Biologics are a growing area of drug development, including life-threatening and life-changing disorders such as cancer and rheumatoid arthritis. However, many biologics have short half-lives, and need to be dosed daily. To make them more convenient to use, as well as safer and more effective, researchers are developing delivery systems that keep the biologics in the body for longer, reducing the frequency of dosing. Swedish company Affibody is using the natural affinity of a naturally-occurring protein, albumin, to extend the half-life of biologics, and improve its distribution around the body.
ASSOCIATING WITH ALBUMIN
Albumin is the main protein found in the blood and has a half-life of 17-19 days. Moving freely between the blood vessels and tissues, its role is to balance the levels of fluid. Affibody’s Albumod™ technology is based on a 5 kDa small albumin-binding domain (ABD).
In animal studies, fusion proteins created from ABD and monoclonal antibodies have a similar half-life to albumin alone, and up to 10-fold longer than the original biologicals, which should mean that treatments based on the Albumod technology may need dosing less often, potentially improving adherence. Because the fusion protein travels quickly from the blood to the tissues, and is preferentially taken up into the cancer cells, the right dose gets to the right place – the cancer – without accumulating in the healthy tissues. This should mean better efficacy and lower side effects. The researchers have seen no increase in immunogenicity in animals, with no antibodies appearing even after long-term or repeated doses.
SOLVING THE IMMUNOGENICITY ISSUE TO CREATE A LEAD
The T-cell epitopes of the wild-type form of ABD, a naturally occurring bactericidal protein, trigger an immune response. To create a product that could be tested in the clinic, Affibody needed to develop a version of ABD that had no significant immunogenicity.
Using an in silico mapping and mutation program, the researchers reduced the number of B- and T-cell epitopes, finally selecting 133 ABD sequences for further in silico analysis and validation by Algonomics/Lonza. This process resulted in the selection of three leads, ABD088, ABD094, and ABD095 based on in silico scoring, affinity, Tm, and solubility.
In the next step, the three molecules and the wild type ABD moved from in silico to in vitro screening. In a CD4+ T cell proliferation assay on peripheral blood mononuclear cells (PBMCs) from Caucasian donors, only the wild type triggered a T-cell response. ABD094 showed no significant immunogenicity, so Affibody selected this as a lead candidate.
Affibody has signed agreements with Daewoong Pharmaceutical and Daiichi Sankyo to use the Albumod platform to extend the half-life of undisclosed biologics.