Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR

Panousis, Con; Rayzman, Veronika; Johns, Terrance G.; Renner, Christoph; Liu, Zhanqi; Cartwright, Glenn A.; Lee, Fook-Thean; Wang, Deshou; Gan, Hui; Cao, Diana; Kypridis, A.; Smyth, Fiona E; Brechbiel, Martin W.; Burgess, Antony W.; Old, Lloyd J.; Scott, Andrew M.

doi:10.1038/sj.bjc.6602470

Cited by 46 publications

(49 citation statements)

References 46 publications

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“…Extensive preclinical studies have shown that ch806 has identical specificity to mAb 806 and high affinity for the 806 epitope on EGFR (32). Preclinical in vivo studies have also demonstrated similar tumor growth inhibition of xenografts by ch806 compared with mAb 806 (32). These findings collectively indicate that ch806 has one of the most selective patterns of tumor antigen binding yet reported, and with preclinical data showing potent tumor activity ch806 represents an important potential therapeutic in cancer patients.…”

supporting

confidence: 61%

mentioning

confidence: 76%

“…To develop a humanized form of mAb 806 suitable for clinical development, a chimeric form of mAb 806 (ch806) has been produced under cGMP conditions (32). Extensive preclinical studies have shown that ch806 has identical specificity to mAb 806 and high affinity for the 806 epitope on EGFR (32).…”

mentioning

confidence: 99%

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A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Scott

Lee

Tebbutt

et al. 2007

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

201

136

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An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.

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confidence: 61%

mentioning

confidence: 76%

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A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Scott

Lee

Tebbutt

et al. 2007

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

201

136

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“…ABT-806-binding properties and published results with mAb 806 and ch806 suggested that ABT-806 may also be effective against tumor cells overexpressing wild-type EGFR (6,13,16). Because EGFR is frequently overexpressed in squamous tumors, the antitumor efficacy of ABT-806 was compared with cetuximab in the A431 squamous xenograft model that expresses amplified EGFR (22).…”

Section: Abt-806 In Vivo Potency In Squamous Cell Carcinoma Tumor Modmentioning

confidence: 99%

“…The human tumor cell lines A431 (human vulvar squamous carcinoma), U87MG (human glioma), and U87MGde2-7 (engineered from U87MG to overexpress EGFRvIII) utilized in previous published work with mAb806 and ch806 were provided by the Ludwig Institute for Cancer Research (Melbourne, Victoria, Australia) in 2010 (9,13). SCC15 cells, human head and neck squamous cell carcinoma (HNSCC), were acquired from the ATCC in 2002.…”

Section: Cell Culturementioning

confidence: 99%

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Reilly

Phillips

Buchanan

et al. 2015

Molecular Cancer Therapeutics

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Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indiumlabeled version of ABT-806, [ 111 In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIIIexpressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.

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Imaging EGFR and HER2 by PET and SPECT: A Review

Corcoran

Hanson

2013

Medicinal Research Reviews

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In an effort to discover a noninvasive method for predicting which cancer patients will benefit from therapy targeting the EGFR and HER2 proteins, a large body of the research has been conducted toward the development of PET and SPECT imaging agents, which selectively target these receptors. We provide a general overview of the advances made toward imaging EGFR and HER2, detailing the investigation of PET and SPECT imaging agents ranging in size from small molecules to monoclonal antibodies.

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Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR

Cited by 46 publications

References 46 publications

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Imaging EGFR and HER2 by PET and SPECT: A Review

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