GOALS
The goal of the project is to develop a cancer drug candidate based on recombinant FGF2 protein, fused with two distinct cytotoxins which work together to kill cancer cells using two different mechanism. The targeted therapy will be aimed at tumors expressing the FGF receptor 1, present in multiple types of cancer. Drug candidate, proven to exhibit anti-cancer effect in animal models, will be ready for preclinical development at the end of the project, including a pre-GMP documentation package regarding its production in a bacterial system.
DESCRIPTION
Effective cancer therapy is the most important goal in oncology. The progress in antibody drug conjugates encouraged us to verify here if attachment of two different cytotoxins to a targeting protein will lead to a more efficient conjugate. The project stems from findings that fibroblast growth factor 2 (FGF2) can replace antibody as a targeting protein. FGF2 conjugated with monomethyl auristatin E (MMAE) can be internalized and destroy cancer cells expressing FGF receptor 1. We will produce FGF2 conjugates containing two extremely cytotoxic warheads: MMAE and 𝛼-amanitin (AMN). Simultaneous application of two drugs is an alternative for conventional combination therapy. MMAE blocks microtubule formation and AMN is RNA polymerase II and III inhibitor. Both warheads should act in concert in a single cancer cell. Further, MMAE can be secreted from cancer cell and via so-called bystander effect destroy neighboring cells and AMN shows outstanding activity in cells expressing multi-drug resistant transporters. The approach is highly original and addresses trends in anti-cancer drug development: specific delivery, high level of drug loading combined with defined stoichiometry and overall homogeneity of conjugate. Most impatiently our proposed targeted strategy will have not only the potential to efficiently kill tumor cells reducing the side effects on healthy cells, but also to limit their ability to develop resistance.
PURE BIOLOGICS ROLE
Pure Biologics will be involved in Work Package 5 of the project, comprising scale-up of FGF2 conjugate preparation, both at the stage of recombinant protein production and chemical conjugation to cytotoxic drugs.
CURRENT STAGE
So far, mutant FGF2 proteins have been designed and produced, and various cytotoxic payloads, such as MMAE, have been attached to them. The conjugates are being analysed in vitro, as well as pending preparations for in vivo mice study for anti-cancer efficacy by the Norwegian partners.
PROJECT DATA SHEET
Title: Novel targeted therapy based on dual warhead conjugates against FGFR-dependent cancer
Program: Programme ‘Applied Research’ under the POLNOR 2019 call of EEA and Norway Grants. Fundusze Norweskie i Fundusze Europejskiego Obszaru Gospodarczego (EOG).
Project value: 157.550 PLN (the entire consortium: 6,571,292 PLN)
Contribution of European Funds: PLN 94.530 PLN (the entire consortium: 6,508,272.00 PLN)
Start: 1st October 2021
End: 31st March 2023
Consortium members: University of Wrocław (Poland), Oslo University Hospital (Norway), Pure Biologics S.A.(Poland)
