The potential for protein therapeutics to produce harmful immune responses that inactivate the protein’s therapeutic effect has been a long standing barrier to the development and acceptance of protein drugs. Even naturally occurring human proteins can be immunogenic, and neutralizing antibodies have been observed against a variety of biotherapeutics. Even though the immunogenicity of most protein therapeutics is manageable in the clinic, today’s heightened scrutiny of drug safety requires proactive consideration of immunogenicity risk early in development. Immunogenicity can both reduce the efficacy of a therapeutic and cause severe immune reactions.
Xencor developed ImmunoPDA technology to target all the steps required to raise an immune response, including solution stability, immune system recognition and delivery route. Our ImmunoPDA technology is the only comprehensive approach that simultaneously addresses all of these challenges. ImmunoPDA:
- Improves protein stability and solubility to minimize aggregation, thereby reducing initial uptake of protein by the immune system.
- Identifies and removes recognition sequences (e.g., MHC Class II T cell epitopes) while maintaining structure and function, enabling proteins to evade the molecular basis of cellular immunity.
- Incorporates specific PEGylation or glycosylation sites, thereby optimizing pharmacokinetics, enhancing solution properties, and masking immune recognition sites.
ImmunoPDA integrates immunogenicity detection using our ImmunoFilter™ database with in vitro testing of potential immunogenic protein segments to determine the most likely sites of immunogenicity in a protein. These potentially immunogenic sequences are then designed out of the protein while still maintaining protein function using PDA® technology. This integration of protein design and immunogenicity detection makes ImmunoPDA technology the single most comprehensive approach to addressing protein immunogenicity challenges. We have been applying ImmunoPDA technology to avoid immunogenicty in our own therapeutic candidates including our XPro® protein therapeutics and our XmAb® antibody therapeutics. Eli Lilly and Centocor have licensed elements of ImmunoPDA technology for use in their discovery programs.