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Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect.

ABSTRACT: Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

SUBMITTER: Nicolaou KC

PROVIDER: S-EPMC8237573 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect.

Nicolaou K C KC Rigol Stephan S Pitsinos Emmanuel N EN Das Dipendu D Lu Yong Y Rout Subhrajit S Schammel Alexander W AW Holte Dane D Lin Baiwei B Gu Christine C Sarvaiya Hetal H Trinidad Jose J Barbour Nicole N Valdiosera Amanda M AM Sandoval Joseph J Lee Christina C Aujay Monette M Fernando Hanan H Dhar Anukriti A Karsunky Holger H Taylor Nicole N Pysz Marybeth M Gavrilyuk Julia J

Proceedings of the National Academy of Sciences of the United States of America 20210601 25

Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, <i>N</i>-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined ...[more]

PMID: 34155147

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Project description:Antibody-drug conjugates (ADCs) are designed to target antigen expressing (Ag+) cells in a tumor. Once processed by the Ag+ cells, ADCs can release cytotoxic drug molecules that can diffuse out of Ag+ cells into the neighboring antigen-negative (Ag-) cells to induce their cytotoxicity. This additional efficacy of ADCs on Ag- cells in the presence of Ag+ cells is known as the 'bystander effect'. Although the importance of this phenomena is widely acknowledged for effective killing of a heterogeneous tumor, the rate and extent of the bystander killing in a heterogeneous system is not quantitatively understood yet. Thus, the objectives of this manuscript were to: (1) synthesize and characterize a tool ADC Trastuzumab-vc-MMAE that is capable of exhibiting bystander effect, (2) quantify the time course of the bystander effect for the tool ADC using in vitro co-culture systems created using mixture of various HER2-expressing cell lines, and (3) develop a pharmacodynamic (PD) model that is capable of characterizing the bystander effect of ADCs. Co-culture studies conducted using GFP labelled MCF7 cells as Ag- cells and N87, BT474, and SKBR3 as Ag+ cells revealed that the bystander effect of ADC increases with increasing fraction of Ag+ cells in a co-culture system, and with increased expression level of target on Ag+ cells. A notable lag time after ADC incubation was also observed prior to significant bystander killing of Ag- cells. Based on our results we hypothesize that there may be other determinants apart from the antigen expression level that can also influence the ability of Ag+ cells to demonstrate the bystander effect in a co-culture system. The co-culture analysis also suggested that the bystander effect of the ADC can dissipate over the period of time as the population of Ag+ cells declines. A novel PD model was developed to mathematically characterize the bystander effect of ADCs by combining two different cell distribution models to represent the population of Ag+ and Ag- cells in a co-culture system. This PD model can be integrated with the systems PK model for ADCs in the future to generate a quantitative framework that is capable of supporting the discovery and development of novel ADCs with optimal bystander killing capabilities.

Dataset Information

Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect.

Publications

Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect.

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