PubMed:26260789 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/26260789","sourcedb":"PubMed","sourceid":"26260789","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/26260789","text":"Impact of Cell-surface Antigen Expression on Target Engagement and Function of an Epidermal Growth Factor Receptor × c-MET Bispecific Antibody.\nThe efficacy of engaging multiple drug targets using bispecific antibodies (BsAbs) is affected by the relative cell-surface protein levels of the respective targets. In this work, the receptor density values were correlated to the in vitro activity of a BsAb (JNJ-61186372) targeting epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET). Simultaneous binding of the BsAb to both receptors was confirmed in vitro. By using controlled Fab-arm exchange, a set of BsAbs targeting EGFR and c-MET was generated to establish an accurate receptor quantitation of a panel of lung and gastric cancer cell lines expressing heterogeneous levels of EGFR and c-MET. EGFR and c-MET receptor density levels were correlated to the respective gene expression levels as well as to the respective receptor phosphorylation inhibition values. We observed a bias in BsAb binding toward the more highly expressed of the two receptors, EGFR or c-MET, which resulted in the enhanced in vitro potency of JNJ-61186372 against the less highly expressed target. On the basis of these observations, we propose an avidity model of how JNJ-61186372 engages EGFR and c-MET with potentially broad implications for bispecific drug efficacy and design.","tracks":[{"project":"sentences","denotations":[{"id":"T1","span":{"begin":0,"end":143},"obj":"Sentence"},{"id":"T2","span":{"begin":144,"end":309},"obj":"Sentence"},{"id":"T3","span":{"begin":310,"end":514},"obj":"Sentence"},{"id":"T4","span":{"begin":515,"end":589},"obj":"Sentence"},{"id":"T5","span":{"begin":590,"end":828},"obj":"Sentence"},{"id":"T6","span":{"begin":829,"end":997},"obj":"Sentence"},{"id":"T7","span":{"begin":998,"end":1208},"obj":"Sentence"},{"id":"T8","span":{"begin":1209,"end":1392},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"T1","pred":"source","obj":"sentences"},{"subj":"T2","pred":"source","obj":"sentences"},{"subj":"T3","pred":"source","obj":"sentences"},{"subj":"T4","pred":"source","obj":"sentences"},{"subj":"T5","pred":"source","obj":"sentences"},{"subj":"T6","pred":"source","obj":"sentences"},{"subj":"T7","pred":"source","obj":"sentences"},{"subj":"T8","pred":"source","obj":"sentences"}]},{"project":"Glycosmos6-MAT","denotations":[{"id":"T1","span":{"begin":743,"end":747},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"}],"attributes":[{"subj":"T1","pred":"source","obj":"Glycosmos6-MAT"}]},{"project":"mondo_disease","denotations":[{"id":"T1","span":{"begin":752,"end":766},"obj":"Disease"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MONDO_0001056"},{"subj":"T1","pred":"source","obj":"mondo_disease"}]},{"project":"HP-phenotype","denotations":[{"id":"T1","span":{"begin":752,"end":766},"obj":"Phenotype"}],"attributes":[{"id":"A1","pred":"hp_id","subj":"T1","obj":"HP:0012126"},{"subj":"T1","pred":"source","obj":"HP-phenotype"}],"namespaces":[{"prefix":"HP","uri":"http://purl.obolibrary.org/obo/HP_"}]},{"project":"Anatomy-UBERON","denotations":[{"id":"T1","span":{"begin":82,"end":98},"obj":"Body_part"},{"id":"T2","span":{"begin":428,"end":444},"obj":"Body_part"},{"id":"T3","span":{"begin":472,"end":482},"obj":"Body_part"},{"id":"T4","span":{"begin":614,"end":617},"obj":"Body_part"},{"id":"T6","span":{"begin":743,"end":747},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/UBERON_0000021"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_0000021"},{"id":"A3","pred":"uberon_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/CL_0000182"},{"id":"A4","pred":"uberon_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/UBERON_0001460"},{"id":"A5","pred":"uberon_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/UBERON_0003822"},{"id":"A6","pred":"uberon_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"subj":"T1","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T2","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T3","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T4","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T6","pred":"source","obj":"Anatomy-UBERON"}]},{"project":"Anatomy-MAT","denotations":[{"id":"T1","span":{"begin":743,"end":747},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"mat_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"subj":"T1","pred":"source","obj":"Anatomy-MAT"}]},{"project":"CL-cell","denotations":[{"id":"T1","span":{"begin":472,"end":482},"obj":"Cell"},{"id":"T2","span":{"begin":760,"end":771},"obj":"Cell"}],"attributes":[{"id":"A1","pred":"cl_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL:0000182"},{"id":"A2","pred":"cl_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/CL:0001064"},{"subj":"T1","pred":"source","obj":"CL-cell"},{"subj":"T2","pred":"source","obj":"CL-cell"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"sentences","color":"#ec93df","default":true},{"id":"Glycosmos6-MAT","color":"#93ecdf"},{"id":"mondo_disease","color":"#ecc493"},{"id":"HP-phenotype","color":"#aa93ec"},{"id":"Anatomy-UBERON","color":"#95ec93"},{"id":"Anatomy-MAT","color":"#ec93af"},{"id":"CL-cell","color":"#93c9ec"}]}]}}