Natural Products as Exquisitely Potent Cytotoxic Payloads for Antibody- Drug Conjugates

Abstract

Antibody-drug conjugates (ADCs) are an emerging area of study within medicinal chemistry and are thought of as sophisticated drug delivery systems due to their specificity to a disease-targeted antigen. ADCs have been actively utilized as therapeutics for hematological and solid tumor cancers due to their capability to deliver a cytotoxic compound to a specific cancer cell without affecting normal cells. An antibody drug conjugate has three major constituents: a monoclonal antibody (mAb), a chemical linker, and a potent cytotoxic payload. There has been a continuing effort to optimize antibody-drug conjugates, with the primary focus of design and development directed at either the mAb or the chemical linker, with little effort devoted to the optimization of payload compounds. In fact, among the 114 ongoing or recently completed clinical trials, there is generally a lack of diversity in the cytotoxic payloads that are utilized, with only seven payload compounds reported (four additional trials are ongoing with structures that have not been reported). Six of these seven payload compounds are derived from natural product sources, highlighting the importance of natural products as cytotoxic payloads for ADC.

Emerging formats for next-generation antibody drug conjugates

“…This high potency is now a recognized prerequisite as < 0.1% of the ADC will reach the tumour site and even less will find the molecular target [5]. A detailed discussion on current and emerging payloads can be found in excellent reviews [15][16][17]. Some example payloads are shown in Table 1, which illustrates the range of chemical structures, and functional groups (handles) being used to conjugate to antibodies.…”

Antibody–Drug Conjugates Derived from Cytotoxic seco-CBI-Dimer Payloads Are Highly Efficacious in Xenograft Models and Form Protein Adducts In Vivo

“…The majority of clinical-stage ADCs incorporate cytotoxic molecules that bind to tubulin and disrupt its proper function during cell division. − However, several next-generation ADCs that are the subject of recent clinical testing employ DNA minor groove alkylating agents as their payloads. Examples of these DNA-damaging compounds include pyrrolobenzodiazepine (PBD)-dimer (compound 1 ) − and a duocarmycin analog (compound 2 , seco -DUBA, seco -duocarmycin-hydroxybenzamide-azaindole), , which respectively form covalent interactions with the C2–NH 2 group of guanine and the N3 position of adenine in the DNA minor groove (Figure ).…”

Antibody–drug conjugates as novel anti-cancer chemotherapeutics

“…Clinical trials of ADCs that utilize both types of drugs have however shown that they are commonly associated with neutropenia or thrombocytopenia [198,199] which may in some cases limit their maximum dose [200]. As more cytotoxins are being identified, it is likely that the future of ADCs will produce a diverse range of drugs with different mechanisms of action and fewer side effects [201].…”