Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate

Phillips, Andrew C.; Boghaert, Erwin R.; Vaidya, Kedar S.; Falls, Hugh D.; Mitten, Michael J.; DeVries, Peter J.; Benatuil, Lorenzo; Hsieh, Chung-Ming; Meulbroek, Jonathan A.; Panchal, Sanjay C.; Buchanan, Fritz G.; Durbin, Kenneth R.; Voorbach, Martin J.; Reuter, David R.; Mudd, Sarah R.; Loberg, Lise I.; Ralston, Sherry L.; Cao, Diana; Gan, Hui; Scott, Andrew M.; Reilly, Edward B.

doi:10.1158/1535-7163.mct-17-0710

Cited by 42 publications

(35 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another strategy is to design an EGFR ADC targeting a conformation epitope that is more frequently presented in EGFR amplified or overexpressed tumors than normal tissues [ 14 - 16 ]. Indeed, early clinical data of this approach indicated the absence of conventional EGFR inhibitors mediated toxicities [ 17 - 19 ]. Others chose to target the unique epitope found in the tumor specific extracellular domain truncation mutant EGFRvIII, which is commonly present in glioblastoma, to totally avoid the wild-type receptors [ 20 - 22 ].…”

Section: Discussionmentioning

confidence: 99%

RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models

Wong

Tran

et al. 2018

Oncotarget

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) is a clinically validated target and often overexpressed in some solid tumors. Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies have been approved for treatment of NSCLC, head and neck cancers and colorectal cancers. However, clinical response is limited and often accompanied by significant toxicities due to normal tissue expression. To improve the effectiveness of targeting EGFR while minimizing the toxicities on normal tissues, we developed a low-affinity anti-EGFR antibody drug conjugate (ADC), RN765C. Potent in vitro cytotoxicity of RN765C, with nanomolar to subnanomolar EC50, was observed on a panel of cancer cell lines expressing moderate to high level of EGFR. In contrast, RN765C was less effective in killing normal human keratinocytes, presumably due to its lower receptor expression. Mechanistically, RN765C has multiple modes of action: inducing payload mediated mitotic arrest and cell death, blocking EGFR pathway signal and mediating antibody dependent cell cytotoxicity. In preclinical studies, a single dose of RN765C at 1.5-3 mg/kg was generally sufficient to induce tumor regression in multiple cell line and patient-derived xenograft models, including those that are resistant to EGFR-directed tyrosine kinase inhibitors. Our data support further investigation of RN765C in the clinic to treat EGFR expressing solid tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models

Wong

Tran

et al. 2018

Oncotarget

View full text Add to dashboard Cite

show abstract

“…The ability of mAb806 ADCs to target a conformational epitope exposed in tumor-specific conditions allows effective tumor targeting without the conventional EGFR inhibitor-mediated toxicities [ 13 ]. MAb806 ADCs were shown to retain affinity to the mAb806 epitope comparable to a nonconjugated antibody, thus ensuring a high tumor uptake [ 15 , 18 ]. This approach was successful in the management of glioblastoma and demonstrated efficacy in a range of treatment refractory-advanced solid tumors with an acceptable toxicity profile [ 19 , 20 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Female NOD scid gamma (NSG) and BALB/c nu / nu mice were obtained from the Bio-Resource Facility at Austin Health, Melbourne, VIC, Australia. All animal studies were approved by the Austin Hospital Animal Ethics Committee, Melbourne, VIC, Australia and were conducted in compliance with the Australian Code for the care and use of animals for scientific purposes and were performed as previously described [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…Depatux-M has shown efficacy in patients with EGFR -amplified recurrent glioblastoma [ 16 , 17 ]. ABBV-221 is comprised of an affinity-matured ABT-806 conjugated to MMAE by a valine-citrulline linker and has a higher affinity for overexpressed EGFR than ABT-414 [ 18 ]. ABBV-221 was evaluated in a phase I clinical trial in patient EGFR-expressing solid tumors [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma

et al. 2020

Self Cite

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate—ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.

show abstract

“…Antibodies that do not impact the normal function of the target could also improve the safety and tolerability of the ADC (6). For example, the anti-EGFR ADCs depatuxizumab mafodotin and ABBV-221 target a tumor-selec-tive EGFR epitope, with low normal tissue binding (9). Furthermore, improvements in antibody technology enable isolation of candidate antibodies with the desired binding affinity, species cross-reactivity, cellular internalization, and biological activity or lack thereof (10).…”

Section: Introductionmentioning

confidence: 99%

Treating Tissue Factor–Positive Cancers with Antibody–Drug Conjugates That Do Not Affect Blood Clotting

Theunissen

Cai

Bhatti

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The primary function of tissue factor (TF) resides in the vasculature as a cofactor of blood clotting; however, multiple solid tumors aberrantly express this transmembrane receptor on the cell surface. Here, we developed anti-TF antibody-drug conjugates (ADC) that did not interfere with the coagulation cascade and benchmarked them against previously developed anti-TF ADCs. After screening an affinity-matured antibody panel of diverse paratopes and affinities, we identified one primary paratope family that did not inhibit conversion of Factor X (FX) to activated Factor X (FXa) and did not affect conversion of prothrombin to thrombin. The rest of the antibody panel and previously developed anti-TF antibodies were found to perturb coagulation to varying degrees. To compare the anticancer activity of coagulation-inert and -inhibitory antibodies as ADCs, a selection of antibodies was conjugated to the prototypic cytotoxic agent monomethyl auristatin E (MMAE) through a protease-cleavable linker. The coagulation-inert and -inhibitory anti-TF ADCs both killed cancer cells effectively. Importantly, the coagulation-inert ADCs were as efficacious as tisotumab vedotin, a clinical stage ADC that affected blood clotting, including in patient-derived xenografts from three solid tumor indications with a need for new therapeutic treatments-squamous cell carcinoma of the head and neck (SCCHN), ovarian, and gastric adenocarcinoma. Furthermore, a subset of the anti-TF antibodies could also be considered for the treatment of other diseases associated with upregulation of membranous TF expression, such as macular degeneration. .

show abstract

Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate

Cited by 42 publications

References 29 publications

RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models

RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models

Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma

Treating Tissue Factor–Positive Cancers with Antibody–Drug Conjugates That Do Not Affect Blood Clotting

Contact Info

Product

Resources

About