Naslov
FABS FROM PURIFIED HUMABS OPEN TO THE INTRATHECAL THERAPY OF TETANUS

Autori
Pirazzini, Marco ; Fabris, Federico ; Šoštarić, Petra ; Meglić, Patrik ; Tonellato, Marika ; Alessandro, Grinzato ; Davide, Corti ; Antonio, Lanzavechhia ; Giampietro, Schiavo ; Ornella, Rossetto ; Giuseppe, Zanotti ; Cesare, Montecucco ; Matak, Ivica

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
10TH CROATIAN CONGRESS OF PHARMACOLOGY AND THE 1ST CROATIAN CONGRESS OF CLINICAL PHARMACOLOGY WITH INTERNATIONAL PARTICIPATION / Mršić Pelčić, Jasenka ; Vitezić, Dinko ; Janković, Tamara - : Pharmaca, 2022, 131-131

Skup
10. hrvatski kongres farmakologije ; 1. hrvatski kongres kliničke farmakologije s međunarodnim sudjelovanjem = 10th Croatian Congress of Pharmacology ; 1st Croatian Congress of Clinical Pharmacology and Therapeutics with International Participation

Mjesto i datum
Opatija, Hrvatska, 22.09.2022. - 25.09.2022

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
FABS, TeNT

Sažetak
Tetanus neurotoxin (TeNT) is the causative agent of tetanus, a fatal disease characterized by neuromuscular spastic paralysis caused by TeNT activity in inhibitory interneurons in the spinal cord. Although tetanus can be prevented using a highly effective vaccine, a worldwide clinical practice is the administration of anti- TeNT immunoglobulins (TIG) for prophylaxis and/or treatment of patients already experiencing tetanus symptoms. TIG neutralizes TeNT in peripheral body fluids before it enters peripheral nerves and is retrotransported to the spinal cord. Intrathecal administration of TIG to block TeNT at its site of action would be more effective, but this approach is limited by the low level of anti-TeNT antibodies present in TIG and the amount of protein that can be safely injected into the cerebrospinal fluid. All of these drawbacks can be overcome by highly purified human monoclonal antibodies (humAbs), which are emerging as superior therapeutics against several diseases. By screening immortalized memory B cells pooled from the blood of immunized human donors, we isolated TT104 and TT110, two humAbs that display an unprecedented neutralization ability against TeNT. We produced the Fab derivatives to determine the epitopes they recognize using cryoelectron microscopy, i.e. epitopes essential for toxin binding to target neurons and light chain translocation inside the neuronal cytosol. TT104 and TT110 humAbs display in mice a prophylactic activity comparable to TIG when injected long before TeNT and the combination of TT104-Fab and TT110-Fab prevent tetanus in postexposure experiments if injected within 6 hours after TeNT, again comparably to TIG. Crucially, none of these treatments can prevent tetanus when administered later than 12 hours after TeNT inoculation, while it can be prevented by the TT104-Fab and TT110-Fab combination administered via the intrathecal route. In rats, intrathecal Fabs administered up to 24 hours after TeNT reduce the severity and duration of tetanus symptoms to a greater degree than intramuscular TIG. In conclusion, TT104 and TT110 humAbs meet all the requirements to improve the current prophylaxis and therapy of human tetanus and are ready for clinical trials while TT104- and TT110-Fab derivatives open to effective intrathecal therapy of symptomatic tetanus.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA