RE: The conference29 Mar 2022 08:43
Presenter/Authors
Fiona McLaughlin, Sarah E. Poplawski, David G. Sanford, Andrew Saunders, Jack H. Lai, Matthew Vincent, William W. Bachovchin, Neil Bell. Avacta Life Sciences, London, United Kingdom, Tufts Medical School, Boston, MA, Linden Oncology, London, United Kingdom, Avacta Life Sciences, Boston, MA
Disclosures
F. McLaughlin, None.
S. E. Poplawski,
Bach Biosciences Other, Employment compensation, Yes.
D. G. Sanford,
Bach Biosciences Employment compensation, Yes.
A. Saunders, None.
J. H. Lai,
Bach Bioscience Other Intellectual Property, Other, Employment compensation, Yes.
M. Vincent, None.
W. W. Bachovchin,
Bach Biosciences Employment, Other Business Ownership, Other Intellectual Property, Yes.
Avacta Stock Option, Grant/Contract, Other Intellectual Property, Yes.
Point BioPharma Stock Option, Grant/Contract, Other Intellectual Property, No.
N. Bell, None.
Abstract
AVA6000 is a therapeutic product based on proprietary pre|CISION™ technology which incorporates a substrate that is sensitive to cleavage by FAP. The pre|CISION™ substrate can be utilized in a drug conjugate linker or to generate chemotherapy prodrugs that are only activated in the tumor microenvironment. AVA6000 consists of a doxorubicin molecule covalently bonded to a dipeptide (pyridine-4-carbonyl)-D-Ala-L-Pro), which is designed to be susceptible to hydrolysis by Fibroblast Activation Protein a (FAP) but is resistant to hydrolysis by both closely related and wider mammalian peptidases. FAP, a post-prolyl endopeptidase, is overexpressed on the surface of activated fibroblastic cells which are abundant in the supporting stroma of over 90% of malignant epithelial cancers, as well as in bone and soft tissue sarcoma. While FAP is also present both in normal tissues and as a soluble enzyme in plasma, levels are significantly lower than those present in malignant epithelial cancers. Consequently, AVA6000 has the potential to deliver doxorubicin directly to the tumor microenvironment, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. The primary mechanism of action of doxorubicin is thought to involve stabilisation of a topoisomerase-II-DNA cleavable complex through non-specific DNA-intercalation. The non-specific DNA-intercalation causes a number of downstream effects, which may ultimately result in apoptotic cell death. Although doxorubicin has been one of the most effective and widely used chemotherapeutic agents for the treatment of various solid malignancies for over 40 years, its clinical utility is limited by dose-limiting toxicities, including myelosuppression and cardiotoxicity. The unique FAP specificity of the N-(pyridine-4-carbonyl)-D-Ala-L-Pro leaving group conjugated to doxorubicin in AVA6000 is supported by the absence of cleavage of the fluorogenic analogue, 3114-AMC, in FAP gene-knockout mice (Fap-/-).
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