Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors

Paz‐Ares, Luis; Gomez‐Roca, Carlos; Delord, Jean‐Pierre; Cervantes, Andrés; Markman, Benjamin; Corral, J.; Soria, Jean‐Charles; Berge, Yann; Russell-Yarde, Fiona; Hollingsworth, Simon J.; Baselga, José; Umaña, Pablo; Manenti, Luigi; Tabernero, Josep

doi:10.1200/jco.2011.34.8888

Cited by 73 publications

(41 citation statements)

References 28 publications

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“…The best strategy for overcoming the limitation of direct cetuximab treatment because of the lack of response of tumors that have mutations in any of KRAS, BRAF, or PIK3CA may, therefore, be the development of antibodies to ERBB1, and possibly also to ERBB2 and ERBB3 (that are much more effective in immune-mediated killing), which is not subject to this limitation (33). From our studies of ERBB1 levels in the cell lines, it would be likely that at least 70-80% of colorectal tumors should be susceptible to such treatment.…”

Section: Discussionmentioning

confidence: 99%

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Ashraf

Nicholls

Wilding

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erbb) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/ PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms.anti-ERBB1 therapy | immune-mediated killing | high throughput screening M onoclonal antibodies against the epidermal growth factor receptor, ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF], including in particular cetuximab, are now commonly used in colorectal cancer (CRC) treatment (1-3). However, only 20% of patients respond to anti-ERBB1 monotherapy (3). The search for predictive markers to improve clinical outcomes (1, 3) has identified that the presence of a KRAS mutation predicts an adverse response leading to routine KRAS testing before anti-ERBB1 therapy (4). However, KRAS mutations are present in only 30-40% of CRC tumors and a significant proportion of KRAS wildtype (WT) patients (50-65%) do not respond to anti-ERBB1 therapy (3). To improve therapeutic outcomes (5), we therefore need to improve understanding of the roles of different antibodykilling mechanisms and the properties of tumors that determine their response to antibody treatment.The relative contributions of immune [for example antibodydependant cellular cytotoxicity (ADCC) and antibody-dependant cellular phagocytosis (ADCP)] and nonimmune processes (competitive blocking of receptor-ligand binding) to tumor response following antibody therapy are not yet clear (5, 6). The FcγR polymorphism has been shown to be an independent predictor of response to cetuximab in CR...

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Section: Discussionmentioning

confidence: 99%

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Ashraf

Nicholls

Wilding

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…A431 cells were transfected with 25 nM negative control siRNA or EGFRspecific siRNA #2 for 72 h. MNCs (E:T ratio 80:1) served as the effector source in [ activity triggered by cetuximab against KRAS-mutated tumor cells was significantly enhanced by protein-or glyco-engineering of cetuximab's Fc region (17). Interestingly, a glyco-engineered EGFR Ab induced clinical responses in individual CRC patients carrying KRAS-mutated tumors in a phase I clinical trial (51).…”

Section: Discussionmentioning

confidence: 99%

“…Low levels of EGFR cell surface expression impaired PMN-mediated ADCC (C) and CDC (D) activity. A431 cells were transfected with 25 nM control siRNA or EGFR-specific siRNA #2 for 72 h. PMNs (E:T ratio 80:1) or plasma served as effector sources in [ 51 Cr]-release assays using C225 or control Ab (both at 10 mg/ml). (E) Downregulation of EGFR by siRNA did not generally affect tumor cell susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Derer

Bauer

Lohse

et al. 2012

The Journal of Immunology

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The epidermal growth factor receptor (EGFR) is a widely expressed Ag that is successfully targeted in tumor patients by mAbs or tyrosine kinase inhibitors. A clinical study in non-small cell lung cancer patients demonstrated a positive correlation between EGFR expression levels and the therapeutic efficacy of the EGFR mAb cetuximab. However, the impact of EGFR expression on the different mechanisms of action (MoAs) triggered by the EGFR mAb has not been defined. In this study, BHK-21 cells were stably transfected to express different EGFR levels, which were quantified by immunofluorescence and immunohistochemistry and compared with EGFR levels of clinical non-small cell lung cancer samples. These cells were used to systematically investigate the impact of target Ag expression levels on Fab- or Fc-mediated MoAs of EGFR mAb. A negative correlation between EGFR levels and potency of Fab-mediated MoA was observed. Interestingly, Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells, monocytes, or polymorphonuclear cells as well as complement-dependent cytotoxicity positively correlated with the number of EGFR molecules. In comparison with ADCC by mononuclear cells, polymorphonuclear cell-mediated ADCC and complement-dependent cytotoxicity required higher EGFR expression levels and higher mAb concentrations to trigger significant tumor cell killing. This correlation between EGFR expression levels and Fc-mediated MoA was confirmed in an independent panel of human tumor cell lines carrying diverse genetic alterations. Furthermore, RNA interference-induced knockdown experiments reinforced the impact of EGFR expression on tumor cell killing by EGFR mAb. In conclusion, these results suggest that EGFR expression levels may determine distinct patterns of MoAs that contribute to the therapeutic efficacy of EGFR mAb.

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“…It is likely that the above-described mechanism of cetuximab action is insufficient for efficient EGFR targeting due to the plasticity/promiscuity of the receptor. More effective EGFR targeting strategies are in clinical development, including mixtures of anti-EGFR antibodies that induce EGFR degradation and secondary effector enhanced antibodies (29)(30)(31)(32)(33). Whether or not these will turn out to be superior to cetuximab remains to be seen.…”

Section: Introductionmentioning

confidence: 99%

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Kjær

Lindsted

Fröhlich

et al. 2016

Molecular Cancer Therapeutics

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Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo. Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro. To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. Ó2016 AACR.

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Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors

Cited by 73 publications

References 28 publications

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

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