点化学偶联。迄今为止，已经通过这种方法合成了有限数量的抗体药物偶联物（ADC），但没有报道毒理学研究。本文描述了 AJICAP 技术的兼容性和稳健性，该技术能够合成各种 ADC。通过 AJICAP 技术合成的巯基修饰抗体的稳定性评估表明，在长时间储存过程中没有明显的聚集或分解增加，这表明出乎意料的稳定的巯基中间体具有很大的潜力用于payload 或连接子筛选或大规模生产。用这种稳定的巯基中间体进行payload 偶联生成了几种 AJICAP-ADC。异种移植研究表明，与基准 ADC Kadcyla 相比，AJICAP-ADC 显示出显著的肿瘤抑制作用。此外，大鼠药代动力学分析和毒理学研究表明，与随机偶联技术相比，最大耐受剂量增加，表明 AJICAP-ADC 的治疗指数扩大。这是首次利用 Fc 亲和力试剂偶联来估计定点 ADC 治疗指数的报告。所描述的定点偶联技术是一个强大的平台，可通过降低异质性和提高治疗指数来实现下一代 ADC。
