Prediction of immunogenicity for humanized and full human therapeutic antibodies

Abstract

Immunogenicity is an important concern for therapeutic antibodies during drug development. By analyzing co-crystal structures of idiotypic antibodies and their antibodies, we found that anti-idiotypic antibodies usually bind the Complementarity Determining Regions (CDR) of idiotypic antibodies. Sequence and structural features were identified for distinguishing immunogenic antibodies from non-immunogenic antibodies. For example, non-immunogenic antibodies have a significantly larger cavity volume at the CDR region and a more hydrophobic CDR-H3 loop than immunogenic antibodies. Antibodies containing no Gly at the turn of CDR-H2 loop are often immunogenic. We integrated these features together with a machine learning platform to Predict Immunogenicity for humanized and full human THerapeutic Antibodies (PITHA). This method achieved an accuracy of 83% in leave-one-out experiment for 29 therapeutic antibodies with available crystal structures. The accuracy decreased to 65% for 23 test antibodies with modeled structures, because their crystal structures were not available, and the prediction was made with modeled structures. The server of this method is accessible at http://mabmedicine.com/PITHA.