Site-Specific Conjugation of Auristatins onto Engineered scFv Using Second Generation Maleimide to Target HER2-positive Breast Cancer <i>in Vitro</i>

Aubrey, Nicolas; Allard-Vannier, Émilie; Martin, Camille; Bryden, Francesca; Letast, Stéphanie; Colas, Cyril; Lakhrif, Zineb; Collinet, Nils; Dimier‐Poisson, Isabelle; Chourpa, Igor; Viaud‐Massuard, Marie‐Claude; Joubert, Nicolas

doi:10.1021/acs.bioconjchem.8b00668

Cited by 20 publications

(27 citation statements)

References 22 publications

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“…This approach thus does not compromise the foldamer’s mechanism of action. The selected linker included a diphenylthiomaleimide bioconjugation function as a next generation maleimide, able to rebridge previously reduced interchain disulfide bridges of an antibody while incorporating up to four desired payloads for an IgG1 [ 25 , 26 , 27 , 28 ]. The diphenylthio-maleimidocaproic acid 2 (diphenylthio-Mal-Cap, Figure 1 B) was synthesized according to previously reported procedures [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

et al. 2021

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Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

et al. 2021

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“…As part of this strategy, more recently, the site-specific conjugation of an auristatin derivative to an anti-HER2 scFv (derived from trastuzumab) generated two new scFv-drug conjugates (SDCs, Figure 5) [78]. Two cysteines have been judiciously incorporated near the hexahistidine tag (at the C-terminal position) in order to allow controlled bioconjugation of a heterobifunctional linker comprising of a second generation maleimide, cleavable (for MMAE) or non-cleavable (for MMAF) [2].…”

Section: Alternative Adc Formatsmentioning

confidence: 99%

Antibody–Drug Conjugates: The Last Decade

et al. 2020

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An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of.

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“…The delivery of drugs with anti-tumour activity to tumour sites by antibody is currently the most important tumour targeted therapeutic method [80][81][82]. By gene fusion or chemical coupling, antibody fragments can be bind to anti-tumour active drugs to form a targeted drug delivery system [83,84]. Antibody fragments as vectors and targeting moieties are critical for the construction of targeted drug delivery systems.…”

Section: Targeted Drug Delivery Of Antibody Fragmentmentioning

confidence: 99%

A promising cancer diagnosis and treatment strategy: targeted cancer therapy and imaging based on antibody fragment

Zhao

Ning

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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With the arrival of the precision medicine and personalized treatment era, targeted therapy that improves efficacy and reduces side effects has become the mainstream approach of cancer treatment. Antibody fragments that further enhance penetration and retain the most critical antigen-specific binding functions are considered the focus of research targeting cancer imaging and therapy. Thanks to the superior penetration and rapid blood clearance of antibody fragments, antibody fragment-based imaging agents enable efficient and sensitive imaging of tumour sites. In tumour-targeted therapy, antibody fragments can directly inhibit tumour proliferation and growth, serve as an ideal carrier for delivery of anti-tumour drugs, or manipulate the immune system to eliminate tumour cells. In this review, the excellent physicochemical properties and the basic structure of antibody fragments are expressly depicted depicted, the progress of antibody fragments in cancer therapy and imaging are thoroughly summarized, and the future development of antibody fragments is predicted.

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Site-Specific Conjugation of Auristatins onto Engineered scFv Using Second Generation Maleimide to Target HER2-positive Breast Cancer in Vitro

Cited by 20 publications

References 22 publications

Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

Antibody–Drug Conjugates: The Last Decade

A promising cancer diagnosis and treatment strategy: targeted cancer therapy and imaging based on antibody fragment

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