title: Therapeutic mechanism and efficacy of the antibody-drug conjugate BAY 79-4620 targeting human carbonic anhydrase 9.
abstract: Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody-drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors.
authors.affiliation: Bayer HealthCare AG, Berlin 13342, Germany. Heike.Petrul@bayer.com
authors.forename: Heike M
authors.initials: HM
authors.lastname: Petrul
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Schatz
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Kopitz
authors.forename: Lila
authors.initials: L
authors.lastname: Adnane
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McCabe
authors.forename: Pamela
authors.initials: P
authors.lastname: Trail
authors.forename: Sha
authors.initials: S
authors.lastname: Ha
authors.forename: Yong S
authors.initials: YS
authors.lastname: Chang
authors.forename: Andrei
authors.initials: A
authors.lastname: Voznesensky
authors.forename: Gerald
authors.initials: G
authors.lastname: Ranges
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tamburini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D016466:CHO Cells; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D019151:Peptide Library; D014018:Tissue Distribution; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C572749:BAY 79-4620; D004791:Enzyme Inhibitors; D007140:Immunoglobulin Fab Fragments; D009842:Oligopeptides; D019151:Peptide Library; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases