Philippe Stas is CEO at Algonomics, a firm that looks at both sides of the immunogenicity question. “With an ever-increasing number of protein therapeutics reaching the patient, the specific challenges of this class of drugs are under scrutiny,” he states. “A key issue, immunogenicity, is driven by aggregates as well as by the protein sequence.”
On the one hand, the company is exploiting methods to increase the immunogenicity of the HIV GAG protein, in order to develop a more effective vaccine for this disease. According to Stas, Epibase® software allows predictions of immunoreactivity based on the binding of the GAG peptides to the T-cell receptor.
By replacing weakly immunostimulatory amino acid sequences with more reactive ones, it should be possible to build a more effective vaccine. The HLA receptor present on the T-cell has been extensively studied, and accurate 3-D modeling of antigen binding is possible. So far it has not been possible to design an HIV vaccine that provokes both arms of the immune system, the humoral and cell based, so Algonomics’ approach may represent an important step in resolving this puzzle.
The other side of the question is the suppression of the immune response, essential to the engineering of effective protein-based therapeutics. Algonomics has addressed this problem, taking into account regulatory guidelines formulated by the EMEA. At present, no systems are available to characterize human antidrug antibodies at a preclinical level. Animal studies are not always predictive of response in humans, so other methodologies are greatly in demand.
“Protein aggregates are highly problematic, typically leading to a transient immune response with low affinity anti-drug-antibodies,” Stas notes. “But they can contribute to immunogenicity in conjunction with T-cell epitopes, boosting the system toward a T-cell driven memory response.”
While in the final analysis clinical studies are necessary to determine whether the immunogenicity of a protein therapeutic makes it an unsuitable drug, Algonomics hopes to eliminate the worst of the lot before they reach this stage. In vitro studies may require inordinate amounts of protein, so the in silico approach may be a satisfactory alternative. The strategy is to select a protein with the fewest HLA-binding peptides, on the assumption that these would be the least troublesome.
In later stages of investigation, in vitro T-cell activation studies will provide additional information that may result in the elimination of unsuitable drug candidates. This will allow the most parsimonious selection of final candidates for animal and later human trials.