title: 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.affiliation: 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.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Computer Science, Dartmouth, 6211 Sudikoff Laboratory, Hanover, NH 03755, USA.
authors.forename: Deeptak
authors.initials: D
authors.lastname: Verma
authors.affiliation: Thayer School of Engineering at Dartmouth, 14 Engineering Drive, Hanover, NH 03755, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Computer Science, Dartmouth, 6211 Sudikoff Laboratory, Hanover, NH 03755, USA.
authors.forename: Yoonjoo
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Thayer School of Engineering at Dartmouth, 14 Engineering Drive, Hanover, NH 03755, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Ndong
authors.affiliation: Department of Microbiology and Immunology, Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center at Dartmouth, Lebanon, NH 03766, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: Department of Computer Science, Dartmouth, 6211 Sudikoff Laboratory, Hanover, NH 03755, USA. Electronic address: cbk@cs.dartmouth.edu.
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
authors.affiliation: 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.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Griswold
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000906:Antibodies / Q000276:immunology*; D000917:Antibody Formation; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008248:Lysostaphin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000473:pathology / Q000662:veterinary
chemical_list: D000900:Anti-Bacterial Agents; D000906:Antibodies; D018984:Epitopes, T-Lymphocyte; D008248:Lysostaphin