Evaluation of Quantitative Relationship Between Target Expression and Antibody-Drug Conjugate Exposure Inside Cancer Cells.

Published on Feb 21, 2020in Drug Metabolism and Disposition3.231
· DOI :10.1124/DMD.119.089276
Sharad Sharma7
Estimated H-index: 7
(UB: University at Buffalo),
Zhe Li5
Estimated H-index: 5
(UB: University at Buffalo)
+ 1 AuthorsDhaval K. Shah18
Estimated H-index: 18
(UB: University at Buffalo)
Antibody-drug conjugates (ADCs) employ overexpressed cell surface antigens to deliver cytotoxic payloads inside cancer cells. However, the relationship between target expression and ADC efficacy remains ambiguous. In this manuscript we have addressed a part of this ambiguity by quantitatively investigating the effect of antigen expression levels on ADC exposure within cancer cells. Trastuzumab-vc-MMAE was used as a model ADC, and four different cell lines with diverse levels of human epidermal growth factor receptor 2 (HER2) expression were used as model cells. The PK of total trastuzumab, released MMAE, and total MMAE were measured inside the cells and in the cell culture media following incubation with two different concentrations of ADC. In addition, target expression levels, target internalization rate, and cathepsin B and MDR1 protein concentrations were determined for each cell line. All the PK data was mathematically characterized using a cell-level systems PK model for ADC. It was found that SKBR-3, MDA-MB-453, MCF-7, and MDA-MB-468 cells had ~800,000, ~250,000, ~50,000, and ~10,000 HER2 receptors per cell, respectively. A strong linear relationship (R2>0.9) was observed between HER2 receptor count and released MMAE exposure inside the cancer cells. There was an inverse relationship found between HER2 expression level and internalization rate, and cathepsin B and MDR1 expression level varied slightly among the cell lines. The PK model was able to simultaneously capture all the PK profiles reasonably well, while estimating only 2 parameters. Our results demonstrate a strong quantitative relationship between antigen expression level and intracellular exposure of ADCs in cancer cells. SIGNIFICANCE STATEMENT In this manuscript we have demonstrated a strong linear relationship between target expression level and ADC exposure inside cancer cells. We have also shown that this relationship can be accurately captured using the cell-level systems PK model developed for ADCs. Our results indirectly suggest that the lack of relationship between target expression and efficacy of ADC may stem from differences in the pharmacodynamic properties of cancer cells.
📖 Papers frequently viewed together
5 Authors (Aman P. Singh, ..., Dhaval K. Shah)
7 Citations
5 Citations
4 Citations
#1Niña G. Caculitan (Genentech)H-Index: 1
#2Josefa Chuh (Genentech)H-Index: 11
Last. Andrew Polson (Genentech)H-Index: 21
view all 15 authors...
Antibody–drug conjugates (ADC) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline [VC(S)] linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsi...
55 CitationsSource
#1K L Moek (UG: University of Groningen)H-Index: 1
#2Derk Jan A. de Groot (UG: University of Groningen)H-Index: 15
Last. Rudolf S N Fehrmann (UG: University of Groningen)H-Index: 31
view all 4 authors...
Background: Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods: PubMed and Clin...
24 CitationsSource
#1Aman P. Singh (UB: University at Buffalo)H-Index: 8
#2Dhaval K. Shah (UB: University at Buffalo)H-Index: 18
The main objective of this work was to understand and mathematically characterize the cellular disposition of a tool antibody-drug conjugate (ADC), trastuzumab–valine-citrulline–monomethyl auristatin E (T-vc-MMAE). Toward this goal, three different analytical methods were developed to measure the concentrations of different ADC-related analytes in the media and cell lysate. A liquid chromatography–tandem mass spectrometry method was developed to quantify unconjugated drug (i.e., MMAE) concentrat...
16 CitationsSource
#1Yvette N. Lamb (Springer Science+Business Media)H-Index: 14
Intravenous inotuzumab ozogamicin (Besponsa®; Pfizer) is an anti-CD22 monoclonal antibody-calicheamicin conjugate that binds to CD22-expressing tumour cells. Upon binding, the complex is internalised and the cytotoxic calicheamicin derivative is released inside the cell, inducing double-strand DNA breakage and subsequent cell death. In June 2017, the EMA granted inotuzumab ozogamicin approval as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor ac...
84 CitationsSource
#1Muhammad KalimH-Index: 3
#2Jie ChenH-Index: 2
Last. Jinbiao ZhanH-Index: 4
view all 9 authors...
Antibody-drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intr...
39 CitationsSource
#1Sihem Ait-Oudhia (UF: University of Florida)H-Index: 9
#2Weiyan Zhang (SUNY: State University of New York System)H-Index: 1
Last. Donald E. Mager (SUNY: State University of New York System)H-Index: 40
view all 3 authors...
Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A phar...
10 CitationsSource
#1Aman P. Singh (UB: University at Buffalo)H-Index: 8
#2Dhaval K. Shah (UB: University at Buffalo)H-Index: 18
Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (MS 18(4):861–875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models. The preclinical data was used to estimate the efficacy parameters for T...
24 CitationsSource
#1John M. Lambert (ImmunoGen, Inc.)H-Index: 52
#2Charles Q. Morris (ImmunoGen, Inc.)H-Index: 1
Attaching a cytotoxic “payload” to an antibody to form an antibody–drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It wa...
161 CitationsSource
#1Alain BeckH-Index: 56
#2Liliane GoetschH-Index: 17
Last. Nathalie CorvaiaH-Index: 35
view all 4 authors...
Antibody–drug conjugate (ADCs), which aim to target highly cytotoxic drugs specifically to cancer cells, are one of the fastest growing classes of anticancer therapeutics, with more than 50 such agents currently in clinical trials. This Review discusses lessons learned and emerging strategies in the development of ADCs, including aspects such as target selection, the development of warheads, the optimization of linkers and new conjugation chemistries, and provides an overview of agents that are ...
931 CitationsSource
ABSTRACT The antibody drug conjugate platform and why it has not reached the potential of this technology. Antibody drug conjugates are complex delivery systems for selective delivery of cytotoxic payloads. Yet despite the potential for this therapeutic platform and hundreds of clinical studies only three ADCs have been approved by regulatory agencies and only two are currently marketed. The difficulties for this class of compounds are both categorized and explored in this review, and potential ...
81 CitationsSource
Cited By6
#1Huina Zhang (URMC: University of Rochester Medical Center)H-Index: 22
#2Hani Katerji (URMC: University of Rochester Medical Center)H-Index: 2
Last. David G. Hicks (URMC: University of Rochester Medical Center)H-Index: 69
view all 4 authors...
Objectives null Recent clinical trials have demonstrated significant clinical benefits from novel therapeutic compounds in breast cancer patient with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) score of 1+ or 2+ and negative in situ hybridization (ISH) result. A new concept of "HER2-low" breast cancer has been proposed and applied in the recent and ongoing clinical trials. In this article, we review the literature on the topic of HER2-low breast cancer. null Methods...
#1Andrew T. Lucas (UNC: University of North Carolina at Chapel Hill)H-Index: 9
#2Amber S. Moody (UNC: University of North Carolina at Chapel Hill)
Last. William C. Zamboni (UNC: University of North Carolina at Chapel Hill)H-Index: 54
view all 4 authors...
Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential...
#1Mikiko Suzuki (National Cancer Research Institute)
#2Shigehiro YagishitaH-Index: 10
Last. Kosei Hasegawa (Saitama Medical University)H-Index: 19
view all 13 authors...
Purpose: We assessed the intra-tumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC), using phosphor-integrated dots (PID) imaging analysis to elucidate its pharmacologic mechanism. Experimental design: We used two mouse xenograft models administered T-DXd at the concentration of 4 mg/kg: (i) a heterogeneous model in which HER2-positive and -negative cell lines were mixed,...
#1Marta Poźniak (UWr: University of Wrocław)
#2Natalia Porębska (UWr: University of Wrocław)H-Index: 3
Last. Łukasz Opaliński (UWr: University of Wrocław)H-Index: 7
view all 10 authors...
BACKGROUND Antibody drug conjugates (ADCs) represent one of the most promising approaches in the current immuno-oncology research. The precise delivery of cytotoxic drugs to the cancer cells using ADCs specific for tumor-associated antigens enables sparing the healthy cells and thereby reduces unwanted side effects. Overexpression of fibroblast growth factor receptor 1 (FGFR1) has been demonstrated in numerous tumors and thereby constitutes a convenient molecular target for selective cancer trea...
1 CitationsSource
#1David Bussing (UB: University at Buffalo)H-Index: 2
#2Sharad Sharma (UB: University at Buffalo)H-Index: 7
Last. Dhaval K. Shah (UB: University at Buffalo)H-Index: 18
view all 5 authors...
Antibody-drug conjugates (ADCs) rely on high expression of target antigens on cancer cells to effectively enter the cell and release a cytotoxic payload. Previous studies have shown that ADC efficacy is not always tied to antigen expression. However, our recent in vitro study suggests a linear relationship between antigen expression and the intracellular levels of the ADC payload. In this study, we have explored the relationship between antigen expression and intratumoral ADC exposure in vivo. U...