Bolder BioTechnology received a Phase I SBIR grant totaling $600,000 from the NIAID to conduct research in acute radiation syndrome (ARS) treatment. The firm will attempt to demonstrate the feasibility of using its long-acting IL-11 analog to accelerate platelet recovery and improve survival in a mouse model of ARS. Receipt of the entire grant award is contingent upon the achievement of certain research milestones.
Bone marrow is one of the most sensitive tissues to radiation damage. Impaired production of blood cells is one of the first clinical signs of excessive radiation exposure, often resulting in death. IL-11 is a protein that stimulates bone marrow cells to divide and differentiate into platelets.
Recent studies indicate that IL-11 can mitigate some of the hematopoietic and gastrointestinal complications of radiation exposure and improve survival in animal models of ARS, according to Bolder. IL-11 has a short half-life in humans, which necessitates daily dosing, and may not optimize therapeutic benefits of the protein for patients. A long-acting IL-11 analog that does not require frequent dosing could provide significant treatment advantages in a nuclear emergency setting.
Bolder BioTechnology has a site-specific PEGylated IL-11 analog, BBT-045, which is being developed to reverse thrombocytopenia, a frequent side-effect of chemotherapy in cancer patients. It reportedly stimulates platelet formation for up to a week following a single injection in rodents.
The company uses polyethylene glycol (PEG) for covalent modification of proteins to extend the circulating half-lives of proteins like IL-11. The most commonly employed method for PEGylating proteins uses compounds that attach PEG to free amines, Bolder notes. A critical limitation of this approach is that proteins typically contain several lysines, resulting in a heterogeneous product mixture consisting of mono-, di-, tri-, etc., PEGylated species modified at different lysine residues and the N-terminus, the firm explains. The different PEGylated species often possess different intrinsic biological activities.
Bolder BioTechnology says that its site-specific PEGylation technique overcomes the problems of product heterogeneity and loss of biological activity. It allows a protein to be selectively modified with PEG at a single, unique, predetermined site, the company remarks. It is thus possible to create PEGylated proteins that are homogeneously modified and have no significant loss of biological activity.
Site-specific PEGylation is achieved by introducing a free cysteine residue, i.e., a cysteine residue not involved in a disulfide bond, into a target protein using site-directed mutagenesis. The free cysteine residue serves as the attachment point for covalent modification of the protein with a cysteine-reactive PEG molecule. Attachment of the PEG molecule to the free cysteine residue is highly specific because most native cysteine residues in proteins participate in disulfide bonds and are not available for PEGylation using cysteine-reactive PEGs.