AMC303 - Mode of Action
CD44v6, an isoform of the CD44 family of adhesion molecules, is an essential co-receptor to the receptor tyrosine kinases c-Met, VEGFR-2, and RON, which are relevant and essential in promoting tumor growth, angiogenesis, and the development and growth of metastases. CD44v6 is often highly expressed in epithelial tumors and high expression levels typically correlate with a poor prognosis.
Our first-in-class drug candidate AMC303 is a cyclic peptide with high nanomolar affinity and specificity for CD44v6. By binding to CD44v6, AMC303 inhibits the three receptor tyrosine kinases c-Met, VEGFR-2, and RON and suppresses cellular functions relevant to tumorigenesis, such as cell migration and invasion, angiogenesis and vascular permeability, epithelial to mesenchymal transition as well as immune system modulation.
Currently available treatment options address only the receptor tyrosine kinases or their activating ligands. Our first-in-class inhibitor AMC303 has a different mode of action: Blocking the signaling of receptor tyrosine kinases and modulation of the tumor microenvironment.
Along with a comprehensive biomarker program, amcure has started a two part Phase I/Ib trial for AMC303 in October 2016. The trial, conducted in Belgium and Spain, is designed to assess the safety, tolerability and pharmacokinetics of multiple and increasing doses of AMC303 as monotherapy in patients with advanced metastatic malignant solid tumors of epithelial origin. In the first part, the dose escalation, the study design included a broad variety of tumor types irrespective of the target expression. In the second part, the expansion cohort, amcure focuses its patient selection on patients with a moderate to high expression of the target molecule CD44v6 in four specific tumor types of squamous tumors. The first part of the clinical study, the dose escalation study, has already been successfully completed and confirmed the safety and tolerability of AMC303.
Phase I/Ib - Part 1 (completed)
The dose escalation study with a 3+3 design investigated safety, tolerability and pharmacokinetics of AMC303 at a dose of 0.1-20 mg/kg twice weekly. The all-comer study included a broad variety of tumor types irrespective of the target expression.
No drug-related serious adverse events were reported from the 27 patients in the dose escalation study. The most frequent adverse events were of grade 1 and 2 and could be well managed in the clinic.
Phase I/Ib - Part 2 (ongoing)
Since AMC303 was proven to be safe and well tolerated up to 20 mg/kg, Phase Ib of the clinical trial was initiated with the recommended dose of 10 mg/kg (RP2D). The four tumor types with the highest CD44v6 expression, head and neck squamous cell carcinoma (HNSCC), esophageal and cervical carcinoma, and non-small-cell lung carcinoma (NSCLC) were chosen for this study. The ongoing expansion cohort will enroll up to 28 patients, 7 per indication, with confirmed expression of CD44v6. Tumors will be assessed (RECIST) every 8 weeks and mandatory paired biopsies will be performed in 60% of the patients.
For more information on the trial design, please visit:
Posters & Publications
AACR 2018: The allosteric inhibitor of CD44v6 AMC303 blocks c-MET, RON and VEGFR-2 dependent signaling and cellular processes
Oliver Coutelle, Martin Augsten et al.
AACR 2017: Allosteric inhibition of the Receptor Tyrosine Kinases c-MET, RON and VEGFR-2 via the co-receptor CD44v6 by the novel compound AMC303
Vanessa Al-Rawi, Thorsten Läufer et al.
Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling.
Matzke-Ogi A, Jannasch K, Shatirishvili M, Fuchs B, Chiblak S, Morton J, Tawk B, Lindner T, Sansom O, Alves F, Warth A, Schwager C, Mier W, Kleeff J, Ponta H, Abdollahi A, Orian-Rousseau V., Gastroenterology. 2016 Feb;150(2):513-25. Epub 2015 Oct 24.
CD44, a therapeutic target for metastasising tumours.
Orian-Rousseau V., Eur J Cancer. 2010 May;46(7):1271-7. Epub 2010 Mar 19. Review. READ MORE
A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis.
Tremmel M, Matzke A, Albrecht I, Laib AM, Olaku V, Ballmer-Hofer K, Christofori G, Héroult M, Augustin HG, Ponta H, Orian-Rousseau V., Blood. 2009 Dec 10;114(25):5236-44. Epub . READ MORE
CD44 is required for two consecutive steps in HGF/c-Met signaling.
Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H. Genes Dev. 2002 Dec 1;16(23):3074-86. READ MORE
amcure is sponsored by a grant from the German Ministry of Education and Research
Short description: Development of a novel compound for the treatment of metastasizing cancers
Support code: 031B0052