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Abstract
Grant Number: 1R43CA130378-01 Project Title: Improving the pharmacokinetics of a new protein-based Pan-HER antagonist.
PI Information: Name Title MONTICELLO, DANIEL J. dmonticello@molecularlogix.com PRESIDENT Abstract: DESCRIPTION (provided by applicant): We have developed a "Pan-HER" dominant negative ligand that blocks activation of HER1, HER3 and HER4. The objective of this project is to determine the feasibility of significantly extending the serum half-life of the "Pan-HER DNL" via PEGylation while retaining the antagonist properties of the molecule. Over the last three years we developed a new therapeutic protein that targets the HER Axis. It is a "dominant negative" variant of Epidermal Growth Factor (EGF). It binds to HER1 (EGFR) and blocks access of the authentic HER1 ligands such as EGF and transforming growth factor (TGF-alpha ), but does not stimulate signal transduction. Since so many other drugs have recently been approved that target individual members of the HER family, we expanded the scope of our efforts and engineered into the protein the properties of several HER ligands, created a protein that binds HER1, HER3 and HER4 - all the receptors in this family that are ligand-activated. This new Pan-HER Dominant Negative Ligand (Pan- HER DNL) represents a new avenue of attack on the HER axis and has the potential to complement or replace the existing therapeutics. However, the Pan-HER DNL lacks one important property that would significantly increase its utility as a drug - extended serum half-life. The Pan-HER DNL is the same size as EGF, and can be expected to have roughly the same pharmacokinetic properties. The serum half-life of EGF is about 10 minutes. In order to be considered for significant oncology applications, a half-life of 5-7 days is desirable. This has been achieved with other protein therapeutics through conjugation of the protein to a larger, metabolically stable molecule. The most success has been achieved with polyethylene glycol (PEG). Our plan is to engineer variant Pan-HER Dominant Negative Ligands with only a single lysine. This will allow monoPEGylation at the remaining lysine, further disrupting binding to the desired region of the receptor. We will evaluate their binding properties and antagonist properties (in vitro) and their serum half-lives in mice. This will allow us to address the central question: can you introduce a large PEG molecule (bigger than 30kd to avoid kidney filtration) to this small protein (53 amino acids), retain binding (and clinically relevant biological activity) through the remaining binding interaction, and the Pan-HER phenotype? The objective of this project is to determine the feasibility of significantly extending the serum half-life of dominant negative variants of epidermal growth factor while retaining their antagonist properties. These new "Pan-HER" Dominant Negative Ligands (Pan-HER DNL) represent a new avenue of attack on the HER axis and have the potential to complement or replace the existing therapeutics. We will engineer variant ligands with only a single lysine, PEGylate them and measure receptor binding and antagonism, and serum stability in a mouse model.
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Institution: MOLECULAR LOGIX, INC. Suite 120 THE WOODLANDS, TX 77381 Fiscal Year: 2007 Department: Project Start: 10-SEP-2007 Project End: 09-MAR-2008 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1