Design and Validation of Linkers for Site-Specific Preparation of Antibody-Drug Conjugates Carrying Multiple Drug Copies Per Cysteine Conjugation Site.

ABSTRACT: 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 whi

SUBMITTER: Kumar A 

PROVIDER: S-EPMC7555909 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature