ABOUT THE TARGETS

Cadherins (CDHs; named for “calcium-dependent adhesion”) play an important role in cell–cell interaction, cell sorting (clustering promotion) and cell migration processes. The RGD motifs (Arg-Gly-Asp), which are only present in a reduced subset of the CDH family members, have been shown to interact with α2β1 integrin and activate the integrin pathway in metastatic cancer cells. RGD motifs are present in three relevant cadherins, which are expressed in different tissues and associated with different tumours:

 CDH17: colorectal cancer

CDH5: breast cancer and melanoma

CDH6: ovary, kidney, thyroid cancer

Overexpression of CDH17 correlates with the presence of metastases and poor survival of colorectal cancer patients. Therapeutic Monoclonal Antibodies developed against the RGD-tripeptide motifs of Cadherins showed to be efficacious in in vitro and in vivo models for the treatment of metastatic colorectal, melanoma, renal, ovary or breast cancers.

Interleukin 13 alpha 2 receptor (IL13Rα2) expression in colorectal cancer is associated with late-stage tumors and lower survival of these patients. IL13Rα2 is also overexpressed in a wide variety of human tumor types such as glioblastoma, renal cell carcinoma, pancreatic, melanoma, head and neck, mesothelioma, and ovary. In glioblastoma, IL13Rα2 has been associated with a more aggressive form and a poorer patient prognosis.

Monoclonal antibodies anti-IL13Rα2 showed the ability to effectively compete and inhibit the binding of IL13 ligand to IL13Rα2 receptor.

OUR LEAD CANDIDATE PA-0661

PA-0661, a monoclonal antibody directed against the Cadherin 17-RGD motif (CDH17-RGD), was selected by ProAlt as the first development candidate for the treatment of advanced metastatic Colorectal Cancer (mCRC), concluding the antibody humanization by the end of 2018 and initiating the preliminary pre-clinical studies.

In vitro and in vivo experiments have demonstrated that candidate PA-0661 (murine and humanized versions) significantly inhibits the activation of β1 integrin mediated by the RGD motif of CDH17. As result, cell adhesion, migration and proliferation are repressed, consequently delaying metastasis progression in all treated animals and avoiding metastasis formation in 50% of the treated individuals.

The fully humanized variant hPA-0661 has been generated in collaboration with the Company Fusion Antibodies (UK) in the framework of the Company’s research project named “METABODIES: Development of therapeutic antibodies for the treatment of tumor metastases in various types of cancer”, intended to develop humanized antibodies against the RGD motif of CDH17 and CDH6 and including some non-regulatory preclinical PK/PD/Tox activities. hPA-0661 antibody reproduced the excellent activity of its murine counterpart in the mCRC animal model.

METABODIES Funding Institutions

This project has received funding from the Ministry of Science, Innovation and Universities – State Research Agency, with reference number RTC-2017-6260-1. It is co-funded by the European Regional Development Fund, whose thematic objective is “to promote technological development, innovation and quality research”