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.

Autor:	Willuda J; Bayer AG, Berlin, Germany., Linden L; Bayer AG, Wuppertal, Germany., Lerchen HG; Bayer AG, Wuppertal, Germany., Kopitz C; Bayer AG, Berlin, Germany., Stelte-Ludwig B; Bayer AG, Wuppertal, Germany., Pena C; Bayer LLC, Whippany, New Jersey., Lange C; Bayer AG, Berlin, Germany., Golfier S; Bayer AG, Berlin, Germany., Kneip C; Bayer AG, Berlin, Germany., Carrigan PE; Bayer AG, Berlin, Germany., Mclean K; Bayer LLC, Mission Bay, San Francisco, California., Schuhmacher J; Bayer AG, Wuppertal, Germany., von Ahsen O; Bayer AG, Berlin, Germany., Müller J; Bayer AG, Berlin, Germany. Joerg.Willuda@bayer.com., Dittmer F; Bayer AG, Wuppertal, Germany., Beier R; Bayer AG, Berlin, Germany., El Sheikh S; Bayer AG, Wuppertal, Germany., Tebbe J; Bayer AG, Wuppertal, Germany., Leder G; Bayer AG, Berlin, Germany., Apeler H; Bayer AG, Wuppertal, Germany., Jautelat R; Bayer AG, Wuppertal, Germany., Ziegelbauer K; Bayer AG, Wuppertal, Germany., Kreft B; Bayer AG, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2017 May; Vol. 16 (5), pp. 893-904. Date of Electronic Publication: 2017 Mar 14.
DOI:	10.1158/1535-7163.MCT-16-0474
Abstrakt:	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 with in vivo efficacy, 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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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