Depletion of T cell epitopes in lysostaphin mitigates anti-drug antibody response and enhances antibacterial efficacy in vivo.

Abstract

The enzyme lysostaphin possesses potent anti-staphylococcal activity and represents a promising antibacterial drug candidate; however, its immunogenicity poses a barrier to clinical translation. Here, structure-based biomolecular design enabled widespread depletion of lysostaphin DRB1(∗)0401 restricted T cell epitopes, and resulting deimmunized variants exhibited striking reductions in anti-drug antibody responses upon administration to humanized HLA-transgenic mice. This reduced immunogenicity translated into improved efficacy in the form of protection against repeated challenges with methicillin-resistant Staphylococcus aureus (MRSA). In contrast, while wild-type lysostaphin was efficacious against the initial MRSA infection, it failed to clear subsequent bacterial challenges that were coincident with escalating anti-drug antibody titers. These results extend the existing deimmunization literature, in which reduced immunogenicity and retained efficacy are assessed independently of each other. By correlating in vivo efficacy with longitudinal measures of anti-drug antibody development, we provide the first direct evidence that T cell epitope depletion manifests enhanced biotherapeutic efficacy.

• Authors: Hongliang Zhao, Deeptak Verma, Wen Li, Yoonjoo Choi, Christian Ndong, Steven N Fiering, Chris Bailey-Kellogg, Karl E Griswold
• Journal: Chemistry & biology (Chem Biol) Vol. 22 Issue 5 Pg. 629-39 (May 21 2015) ISSN: 1879-1301 [Electronic] United States
• PMID: 26000749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Antibodies
• Epitopes, T-Lymphocyte
• Lysostaphin

Topics

• Algorithms
• Amino Acid Sequence
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Antibodies (immunology)
• Antibody Formation
• Epitopes, T-Lymphocyte (genetics, immunology, metabolism)
• Lysostaphin (chemistry, immunology, metabolism)
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Protein Structure, Tertiary
• Staphylococcal Infections (drug therapy, pathology, veterinary)