Oligomerization improves endostatin as antiangiogenic and anticancer drug
Solving the problem of poor pharmacokinetics by using the Fc domain of IgG being conjugated to endostatin, a component of all monoclonal antibodies approved for patients with a number of diseases including cancer.
Endostatin is an antiangiogenic protein first discovered in Folkman's laboratory at Childrens Hospital, Harvard Medical School, and Boston. The antitumor properties of this protein are well established. However, the amount of protein required for injection in patients was beyond production feasibility due to the poor pharmacokinetics of endostatin monomer.
We have shown that the problem of poor pharmacokinetics can be solved by using the Fc domain of IgG being conjugated to endostatin, a component of all monoclonal antibodies approved for patients with a number of diseases including cancer. As a result of employing Fc-endostatin, the half-life in mice was increased to 2 weeks instead of 2 hours for endostatin alone, consistent with pharmacokinetics of monoclonal antibodies.
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We identified a novel molecule, NC1 rather than monomeric endostatin to be the key physiologic molecule exerting antiangiogenic effects. We further provide rational that synthetic dimerization of endostatin via fcconjugation not only improve its pharmacokinetics and therefore the biologic efficacy but also better mimics the effects of the natural trimeric NC1 as compared to monomeric "conventional" endostatin.
We demonstrated that oligomerization of endostatin as observed in NC1 is important for its binding to a large number of extracellular matrix proteins including Fibronectin and cytokines such as VEGF, which are important ligands for exertion of an antiangiogenic property.
- Endostatin is well known and therefore approved in clinical trials
- Established endostatin has as monomer poor efficacy
- Oligomerization of endostatin improves pharmacokinetics
Established endostatin resulted in poor efficacy in clinical trials. In contrast, oligomerization of endostatin toward the natural fragment of collagen 18 (NC1) can improve both, pharmacokinetic as well as the spectrum of targeting molecules for a broader use of endostatin as antiangiogenic and anticancer drug.