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Chem Biol. 2015 May 21;22(5):629-39. doi: 10.1016/j.chembiol.2015.04.017.

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

Author information

1
Thayer School of Engineering at Dartmouth, 14 Engineering Drive, Hanover, NH 03755, USA; Laboratory of Microorganism Engineering, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, People's Republic of China.
2
Department of Computer Science, Dartmouth, 6211 Sudikoff Laboratory, Hanover, NH 03755, USA.
3
Thayer School of Engineering at Dartmouth, 14 Engineering Drive, Hanover, NH 03755, USA.
4
Department of Microbiology and Immunology, Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center at Dartmouth, Lebanon, NH 03766, USA.
5
Department of Computer Science, Dartmouth, 6211 Sudikoff Laboratory, Hanover, NH 03755, USA. Electronic address: cbk@cs.dartmouth.edu.
6
Thayer School of Engineering at Dartmouth, 14 Engineering Drive, Hanover, NH 03755, USA; Norris Cotton Cancer Center at Dartmouth, Lebanon, NH 03766, USA; Department of Biological Sciences, Dartmouth, Hanover, NH 03755, USA. Electronic address: karl.e.griswold@dartmouth.edu.

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.

PMID:
26000749
PMCID:
PMC4441767
DOI:
10.1016/j.chembiol.2015.04.017
[Indexed for MEDLINE]
Free PMC Article

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