Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities

Niesen, Judith; Stein, Christoph; Brehm, Hannes; Hehmann-Titt, Grit; Fendel, Rolf; Melmer, Georg; Fischer, Rainer; Barth, Stefan

doi:10.1007/s00432-015-1975-5

Cited by 37 publications

(67 citation statements)

References 80 publications

(124 reference statements)

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“…A novel hCFP composed of the R201K-mutated GrB and a human fragment scFv1711 derived from Panitumumab was also engineered. This scFv has already been exploited for the design of third generation immunotoxins and is derived from an approved human antibody binding to epidermal growth factor receptor (EGFR), which is overexpressed in several human cancers including the rare childhood cancer rhabdomyosarcoma (RMS), but rarely expressed in surrounding healthy cells [137]. The new hCFP (E)GrBR201K-scFv1711 demonstrated selective binding and potent pro-apoptotic effects at nanomolar concentrations against epidermoid cancer cells, as well as against rhabdomyosarcoma cells in presence or absence of the endosomal disrupting agent chloroquine, making it a promising novel therapeutic agent against several types of solid tumors [138].…”

Section: Results: In Silico and In Vitro Studies On Granzyme B Andmentioning

confidence: 99%

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

et al. 2017

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Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to up-regulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.

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Section: Results: In Silico and In Vitro Studies On Granzyme B Andmentioning

confidence: 99%

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

et al. 2017

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“…The IC50 values of rE/CUS in different cell lines were much lower than those of CUS, and the IC50 values of 7D12 alone showed no difference with control group. The same dose of rE/CUS has different effects in different times tend to result from the internalization of the toxin [65]. Moreover, rE/CUS also significantly reduced the proliferation of HepG2 and A549 by inducing > 70% and > 40% apoptosis at a series of concentration.…”

Section: Discussionmentioning

confidence: 99%

Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiencyin vitro

Deng

Xiong

et al. 2017

Oncotarget

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Epidermal growth factor receptor (EGFR) overexpression is related to the increased aggressiveness, metastases, and poor prognosis in various cancers. In this study, we successfully constructed a new EGFR nanobody-based immunotoxin rE/CUS containing cucurmosin (CUS), The immunotoxin was expressed by prokaryotic system and we obtained a yield of 5 mg protein per liter expression medium. The percentage of it's binding ability totumor cell lines A549, HepG2, SW116, which highly expressed EGFR was 55.6%, 79.6% and 97.1%, respectively, but SW620 was only 4.45%. rE/CUS has the ability to bind A549, HepG2, SW116 cells specifically, and the antigen binding capability was not affected because of extra part of CUS component. The rE/CUS significantly inhibited the cell viability against EGFR over expression tumor cell lines in a dose-and time-dependent manner. Moreover, rE/CUS also induced apoptosis of HepG2 and A549 mightily. Our results demonstrate that rE/CUS is a potential therapeutic strategy for treating EGFR-positive solid tumors.

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“…cetuksymabu i panitumumabu, m.in. w raku okrężnicy [20], piersi, prostaty, trzustki oraz mięsakach [56]. Badania in vitro oraz in vivo (w modelu mysim) dowiodły, że w przypadku stosowania przeciwciał anty-EGFR w raku okrężnicy (co wykazano zarówno dla cetuksymabu, jak i panitumumabu) można skutecznie zapobiegać rozwojowi oporności na te preparaty poprzez użycie ich w skojarzeniu z modulatorami szlaku kinaz Ras/Raf/MEK, gdyż pobudzenie tego szlaku stanowi główny mechanizm oporności w trakcie terapii opartej na modulacji EGFR [52].…”

Section: Przeciwciała Stosowane W Innych Typach Nowotworów Złośliwychunclassified

“…Po połączeniu z EGFR, ETA zostaje wprowadzona do komórki docelowej, wykorzystując mechanizmy endocytozy, gdzie oddziałując na siateczkę śródplazmatyczną, hamuje syntezę białek w nieodwracalny sposób. Konstruowane są również inne koniugaty przeciwciał anty-EGFR, które na razie w znacznej części pozostają w fazie badań przedklinicznych [7,18,56,62].…”

Section: Terapia Skojarzonaunclassified

Monoclonal antibodies in regulation of signal transduction of Epidermal Growth Factor Receptor (EGFR) pathway in cancer cells

Kampa¹,

Bednarek²,

Sypniewski³

2018

Ann. Acad. Med. Siles.

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ST R ES ZCZ E NI EReceptor naskórkowego czynnika wzrostu EGFR (Epidermal Growth Factor Receptor), ze względu na jego ważny udział w patogenezie nowotworów złośliwych, jest obiektem intensywnych badań naukowych ostatnich lat. W wielu typach nowotworów wewnątrzkomórkowe szlaki sygnalizacyjne pobudzane przez EGFR mają wręcz kluczowe znaczenie w ich rozwoju. Z drugiej strony wykazano, iż EGFR może stanowić bardzo obiecujący punkt uchwytu dla czynników terapeutycznych. Podjęto próby modyfikacji transdukcji sygnału przekazywanego przez aktywny EGFR wewnątrz komórek poprzez blokowanie aktywności elementów tego szlaku bądź samego receptora. Wykazano też, że blokowanie receptora EGFR przez przeciwciała monoklonalne podwyższa efektywność stosowanych w terapii konwencjonalnych czynników przeciwnowotworowych, np. cisplatyny. Dodatkowo opracowano wiele terapii przeciwnowotworowych opierając się na zastosowaniu inhibitorów wybranych, kluczowych składowych szlaku sygnalizacyjnego EGFR, z których wiele bazuje na zastosowaniu przeciwciał monoklonalnych.kancerogeneza, terapia przeciwnowotworowa, transdukcja sygnału, EGFR, przeciwciała monoklonalne

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Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities

Abstract: These data demonstrate the potent therapeutic activity of two novel EGFR-specific ETA'-based ITs. Both molecules are promising candidates for further development toward clinical use in the treatment of various solid tumors to supplement the existing therapeutic regimes.

Cited by 37 publications

References 80 publications

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiencyin vitro

Monoclonal antibodies in regulation of signal transduction of Epidermal Growth Factor Receptor (EGFR) pathway in cancer cells

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