Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer

Montagut, Clara; Dalmases, Alba; Bellosillo, Beatríz; Crespo, Marta; Pairet, Silvia; Iglesias, Mar; Salido, Marta; Gallén, Manuel; Marsters, Scot A.; Tsai, Siao Ping; Minoche, André E.; Seshagiri, Somasekar; Serrano, Sergi; Himmelbauer, Heinz; Bellmunt, Joaquim; Rovira, Ana; Settleman, Jeff; Bosch, Francesc; Albanell, Joan

doi:10.1038/nm.2609

Cited by 441 publications

(406 citation statements)

References 7 publications

(1 reference statement)

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“…15,16 More importantly, cetuximab-resistant patients who harbor the S492R mutation responded to treatment with panitumumab. 17 In keeping with the results, Voigt et al 18 revealed that the epitope of panitumumab differs from that of cetuximab, providing a possible explanation for the benefits from panitumumab treatment in some cetuximab-resistant patients. However, as a fully human IgG2 mAb, panitumumab is devoid of natural killer (NK) cellmediated classical ADCC.…”

Section: Introductionmentioning

confidence: 56%

“…36,37 However, clinically relevant extracellular domain mutations of EGFR have been shown to mediate resistance to cetuximab but remain sensitive to panitumumab. 17 This mutation may have a role in providing the clinical benefit of panitumumab in a subset of subjects with mCRC who do not respond to treatment with cetuximab. 38 Additionally, Voigit et al 18 described a distinct binding site for panitumumab that is different from that of cetuximab.…”

Section: Discussionmentioning

confidence: 99%

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Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Yang

Guo

Mao³

et al. 2015

mAbs

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These authors contributed equally to this work.Keywords: monoclonal antibody, EGFR, panitumumab, ADCC, target-selective activation, Probody TM Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; mAb, monoclonal antibody; EGFR, epidermal growth factor receptor; uPA, urokinase-type plasminogen activator; TKI, tyrosine kinase inhibitor; IgG, Immunoglobulin G; ELISA, enzyme-linked immunosorbent assay; SPR, surface plasmon resonance; CI, confidence interval; LC, light chain; HC, heavy chain; EGFR VIII, EGFR Type III Variant; CRC, colorectal cancer; ECD, extracellular domain; SEC, size exclusion chromatography; CCK-8, Cell Counting Kit 8YunPanitumumab, as a commercially available antibody, is an effective anticancer therapeutic against epidermal growth factor receptor (EGFR), although it exerts weak antibody-dependent cell-mediated cytotoxicity (ADCC) activity owing to its IgG2 nature. Here, we firstly engineered panitumumab by grafting its variable region into an IgG1 backbone. The engineered panitumumab (denoted as Pan) retained binding activity identical to the parental antibody while exhibiting stronger ADCC activity in vitro and more potent antitumor effect in vivo. To further enhance the target selectivity of Pan, we generated Pan-P by tethering an epitope-blocking peptide to Pan via a tumor-specific protease selective linker. Pan-P showed almost 40-fold weaker affinity compared with Pan, but functional activity was restored to a similar extent as Pan when Pan-P was selectively activated by urokinase-type plasminogen activator (uPA). More importantly, targeted localization of Pan-P was observed in tumor samples from colorectal cancer (CRC) patients and tumor-bearing nude mice, strongly indicating that specific activation also existed ex vivo and in vivo. Furthermore, Pan-P also exhibited effective in vivo antitumor potency similar to Pan. Taken together, our data evidence the enhanced antitumor potency and excellent target selectivity of Pan-P, suggesting its potential use for minimizing on-target toxicity in anti-EGFR therapy.

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Section: Introductionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Yang

Guo

Mao³

et al. 2015

mAbs

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“…[30][31][32] After 48 or 72h incubation, activated PanP-DM1 inhibited the growth of DiFi, H292 and A431 cancer cells in a dose-dependent manner ( Fig 3A). Importantly, the growth inhibition was significantly stronger compared with activated PanP at the concentration of 1 mg/ml (P<0.001).…”

Section: Panp-dm1 Has Superior In Vitro Anti-tumor Activity Compared mentioning

confidence: 93%

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

Yang¹,

Guo²,

Chen³

et al. 2016

mAbs

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Antibody-drug conjugates (ADCs) have exhibited potent clinical benefits in cancer therapy. However, development of ADCs against epidermal growth factor receptor (EGFR) has limitations because of wide expression of EGFR in both normal and tumor tissues. Previously, we developed an anti-EGFR proteaseactivated antibody (pro-antibody), termed as PanP, which remains inert against EGFR until activated by tumor-specific protease. Herein, we for the first time report a new class of pro-antibody-drug conjugate (PDC) against EGFR, denoted as PanP-DM1. It has been designed to selectively target the EGFRoverexpressing tumor cells and exert greater anti-tumor activity compared with PanP. Our data showed that PanP-DM1 also could be selectively activated by tumor-specific protease 'uPA'. Furthermore, activated PanP-DM1 was potently cytotoxic against EGFR-overexpressing tumor cell lines in vitro. Crucially, our data indicated that PanP-DM1 was significantly more effective in eradicating EGFR-overexpressing tumors in vivo. Additionally, toxicity was preliminarily evaluated in mice as measured by body weight loss. In summary, our study suggests that PanP-DM1, a novel pro-antibody-drug conjugate, has cancer-selectivity, efficacy and safety profile that supports its potential use for EGFR-overexpressing tumors.

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“…A recent study reported that cell lines with acquired resistance to cetuximab showed a mutation of the extracellular domain of the EGFR, 1476C>A, leading to a substitution of serine to arginine at amino acid 492 (S492R). 18 This mutation interferes with binding to cetuximab but not to panitumumab. Indeed, cell lines with the EGFR S492R mutation showed sensitivity to panitumumab but not to cetuximab.…”

Section: Introductionmentioning

confidence: 99%

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

Esposito

Rachiglio

Porta

et al. 2013

Cancer Biology & Therapy

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Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer

Cited by 441 publications

References 7 publications

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

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