Antibodies directed against receptor tyrosine kinases

Fauvel, Bénédicte; Yasri, Abdelaziz

doi:10.4161/mabs.29089

Cited by 71 publications

(47 citation statements)

References 142 publications

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“…estrogen, progesterone, androgen). Excluding classic cytotoxic inhibition of DNA synthesis and cell division, the main targeted therapy classes include ‘biologics’ (monoclonal antibodies with/without linked cytotoxics known as Antibody-Drug Conjugates (ADCs)) (Fauvel and Yasri, 2014), ‘small molecules’ such as tyrosine kinase inhibitors (TKIs) (Leary and Johnston, 2007; Faivre et al, 2006), and more recently, specific gene expression silencing by ‘RNA interference’, (Videira et al, 2014; Deng et al, 2014; Yan et al, 2014) each with their own properties, advantages and disadvantages (Table 1). …”

Section: Targeted Therapiesmentioning

confidence: 99%

Next‐generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity

2014

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The promise of ‘personalized cancer care’ with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized heterogeneity within any given tumor-type from patient to patient (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) as demonstrated by molecular evolution through space (primary tumor to metastasis) and time (after therapy). These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents. Classic trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic ‘oncogenic driver’ aberrations with adequate power. Usual accrual difficulties to clinical trials are exacerbated by low frequencies of any given molecular driver. To address these challenges, there is need for innovative clinical trial designs and strategies implementing novel diagnostic biomarker technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for pre-defined treatment priority algorithms given numerous aberrations commonly observed within any one individual sample. Access to multiple available therapeutic agents simultaneously is crucial. Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression. This report discusses various ‘next-generation’ biomarker-driven trial designs and their potentials and limitations to tackle these recognized molecular heterogeneity challenges. Regulatory hurdles, with respect to drug and companion diagnostic development and approval, are considered. Focus is on the ‘Expansion Platform Design Types I and II’, the latter demonstrated with a first example, ‘PANGEA: Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma’. Applying integral medium-throughput genomic and proteomic assays along with a practical biomarker assessment and treatment algorithm, ‘PANGEA’ attempts to address the problem of heterogeneity towards successful implementation of molecularly targeted therapies.

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Section: Targeted Therapiesmentioning

confidence: 99%

Next‐generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity

2014

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“…Monoclonal antibodies such as cetuximab and panitumumab inhibit activation of the EGFR by partially occluding its extracellular ligand binding region, and by preventing the receptor from adopting the conformation required for dimerization and initiation of signal transduction [2, 3]. In contrast, tyrosine kinase inhibitors such as gefitinib and erlotinib, interfere with the enzymatic activity of the intracellular EGFR tyrosine kinase domain by competing with ATP binding site [4].…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

2016

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The Epidermal Growth Factor Receptor (EGFR) is centrally involved in the regulation of key processes of the epithelia, including cell proliferation, survival, differentiation, and also tumorigenesis. Humanized antibodies and small-molecule inhibitors targeting EGFR were developed to disrupt these functions in cancer cells and are currently used in the treatment of diverse metastatic epithelial cancers. By contrast, these drugs possess significant skin-specific toxic effects, comprising the establishment of a persistent inflammatory milieu. So far, the molecular mechanisms underlying these epiphenomena have been investigated rather poorly. Here we showed that keratinocytes respond to anti-EGFR drugs with the development of a type I interferon molecular signature. Upregulation of the transcription factor IRF1 is early implicated in the enhanced expression of interferon-kappa, leading to persistent activation of STAT1 and further amplification of downstream interferon-induced genes, including anti-viral effectors and chemokines. When anti-EGFR drugs are associated to TNF-α, whose expression is enhanced by the drugs themselves, all these molecular events undergo a dramatic enhancement by synergy mechanisms. Finally, high levels of interferon-kappa can be observed in epidermal keratinocytes and also in leukocytes infiltrating the upper dermis of cetuximab-driven skin lesions. Our data suggest that dysregulated activation of type I interferon innate immunity is implicated in the molecular processes triggered by anti-EGFR drugs and leading to persistent skin inflammation.

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“…NaOH (20 mL, 2.5 m ) was added and then extracted with diethyl ether (3×30 mL). The organic phases were combined, dried over MgSO 4 , and evaporated leaving the desired product, compound 6 , as a clear low viscous oil (94 %, 426 mg); 1 H NMR (400 MHz, 25 °C, CDCl 3 ): δ =7.39 (t, J =7.8 Hz, 2 H), 7.17 (t, J =7.8 Hz, 2 H), 2.97 (t, J =7.0 Hz, 2 H), 2.73 (t, J =7.0 Hz, 2 H), 1.64–1.26 (m, 12 H), 1.16–0.84 ppm (m, 15 H); 13 C NMR (100 MHz, 25 °C, CDCl 3 ): δ =139.5, 139.1, 136.6, 128.5, 43.5, 40.2, 29.0, 27.4, 13.7, 9.5 ppm; MS (ESI): 408–416 [ M +H + ].…”

Section: Methodsmentioning

confidence: 99%

“…Molecular recognition of these proteins can be used for specific treatment of malignant cells, for example, targeted therapy. Monoclonal antibodies (Mabs) are the most used kind of targeting agents, which may act by preventing mitogenic signaling or by eliciting antibody‐dependent or complement‐dependent cytotoxicity . Antitumor action of Mabs might be further enhanced by conjugation of cytotoxic drugs or radionuclides .…”

Section: Introductionmentioning

confidence: 99%

“…Malignant transformation is often associated with an aberrant expression of certain types of cell-surface proteins,f or example, receptors, cell adhesion molecules, or proteins active in embryonic development. [1] Molecular recognition of these proteins can be used fors pecific treatment of malignant cells, for example, targeted therapy.M onoclonal antibodies (Mabs) are the most used kind of targeting agents, which may act by preventingm itogenic signaling [2] or by eliciting antibody-dependent or complement-dependent cytotoxicity. [3] Antitumor action of Mabs might be furthere nhanced by conjugation of cytotoxic drugs or radionuclides.…”

Section: Introductionmentioning

confidence: 99%

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Site‐Specific Radioiodination of HER2‐Targeting Affibody Molecules using 4‐Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity

et al. 2015

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Affibody molecules are small scaffold-based affinity proteins with promising properties as probes for radionuclide-based molecular imaging. However, a high reabsorption of radiolabeled Affibody molecules in kidneys is an issue. We have shown that the use of 125I-3-iodo-((4-hydroxyphenyl)ethyl)maleimide (IHPEM) for site-specific labeling of cysteine-containing Affibody molecules provides high tumor uptake but low radioactivity retention in kidneys. We hypothesized that the use of 4-iodophenethylmaleimide (IPEM) would further reduce renal retention of radioactivity because of higher lipophilicity of radiometabolites. An anti-human epidermal growth factor receptor type 2 (HER2) Affibody molecule (ZHER2:2395) was labeled using 125I-IPEM with an overall yield of 45±3 %. 125I-IPEM-ZHER2:2395 bound specifically to HER2-expressing human ovarian carcinoma cells (SKOV-3 cell line). In NMRI mice, the renal uptake of 125I-IPEM-ZHER2:2395 (24±2 and 5.7±0.3 % IA g−1at 1 and 4 h after injection, respectively) was significantly lower than uptake of 125I-IHPEM-ZHER2:2395 (50±8 and 12±2 % IA g−1at 1 and 4 h after injection, respectively). In conclusion, the use of a more lipophilic linker for the radioiodination of Affibody molecules reduces renal radioactivity.

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Antibodies directed against receptor tyrosine kinases

Cited by 71 publications

References 142 publications

Next‐generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity

Next‐generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity

Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

Site‐Specific Radioiodination of HER2‐Targeting Affibody Molecules using 4‐Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity

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