As it works to carve out a place for itself as a provider of RNAi research tools and services, Bioo Scientific also continues to evaluate the therapeutic potential of its delivery technologies and is developing an antibody-based siRNA delivery technology for therapeutic applications.
“We’re not a therapeutic company in the sense that we want to do siRNA therapeutics or microRNA therapeutics,” Lance Ford, vice president of research and development at Bioo Scientific, told RNAi News this week. “But we do want to develop delivery solutions for people” working in that field.
In line with that goal, the company is using a $100,000 National Science Foundation grant to improve a recently launched technology for targeted siRNA delivery that uses antibodies conjugated to protamine, which associates with nucleic acids such as siRNAs, and develop it for possible therapeutic applications.
“Use of siRNA to silence genes of interest has become a very important mechanism to regulate gene expression … in experimental settings, as well as in diseases,” the grant’s abstract states. “One of the current limitations to using siRNA therapy in vivo is the low uptake by the cells. … [Therefore,] methods that improve siRNA uptake by target cells would … be of great benefit to the scientific and medical communities.
“The use of the cellular uptake mechanisms for the delivery of these potent regulatory molecules into cells further opens the possibility of using specific gene-silencing molecules as therapeutic modalities in vivo,” the abstract adds.
In 2005, researchers from the lab of Judy Lieberman reported in Nature Biotechnology the creation of a protamine-antibody fusion protein capable of delivering siRNAs to HIV-infected or envelope-transfected cells.
According to that paper, the fusion protein was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody, and that siRNAs bound to the fusion protein induced silencing only in cells expressing HIV-1 envelope.
“We’re not a therapeutic company in the sense that we want to do siRNA therapeutics or microRNA therapeutics. But we do want to develop delivery solutions for people” working in that field.
Ford noted that Bioo’s approach uses “chemical conjugation as opposed to the fusion proteins,” as well as “proprietary methods of chemical conjugation that have been optimized to obtain more positively charged proteins per antibody molecule.
“This, along with the larger size in the positively charged protein [that] binds to a greater number of siRNA molecules per antibody, allows for a commercial process which is scalable and can be used with any antibody and siRNA of choice,” he added. He declined to provide additional details, citing the proprietary nature of the technology.
As part of its grant project, Bioo is aiming to increase the number of siRNAs that can be attached to the antibody conjugates.
“We’re taking the approach of adding more [siRNAs] per antibody using a chemical conjugation approach, as well as using … protein molecules [other than protamine] that can bind to nucleic acids bound to the antibody,” he said, adding that Bioo currently can link around five siRNAs to an antibody, he noted.
Additionally, Bioo is working to improve its ability to directly link the oligos to antibodies, Ford noted.
Although Bioo received the grant at the beginning of the year, the company has already introduced four antibody-protamine conjugates for siRNA delivery under a product line termed MaxSuppressor.
The first is a CD4 antibody-protamine conjugate, which the company said is appropriate for delivering siRNAs to T helper cells, regulatory T cells, monocytes, macrophages, and dendritic cells — all of which express the glycoprotein on their surfaces.
The company has also introduced an antibody-protamine conjugate for Her2, a member of epidermal growth factor receptor family that is highly expressed in multiple tumor types include breast, head and neck, bladder, and non-small cell lung cancers.
Other MaxSuppressor antibody conjugates recently launched are ones for CD33, which Bioo said is expressed by monocytic/myeloid lineage cells including most acute myloid leukemias, and vascular endothelial growth factor receptor-2, which is involved in mediating endothelial cell proliferation, survival, and permeability of vasculature.
Ford said that Bioo hopes to expand the number of pre-made conjugates it offers over the coming year as it grows its antibody portfolio from around 50 to an expected 500. “We will pick and choose from that list which ones we want to [include in the portfolio of pre-made] protamine conjugations,” but a final decision will be based on customer interest, he said.