Antibody-targeted drugs and drug resistance—Challenges and solutions

Shefet-Carasso, LeeRon; Benhar, Itai

doi:10.1016/j.drup.2014.11.001

Cited by 122 publications

(95 citation statements)

References 153 publications

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“…Following binding, the complex must be rapidly internalised, allowing the release the cytotoxic agent within the tumour cell (Figure 1) [7,8]. Ideally, the antigen should be well-characterised, proportionally abundant, and accessible on tumour cells compared to surrounding normal cell populations [9,10]. This is to allow the preferential binding and delivery of the ADC to malignant populations, reducing the potential for toxicity to normal cells.…”

Section: Selecting An Appropriate Targetmentioning

confidence: 99%

“…Conventional ADC conjugation involves methods of alkylation of reduced interchain disulphides and alkylation or acylation of lysine residues [9]. These conjugation methods generate heterogeneous mixtures of ADCs with variable drug per antibody ratios (DARs).…”

Section: Antibody–drug Conjugationmentioning

confidence: 99%

“…Peptide linkers, such as the valine-citrulline (vc) dipeptide, contain an engineered lysosomal-specific protease (i.e., cathepsin B) cleavage site, allowing for the chemically unmodified release of cytotoxic payload from the lysosome compartment. Taking advantage of the increased glutathione concentration within tumour cells, the reducible, disulphide bond-based glutathione sensitive linkers are a third major sub-category of cleavable linkers [9,22]. However, low levels of glutathione is also present within the circulation (2.8 ± 0.9 µM) [23].…”

Section: Antibody–drug Conjugationmentioning

confidence: 99%

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Antibody–Drug Conjugates for Cancer Therapy

et al. 2016

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Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting on the clinical success of ADCs in cancer therapy. Like many other developing therapeutic classes, there remain challenges in the design and optimisation of these compounds. As the clinical applications for ADCs continue to expand, key strategies to improve patient outcomes include better patient selection for treatment and the identification of mechanisms of therapy resistance.

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Section: Selecting An Appropriate Targetmentioning

confidence: 99%

Section: Antibody–drug Conjugationmentioning

confidence: 99%

Section: Antibody–drug Conjugationmentioning

confidence: 99%

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Antibody–Drug Conjugates for Cancer Therapy

et al. 2016

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“…[8] Evidence suggests that combinations of HER2-directed agents by other cytotoxic ones may show additive or synergistic effects and lead to improving outcome. [39]…”

Section: Resultsmentioning

confidence: 99%

Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

Moghaddas

Borhani

2016

J Res Pharm Pract

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The National Comprehensive Cancer Network (NCCN) has recommended Ado-trastuzumab emtansine (T-DM1) as a preferred agent for patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer and prior trastuzumab therapy. Overexpression of HER2 was reported in other cancer types such as bladder, gastric and urogenital carcinosarcomas similar to what is discovered in breast cancer. Some preclinical studies demonstrated the potential anti-tumor effects of T-DM1 in HER2-positive non-breast cancers. There is a paucity of data over the clinical evaluation of T-DM1 in human studies of non-breast cancer patients. We review some preclinical and ongoing clinical studies that assessed the efficacy of T-DM1 administration in the treatment of non-breast HER2 positive malignancies. Performing large and well-designed trials in this area is matter of interest and highly recommended.

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“…4 As an alternative to the use of antibodies, synthetic peptides reminiscent of those naturally occurring in the human organism, so called regulatory peptides, are gaining increasing interest in cancer research. 5 Short peptides can be easily synthesized using automated synthesizers and their pharmacokinetic profiles can be improved by making appropriate changes in the peptide sequence.…”

Section: Introductionmentioning

confidence: 99%

Theranostic Nanocages for Imaging and Photothermal Therapy of Prostate Cancer Cells by Active Targeting of Neuropeptide-Y Receptor

Avvakumova¹,

Galbiati²,

Sironi³

et al. 2016

Bioconjugate Chem.

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Gold nanocages (AuNCs) have been shown to be a useful tool for harnessing imaging and hyperthermia therapy of cancer, thanks to their unique optical properties, low toxicity and facile surface functionalization. Herein, we use AuNCs for selective targeting of prostate cancer cells (PC3) via specific interaction between neuropeptide Y (NPY) receptor and three different NPY analogs conjugated to AuNCs. Localized surface plasmon band of the nanoconjugates was set around 800 nm, which is appropriate for in vivo applications. Long-term stability of nanoconjugates in different media was confirmed by UV-vis and DLS studies. Active NPY receptor targeting was observed by confocal microscopy showing time-dependent AuNCs cellular uptake. Activation of ERK1/2 pathway was evaluated by Western blot to confirm the receptor-mediated specific interaction with PC3. Cellular uptake kinetics were compared as a function of peptide structure. Cytotoxicity of nanoconjugates was evaluated by MTS and Annexin V assays, confirming their safety within the concentration range explored.Hyperthermia studies were carried out irradiating the cells, previously incubated with AuNCs, with a pulsed laser at 800 nm wavelength, showing a heating enhancement ranging from 6 to 35 °C above the culture temperature dependent on the irradiation power (between 1.6 and 12.7 W/cm2). Only cells treated with AuNCs underwent morphological alterations in the cytoskeleton structure upon laser irradiation, leading to membrane blebbing and loss of microvilli associated to cell migration. This effect is promising in view of possible inhibition of proliferation and invasion of cancer cells. In summary, our Au-peptide NCs proved to be an efficient theranostic nanosystem for targeted detection and activatable killing of prostate cancer cells.

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Antibody-targeted drugs and drug resistance—Challenges and solutions

Cited by 122 publications

References 153 publications

Antibody–Drug Conjugates for Cancer Therapy

Antibody–Drug Conjugates for Cancer Therapy

Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

Theranostic Nanocages for Imaging and Photothermal Therapy of Prostate Cancer Cells by Active Targeting of Neuropeptide-Y Receptor

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