title: Preclinical Antitumor Efficacy of BAY 1129980-a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody-Drug Conjugate for the Treatment of Non-Small Cell Lung Cancer.
abstract: C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker.In vitro, C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC.In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated within vivoefficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing.Mol Cancer Ther; 16(5); 893-904. ©2017 AACR.
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Willuda
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Linden
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Lerchen
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kopitz
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Stelte-Ludwig
authors.affiliation: Bayer LLC, Whippany, New Jersey.
authors.forename: Carol
authors.initials: C
authors.lastname: Pena
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lange
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Golfier
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kneip
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Carrigan
authors.affiliation: Bayer LLC, Mission Bay, San Francisco, California.
authors.forename: Kirk
authors.initials: K
authors.lastname: Mclean
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schuhmacher
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Ahsen
authors.affiliation: Bayer AG, Berlin, Germany. Joerg.Willuda@bayer.com.
authors.forename: Jörg
authors.initials: J
authors.lastname: Müller
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dittmer
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Beier
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Sherif
authors.initials: S
authors.lastname: El Sheikh
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Tebbe
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Leder
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Apeler
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jautelat
authors.affiliation: Bayer AG, Wuppertal, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.affiliation: Bayer AG, Berlin, Germany.
authors.forename: Bertolt
authors.initials: B
authors.lastname: Kreft
mesh_terms: D062365:Aminobenzoates / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000276:immunology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000276:immunology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology; D017239:Paclitaxel / Q000008:administration & dosage / Q000276:immunology; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; C115145:C4.4 monoclonal antibody; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; C472589:LYPD3 protein, human; D009842:Oligopeptides; C543533:auristatin; D014747:Vinblastine; D017239:Paclitaxel; D002945:Cisplatin; D000077235:Vinorelbine