PMID- 34876673
OWN - NLM
STAT- MEDLINE
DCOM- 20220310
LR  - 20221208
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 126
IP  - 5
DP  - 2022 Mar
TI  - Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab 
      ravtansine.
PG  - 754-763
LID - 10.1038/s41416-021-01658-6 [doi]
AB  - BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of 
      thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic 
      carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a 
      surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and 
      megakaryocyte potentiating factor (MPF), is expressed in limited tissues. 
      However, its expression is present in various cancers, including thymic 
      carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow 
      cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order 
      to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) 
      anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: 
      Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody 
      moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and 
      internalising. ARav was effective at inhibiting the growth of thymic carcinoma 
      cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited 
      T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg 
      cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: 
      These data demonstrate that anetumab ravtansine inhibits the growth of MSLN 
      positive thymic carcinoma cells in vitro and in vivo.
CI  - (c) 2021. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Chen, Vincent
AU  - Chen V
AD  - Georgetown University Medical Center, Washington, DC, USA.
AD  - Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
FAU - Umemura, Shigeki
AU  - Umemura S
AD  - Georgetown University Medical Center, Washington, DC, USA.
FAU - Han, Yumin
AU  - Han Y
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
FAU - Raman, Renuka
AU  - Raman R
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
FAU - Tucker, Robin
AU  - Tucker R
AD  - Georgetown University Medical Center, Washington, DC, USA.
FAU - Chahine, Joeffrey
AU  - Chahine J
AD  - Georgetown University Medical Center, Washington, DC, USA.
FAU - Kim, In-Kyu
AU  - Kim IK
AD  - Georgetown University Medical Center, Washington, DC, USA.
FAU - Schatz, Christoph
AU  - Schatz C
AD  - Bayer AG, Pharmaceuticals, Berlin, Germany.
FAU - Zitzmann-Kolbe, Sabine
AU  - Zitzmann-Kolbe S
AD  - Bayer AG, Pharmaceuticals, Berlin, Germany.
FAU - Sommer, Anette
AU  - Sommer A
AD  - Bayer AG, Pharmaceuticals, Berlin, Germany.
AD  - Pfizer Worldwide Research, Development, and Medicine, Berlin, Germany.
FAU - Onda, Masanori
AU  - Onda M
AD  - National Cancer Institute, Bethesda, MD, USA.
FAU - Lee, Trevor
AU  - Lee T
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
FAU - He, Yongfeng
AU  - He Y
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
FAU - Giaccone, Giuseppe
AU  - Giaccone G
AUID- ORCID: 0000-0002-7392-1965
AD  - Georgetown University Medical Center, Washington, DC, USA. 
      gig4001@med.cornell.edu.
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. 
      gig4001@med.cornell.edu.
LA  - eng
GR  - P30 CA051008/CA/NCI NIH HHS/United States
GR  - P30CA051008/DH | NIHR | Programme Development Grants (NIHR Programme Development 
      Grants)/
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211207
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Immunoconjugates)
RN  - 0 (MSLN protein, human)
RN  - 14083FR882 (Maytansine)
RN  - J27WDC343N (Mesothelin)
RN  - M170940PMI (anetumab ravtansine)
RN  - Q20Q21Q62J (Cisplatin)
RN  - Thymic epithelial tumor
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cisplatin/administration & dosage/pharmacology
MH  - Drug Synergism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - HT29 Cells
MH  - Humans
MH  - Immunoconjugates/*administration & dosage/pharmacology
MH  - Maytansine/administration & dosage/*analogs & derivatives/pharmacology
MH  - Mesothelin/*genetics/*metabolism
MH  - Mice
MH  - Neoplasms, Glandular and Epithelial/*drug therapy/genetics/metabolism
MH  - Thymoma/*drug therapy/genetics/metabolism
MH  - Thymus Neoplasms/*drug therapy/genetics/metabolism
MH  - Up-Regulation/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC8888701
COIS- Anette Sommer, PhD is a shareholder of Bayer AG. Christoph Schatz, PhD is a 
      shareholder of Bayer AG. All other authors declare no conflicts of interests.
EDAT- 2021/12/09 06:00
MHDA- 2022/03/11 06:00
PMCR- 2022/12/07
CRDT- 2021/12/08 06:23
PHST- 2021/04/14 00:00 [received]
PHST- 2021/11/24 00:00 [accepted]
PHST- 2021/10/30 00:00 [revised]
PHST- 2021/12/09 06:00 [pubmed]
PHST- 2022/03/11 06:00 [medline]
PHST- 2021/12/08 06:23 [entrez]
PHST- 2022/12/07 00:00 [pmc-release]
AID - 10.1038/s41416-021-01658-6 [pii]
AID - 1658 [pii]
AID - 10.1038/s41416-021-01658-6 [doi]
PST - ppublish
SO  - Br J Cancer. 2022 Mar;126(5):754-763. doi: 10.1038/s41416-021-01658-6. Epub 2021 
      Dec 7.