Antibody Drug Conjugates: Preclinical Considerations

Bornstein, Gadi Gazit

doi:10.1208/s12248-015-9738-4

Cited by 43 publications

(32 citation statements)

References 96 publications

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“…[12], which are ubiquitously expressed in most mammalian cells [13][14][15]. Moreover, it is well known that only <1% of the injected dose of ADCs targets tumors in patients [16][17][18]. In spite of the improved efficacy of the "bystander effects", the permeable MMAE inevitably released in normal tissues and produced off-target toxicity ( Figure 1A) [19].…”

Section: Introductionmentioning

confidence: 99%

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.

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Section: Introductionmentioning

confidence: 99%

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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“…ADCs work by binding to cancer cells via the antibody backbone, and internalizing inside the cells to release the cytotoxic agent that ultimately kills the cancer cells (Kalim et al, 2017). Most ADCs target cell surface antigens that are overexpressed on cancer cells and have minimal or no expression on normal tissue cells (Bornstein, 2015). Targeting cancer-specific, overexpressed antigens is key for achieving the wide therapeutic index of ADCs (Hinrichs and Dixit, 2015) .…”

Section: Introductionmentioning

confidence: 99%

“…There is a lack of quantitative understanding regarding the relationship between target expression and ADC efficacy. Some in vitro investigations even show that the efficacy of an ADC is not always correlated with the expression levels of the target (O'Brien et al, 2008;Barok et al, 2011;Li et al, 2013;Bornstein, 2015). Consequently, the importance of antigen expression level in selecting the patient population for ADC treatment, and implementation of a precision medicine strategy for ADCs, remains ambiguous.…”

Section: Introductionmentioning

confidence: 99%

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

Sharma

Bussing

et al. 2020

Drug Metab Dispos

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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 (R 2 >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.

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“…In this study, we exploited this capability (namely, longitudinal imaging) and evaluated the biodistribution and tumor targeting of a 5T4-antibody (5T4-Ab) and its companion antibody-drug conjugate (ADC: 5T4-ADC) using FMT imaging. An ADC is composed of an antibody that targets a specific antigen at the site of action (i.e., tumor) and is conjugated via a linker to a cytotoxic agent (payload) that elicits cell death (16,17). Anti-5T4 antibody conjugated to monomethylauristatin F (MMAF), here after referred to as 5T4-ADC, has shown promising results in various in vitro and in vivo cancer models (18,19).…”

Section: Introductionmentioning

confidence: 99%

Biodistribution and Targeting of Anti-5T4 Antibody–Drug Conjugate Using Fluorescence Molecular Tomography

Giddabasappa

Gupta

Norberg

et al. 2016

Molecular Cancer Therapeutics

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Non-invasive imaging using radiolabels is a common technique used to study the biodistribution of biologics. Due to the limited shelf-life of radiolabels and the requirements of specialized labs, non-invasive optical imaging is an attractive alternative for preclinical studies. Previously, we demonstrated the utility of fluorescence molecular tomography (FMT) an optical imaging modality in evaluating the biodistribution of antibody-drug conjugates. As FMT is a relatively new technology, few fluorophores have been validated for in vivo imaging. The goal of this study was to characterize and determine the utility of near-infrared (NIR) fluorophores for biodistribution studies using interleukin-13 receptor subunit alpha-2 antibody (IL13Rα2-Ab). Eight fluorophores (ex/em: 630/800 nm) with an N-hydroxysuccinimide (NHS) linker were evaluated for Ab conjugation. The resulting antibody-fluorophore (Ab-F) conjugates were evaluated in vitro for degree of conjugation, stability and target-binding, followed by in vivo/ex vivo FMT imaging to determine biodistribution in a xenograft model. The Ab-F conjugates (except Ab-DyLight800) showed good in vitro stability and antigen binding. All Ab-F conjugates (except for Ab-BOD630) resulted in a quantifiable signal in vivo and had similar biodistribution profiles, with peak tumor accumulation between 6 and 24 h post-injection. In vivo/ex vivo FMT imaging showed 17-34% ID/g Ab uptake by the tumor at 96 h. Overall, this is the first study to characterize the biodistribution of an Ab using eight NIR fluorophores. Our results show that 3-dimensional optical imaging is a valuable technology to understand biodistribution and targeting, but a careful selection of the fluorophore for each Ab is warranted.

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Antibody Drug Conjugates: Preclinical Considerations

Cited by 43 publications

References 96 publications

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

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

Biodistribution and Targeting of Anti-5T4 Antibody–Drug Conjugate Using Fluorescence Molecular Tomography

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