Journalartikel - Wissenschaftlicher Artikel | 2017 | Peer reviewed

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*innen

Willuda, Jörg ; Linden, Lars ; Lerchen, Hans-Georg ; Kopitz, Charlotte ; Stelte-Ludwig, Beatrix ; El Sheikh, Sherif ; Pena, Carol ; Lange, Claudia ; Golfier, Sven ; Kneip, Christoph ; Carrigan, Patricia E. ; Mclean, Kirk ; Schuhmacher, Joachim ; von Ahsen, Oliver ; Müller, Jörg ; Dittmer, Frank ; Beier, Rudolf ; Tebbe, Jan ; Leder, Gabriele ; Apeler, Heiner ; Jautelat, Rolf ; Ziegelbauer, Karl ; Kreft, Bertolt

Zeitschrift

Molecular cancer therapeutics

DOI

10.1158/1535-7163.MCT-16-0474

Weitere Details

Sprache

englisch

Darstellungsform

Text

Band

Ausgabe

Seitenbereich

893 - 904

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.

Zitierstile

Willuda, J., Linden, L., Lerchen, H.-G., Kopitz, C., Stelte-Ludwig, B., El Sheikh, S., … Kreft, B. (2017). 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. Molecular Cancer Therapeutics, 16(5), 893–904. doi:10.1158/1535-7163.MCT-16-0474

In die Zwischenablage kopieren

Willuda, J., Linden, L., Lerchen, H.-G., Kopitz, C., Stelte-Ludwig, B., El Sheikh, S., Pena, C., Lange, C., Golfier, S., Kneip, C., Carrigan, P.E., Mclean, K., Schuhmacher, J., von Ahsen, O., Müller, J., Dittmer, F., Beier, R., Tebbe, J., Leder, G., Apeler, H., Jautelat, R., Ziegelbauer, K. and Kreft, B., 2017. 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. Molecular cancer therapeutics, 16(5), pp.893–904.

In die Zwischenablage kopieren

Willuda, Jörg u. a. 2017. 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. Molecular cancer therapeutics 16, 5, 893–904.

American Psychological Association 6th edition (DOI)

Anglia Ruskin University - Harvard

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