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

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

doi:10.1158/1535-7163.mct-16-0474

Cited by 35 publications

(22 citation statements)

References 35 publications

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“…Similar findings have been reported in other solid cancers in e.g., breast [51], bladder [52,53], colon [54,55], and esophagus [56,57]. Based on these findings, there is a strong interest in studying C4.4A in various pathological conditions and new experimental tools are being developed to accomplish this-such as C4.4A-deficient mouse models [53] and antibody drug conjugates targeting C4.4A [58]. With this study, we seek to gain structural insights into how the LU-domains in C4.4A are organized and how C4.4A recognizes ligand.…”

Section: Ivyspring International Publishersupporting

confidence: 78%

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

et al. 2020

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Ly6/uPAR/α-neurotoxin domain (LU-domain) is characterized by the presence of 4-5 disulfide bonds and three flexible loops that extend from a core stacked by several conversed disulfide bonds (thus also named three-fingered protein domain). This highly structurally stable protein domain is typically a protein-binder at extracellular space. Most LU proteins contain only single LU-domain as represented by Ly6 proteins in immunology and α-neurotoxins in snake venom. For Ly6 proteins, many are expressed in specific cell lineages and in differentiation stages, and are used as markers. In this study, we report the crystal structures of the two LU-domains of human C4.4A alone and its complex with a Fab fragment of a monoclonal anti-C4.4A antibody. Interestingly, both structures showed that C4.4A forms a very compact globule with two LU-domain packed face to face. This is in contrast to the flexible nature of most LU-domain-containing proteins in mammals. The Fab combining site of C4.4A involves both LU-domains, and appears to be the binding site for AGR2, a reported ligand of C4.4A. This work reports the first structure that contain two LU-domains and provides insights on how LU-domains fold into a compact protein and interacts with ligands.

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Section: Ivyspring International Publishersupporting

confidence: 78%

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

et al. 2020

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“…Anetumab ravtansine showed high potency in the tested cell lines, indicated by IC 50 values in the nanomolar range. In line with in vitro data published for other ADCs [ 39 ], no linear correlation between the in vitro potency and surface mesothelin levels (determined by flow cytometry) could be established (Table 1 ).…”

Section: Resultssupporting

confidence: 60%

Anetumab ravtansine inhibits tumor growth and shows additive effect in combination with targeted agents and chemotherapy in mesothelin-expressing human ovarian cancer models

et al. 2018

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Despite the recent advances in the treatment of ovarian cancer, it remains an area of high unmet medical need. Epithelial ovarian cancer is associated with high levels of mesothelin expression, and therefore, mesothelin is an attractive candidate target for the treatment of this disease. Herein, we investigated the antitumor efficacy of the mesothelin-targeting antibody-drug conjugate (ADC) anetumab ravtansine as a novel treatment option for ovarian cancer in monotherapy and in combination with the antitumor agents pegylated liposomal doxorubicin (PLD), carboplatin, copanlisib and bevacizumab. Anetumab ravtansine showed potent antitumor activity as a monotherapy in ovarian cancer models with high mesothelin expression. No activity was seen in mesothelin-negative models. The combination of anetumab ravtansine with PLD showed additive anti-proliferative activity in vitro, which translated into improved therapeutic in vivo efficacy in ovarian cancer cell line- and patient-derived xenograft (PDX) models compared to either agents as a monotherapy. The combination of anetumab ravtansine with the PI3Kα/δ inhibitor copanlisib was additive in the OVCAR-3 and OVCAR-8 cell lines in vitro, showing increased apoptosis in response to the combination treatment. In vivo, the combination of anetumab ravtansine with copanlisib resulted in more potent antitumor activity than either of the treatments alone. Likewise, the combination of anetumab ravtansine with carboplatin or bevacizumab showed improved in vivo efficacy in the ST081 and OVCAR-3 models, respectively. All combinations were well-tolerated. Taken together, these data support the development of anetumab ravtansine for ovarian cancer treatment and highlight its suitability for combination therapy with PLD, carboplatin, copanlisib, or bevacizumab.

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“…Ly6/PLAUR domain-containing protein3 (LYPD3) has been identified in non-small cell lung cancer, colorectal and breast cancer. It seems to be involved in cell migration, invasion and tumor progression [20][21][22]. LYPD3 protein deserves special attention because it occurred in all the serous OC samples in our study.…”

Section: Hydrolase (Pc00121) 13mentioning

confidence: 72%

Proteomic pattern of cervico-vaginal fluid (CVF) in an ovarian cancer diagnosis — pilot study

et al. 2018

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Objectives: High grade serous ovarian cancer (HGSC) is the most common type of ovarian cancer and is responsible for about 90% of ovarian cancer deaths. The diagnostic tests currently used do not increase the detection rates for ovarian cancer. There is a great necessity to develop new and non-invasive diagnostic tests for ovarian cancer (OC). Cervico-vaginal fluid (CVF) seems to be a potential and valuable source of biomarkers for genital tract diseases including ovarian cancer. The aim of our pilot study was to undertake a preliminary proteomic analysis of CVF derived from ovarian cancer patients and to compare these with results from a control group. Material and methods: We analysed and compared samples from a group of ovarian cancer patients and a control group of healthy patients. The study used MALDI-TOF coupled with nanoLC and ClinProTools software for MS, MS/MS spectra collection and proteomic analysis. results: We identified 404 different proteins in the OC group and 417 proteins in the control group. 239 of the proteins were found to be common to both study groups, 165 proteins were unique to the OC subjects, and 178 proteins were unique to the control subjects. We selected three proteins as the OC markers with the greatest potential: cysteine-rich secretory protein 3, fibronectin and Ly6/PLAUR domain-containing protein 3. Conclusions: The proteins we selected seem to possess great potential as markers for the screening and early detection of OC, especially in non-invasive and low-cost diagnostic tests. However, our findings require more advanced and validated proteomic analysis to confirm the suitability of the selected proteins in everyday medical diagnoses.

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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 metastasisassociated 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

Cited by 35 publications

References 35 publications

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

Anetumab ravtansine inhibits tumor growth and shows additive effect in combination with targeted agents and chemotherapy in mesothelin-expressing human ovarian cancer models

Proteomic pattern of cervico-vaginal fluid (CVF) in an ovarian cancer diagnosis — pilot study

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