Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

Abstract

Abstract. Antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapeutics. The three main components of ADCs are the antibody, the linker, and the payload; the majority of early work focused intensely on improving the functionality of these pieces. Recently, considerable attention has been focused on developing methods to control the site and number of linker/drug conjugated to the antibody, with the aim of producing more homogenous ADCs. In this article, we review popular conjugation methods and highlight recent approaches including "click" conjugation and enzymatic ligation. We discuss current linker technology, contrasting the characteristics of cleavable and noncleavable linkers, and summarize the essential properties of ADC payload, centering on chemotherapeutics. In addition, we report on the progress in characterizing to determine physicochemical properties and on advances in purifying to obtain homogenous products. Establishing a set of selection and analytical criteria will facilitate the translation of novel ADCs and ensure the production of effective biosimilars.

Stable and Potent Selenomab-Drug Conjugates

“…Antibody-drug conjugates (ADCs) are among the most promising next-generation antibody therapeutics for cancer therapy and are being pursued by an increasing number of biotech and pharma companies (Chari et al, 2014; de Goeij and Lambert, 2016; Drake and Rabuka, 2015; McCombs and Owen, 2015; Polakis, 2016). The concept of ADCs is the targeted delivery of a highly cytotoxic drug for selective (as opposed to systemic) chemotherapy, resulting in a higher therapeutic index (Adair et al, 2012; Sievers and Senter, 2013).…”

Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation

“…The long elimination half-lives of antibodies result in increased time for tumor exposure and uptake [26, 31], in contrast to smaller fluorescent probes that are often cleared too quickly and with suboptimal target binding [32]. The structure of antibodies is highly amenable to chemical manipulation, and the large number of active binding sites present on each provides an optimal scaffold for conjugating multiple fluorescent molecules [33–34]. Given their increasing use as therapeutics, many antibodies have pre-existing FDA approval for human use and well-established patient safety profiles [25, 27–28, 31], which can ease and expedite their clinical translation as imaging agents [6].…”

The landscape of new drugs in lymphoma

“…Current toxic payloads predominantly target DNA, such as pyrrolobenzodiazepine (PBD) 77 , or tubulin, such as auristatins (including monomethyl auristatin E/MMAE and MMAF), and maytansinoids (DM1 or DM4) (TABLE 2). Most ADCs that are currently in clinical development in patients with haematological malignancies take advantage of a cleavable linker strategy, with three different types of release mechanism available within this class: firstly, lysosomal protease-sensitive linkers (brentuximab vedotin, polatuzumab vedotin); secondly, acid-sensitive linkers (inotuzumab ozogamicin); and, thirdly glutathione-sensitive linkers (anti-CD19 maytansine conjugate) 78 .…”