Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing.
Sci Adv
; 6(36)2020 09.
Article
de En
| MEDLINE
| ID: mdl-32917596
ABSTRACT
There is a critical need for novel therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant pathogens, and lysins are among the vanguard of innovative antibiotics under development. Unfortunately, lysins' own microbial origins can elicit detrimental antidrug antibodies (ADAs) that undermine efficacy and threaten patient safety. To create an enhanced anti-MRSA lysin, a novel variant of lysostaphin was engineered by T cell epitope deletion. This "deimmunized" lysostaphin dampened human T cell activation, mitigated ADA responses in human HLA transgenic mice, and enabled safe and efficacious repeated dosing during a 6-week longitudinal infection study. Furthermore, the deimmunized lysostaphin evaded established anti-wild-type immunity, thereby providing significant anti-MRSA protection for animals that were immune experienced to the wild-type enzyme. Last, the enzyme synergized with daptomycin to clear a stringent model of MRSA endocarditis. By mitigating T cell-driven antidrug immunity, deimmunized lysostaphin may enable safe, repeated dosing to treat refractory MRSA infections.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Staphylococcus aureus résistant à la méticilline
/
Lysostaphin
Type d'étude:
Screening_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Sci Adv
Année:
2020
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique