Rationally engineered proteins or antibodies with absent or reduced immunogenicity.

ABSTRACT

One challenge associated with the clinical use of protein therapeutics destined for chronic administration is the potential for the development of unwanted anti-drug immune reactions. The molecular basis for this reactivity is the binding of peptide fragments (epitopes) derived from the breakdown of the protein drug to the HLA receptors expressed by the patient's immune cells. If these epitopes are recognized as "foreign" by the immune system, specific helper T lymphocytes (HTL), are activated, which initiate and direct the formation of antibodies against the protein drug. These antibodies can bind and neutralize the protein drug, resulting in either decreased efficacy or total ineffectiveness of the drug. Moreover, various safety concerns, such as allergic reactions and other adverse events, are also frequently associated with the formation of anti-drug antibodies. Herein, we describe the development of "ImmunoStealth", an integrated bioinformatics, biochemical and cellular immunology approach that specifically addresses the issue of unwanted immune responses against protein therapeutics. Unwanted HTL epitopes are identified using in silico sequence analysis methods and high throughput in vitro biochemical evaluations and thereafter confirmed using cellular immunogenicity assays. The "offending" epitopes within the drug are then rationally modified to alter their HLA binding capacity, and thus render them non-recognizable by the immune system. This technology will ultimately facilitate the design of safer, more potent and more economical drugs.