Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice.
Rabies virus causes lethal brain infection in about 61000 people per year. Each year, tens of thousands of people receive anti-rabies prophylaxis with plasma-derived immunoglobulins and vaccine soon after exposure. Anti-rabies immunoglobulins are however expensive and have limited availability. VHH...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4210127?pdf=render |
| _version_ | 1828158077890723840 |
|---|---|
| author | Sanne Terryn Aurélie Francart Sophie Lamoral Anna Hultberg Heidi Rommelaere Angela Wittelsberger Filip Callewaert Thomas Stohr Kris Meerschaert Ingrid Ottevaere Catelijne Stortelers Peter Vanlandschoot Michael Kalai Steven Van Gucht |
| author_facet | Sanne Terryn Aurélie Francart Sophie Lamoral Anna Hultberg Heidi Rommelaere Angela Wittelsberger Filip Callewaert Thomas Stohr Kris Meerschaert Ingrid Ottevaere Catelijne Stortelers Peter Vanlandschoot Michael Kalai Steven Van Gucht |
| author_sort | Sanne Terryn |
| collection | DOAJ |
| description | Rabies virus causes lethal brain infection in about 61000 people per year. Each year, tens of thousands of people receive anti-rabies prophylaxis with plasma-derived immunoglobulins and vaccine soon after exposure. Anti-rabies immunoglobulins are however expensive and have limited availability. VHH are the smallest antigen-binding functional fragments of camelid heavy chain antibodies, also called Nanobodies. The therapeutic potential of anti-rabies VHH was examined in a mouse model using intranasal challenge with a lethal dose of rabies virus. Anti-rabies VHH were administered directly into the brain or systemically, by intraperitoneal injection, 24 hours after virus challenge. Anti-rabies VHH were able to significantly prolong survival or even completely rescue mice from disease. The therapeutic effect depended on the dose, affinity and brain and plasma half-life of the VHH construct. Increasing the affinity by combining two VHH with a glycine-serine linker into bivalent or biparatopic constructs, increased the neutralizing potency to the picomolar range. Upon direct intracerebral administration, a dose as low as 33 µg of the biparatopic Rab-E8/H7 was still able to establish an anti-rabies effect. The effect of systemic treatment was significantly improved by increasing the half-life of Rab-E8/H7 through linkage with a third VHH targeted against albumin. Intraperitoneal treatment with 1.5 mg (2505 IU, 1 ml) of anti-albumin Rab-E8/H7 prolonged the median survival time from 9 to 15 days and completely rescued 43% of mice. For comparison, intraperitoneal treatment with the highest available dose of human anti-rabies immunoglobulins (65 mg, 111 IU, 1 ml) only prolonged survival by 2 days, without rescue. Overall, the therapeutic benefit seemed well correlated with the time of brain exposure and the plasma half-life of the used VHH construct. These results, together with the ease-of-production and superior thermal stability, render anti-rabies VHH into valuable candidates for development of alternative post exposure treatment drugs against rabies. |
| first_indexed | 2024-04-11T23:39:37Z |
| format | Article |
| id | doaj.art-f73ce9c0c0a04bf6ab81b08828be58b4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-11T23:39:37Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f73ce9c0c0a04bf6ab81b08828be58b42022-12-22T03:56:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e10936710.1371/journal.pone.0109367Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice.Sanne TerrynAurélie FrancartSophie LamoralAnna HultbergHeidi RommelaereAngela WittelsbergerFilip CallewaertThomas StohrKris MeerschaertIngrid OttevaereCatelijne StortelersPeter VanlandschootMichael KalaiSteven Van GuchtRabies virus causes lethal brain infection in about 61000 people per year. Each year, tens of thousands of people receive anti-rabies prophylaxis with plasma-derived immunoglobulins and vaccine soon after exposure. Anti-rabies immunoglobulins are however expensive and have limited availability. VHH are the smallest antigen-binding functional fragments of camelid heavy chain antibodies, also called Nanobodies. The therapeutic potential of anti-rabies VHH was examined in a mouse model using intranasal challenge with a lethal dose of rabies virus. Anti-rabies VHH were administered directly into the brain or systemically, by intraperitoneal injection, 24 hours after virus challenge. Anti-rabies VHH were able to significantly prolong survival or even completely rescue mice from disease. The therapeutic effect depended on the dose, affinity and brain and plasma half-life of the VHH construct. Increasing the affinity by combining two VHH with a glycine-serine linker into bivalent or biparatopic constructs, increased the neutralizing potency to the picomolar range. Upon direct intracerebral administration, a dose as low as 33 µg of the biparatopic Rab-E8/H7 was still able to establish an anti-rabies effect. The effect of systemic treatment was significantly improved by increasing the half-life of Rab-E8/H7 through linkage with a third VHH targeted against albumin. Intraperitoneal treatment with 1.5 mg (2505 IU, 1 ml) of anti-albumin Rab-E8/H7 prolonged the median survival time from 9 to 15 days and completely rescued 43% of mice. For comparison, intraperitoneal treatment with the highest available dose of human anti-rabies immunoglobulins (65 mg, 111 IU, 1 ml) only prolonged survival by 2 days, without rescue. Overall, the therapeutic benefit seemed well correlated with the time of brain exposure and the plasma half-life of the used VHH construct. These results, together with the ease-of-production and superior thermal stability, render anti-rabies VHH into valuable candidates for development of alternative post exposure treatment drugs against rabies.http://europepmc.org/articles/PMC4210127?pdf=render |
| spellingShingle | Sanne Terryn Aurélie Francart Sophie Lamoral Anna Hultberg Heidi Rommelaere Angela Wittelsberger Filip Callewaert Thomas Stohr Kris Meerschaert Ingrid Ottevaere Catelijne Stortelers Peter Vanlandschoot Michael Kalai Steven Van Gucht Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. PLoS ONE |
| title | Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. |
| title_full | Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. |
| title_fullStr | Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. |
| title_full_unstemmed | Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. |
| title_short | Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. |
| title_sort | protective effect of different anti rabies virus vhh constructs against rabies disease in mice |
| url | http://europepmc.org/articles/PMC4210127?pdf=render |
| work_keys_str_mv | AT sanneterryn protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT aureliefrancart protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT sophielamoral protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT annahultberg protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT heidirommelaere protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT angelawittelsberger protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT filipcallewaert protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT thomasstohr protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT krismeerschaert protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT ingridottevaere protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT catelijnestortelers protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT petervanlandschoot protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT michaelkalai protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice AT stevenvangucht protectiveeffectofdifferentantirabiesvirusvhhconstructsagainstrabiesdiseaseinmice |