《Design and validation of linkers for site-specific preparation of antibody-drug conjugates carrying multiple drug copies per cysteine conjugation site》 was published in International Journal of Molecular Sciences in 2020. These research results belong to Kumar, Amit; Mao, Shenlan; Dimasi, Nazzareno; Gao, Changshou. Quality Control of 2-Aminopropane-1,3-diol The article mentions the following:
First-generation cysteine-based site-specific antibody-drug conjugates (ADCs) are limited to one drug per cysteine. However, certain applications require a high drug to antibody ratio (DAR), such as when low-potency payloads are used. Higher drug load can be achieved using classical cysteine conjugation methods, but these result in heterogeneity, suboptimal efficacy and pharmacokinetics. Here, we describe the design, synthesis and validation of heterobifunctional linkers that can be used for the preparation of ADCs with a DAR of two, three and four in a site-specific manner per single cysteine conjugation site, resulting in site-specific ADCs with a DAR of four, six and eight. The designed linkers carry a sulfhydryl-specific iodoacetyl reactive group, and multiple cyclic diene moieties which can efficiently react with maleimide-carrying payloads through the Diels-Alder reaction. As a proof of concept, we synthesized site-specific DAR four, six and eight ADCs carrying tubulysin (AZ13601508) using engineered antibodies with a cysteine inserted after position 239 in the antibody CH2 domain. We evaluated and compared the in vitro cytotoxicity of ADCs obtained via the site-specific platform described herein, with ADCs prepared using classical cysteine conjugation. Our data validated a novel cysteine-based conjugation platform for the preparation of site-specific ADCs with high drug load for therapeutic applications. The experimental process involved the reaction of 2-Aminopropane-1,3-diol(cas: 534-03-2Quality Control of 2-Aminopropane-1,3-diol)
2-Aminopropane-1,3-diol(cas: 534-03-2) belongs to anime. Acylation is one of the most important reactions of primary and secondary amines; a hydrogen atom is replaced by an acyl group (a group derived from an acid, such as RCOOH or RSO3H, by removal of ―OH, such as RC(=O)―, RS(O)2―, and so on). Reagents may be acid chlorides (RCOC1, RSO2C1), anhydrides ((RCO)2O), or even esters (RCOOR′); the products are amides of the corresponding acids.Quality Control of 2-Aminopropane-1,3-diol
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