Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex
Tralokinumab, a fully human mAb specifically targeting the IL-13 cytokine, has demonstrated clinical efficacy and safety in patients with moderate-to-severe atopic dermatitis. Tralokinumab binds IL-13 with high affinity, which prevents the interaction of IL-13 with IL-13Rα1 and subsequent signaling....
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | JID Innovations |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667026723000395 |
| _version_ | 1797674117403508736 |
|---|---|
| author | Maxim A.X. Tollenaere Christina Mølck Ian Henderson Scott Pollack Philip Addis Helle Heibroch Petersen Hanne Norsgaard |
| author_facet | Maxim A.X. Tollenaere Christina Mølck Ian Henderson Scott Pollack Philip Addis Helle Heibroch Petersen Hanne Norsgaard |
| author_sort | Maxim A.X. Tollenaere |
| collection | DOAJ |
| description | Tralokinumab, a fully human mAb specifically targeting the IL-13 cytokine, has demonstrated clinical efficacy and safety in patients with moderate-to-severe atopic dermatitis. Tralokinumab binds IL-13 with high affinity, which prevents the interaction of IL-13 with IL-13Rα1 and subsequent signaling. Similarly, tralokinumab-bound IL-13 cannot bind to IL-13Rα2, a proposed decoy receptor that is reported to bind IL-13 with extraordinarily high affinity. It has however not been fully elucidated to what extent tralokinumab interferes with the endogenous regulation of IL-13 through IL-13Rα2. In this mechanistic study, we used biophysical, biochemical, and cellular assays to investigate the effect of tralokinumab on the interaction between IL-13 and IL-13Rα1 and IL-13Rα2, respectively, as well as the effects on IL-13Rα2–mediated IL-13 internalization. We demonstrate that IL-13Rα2 binds IL-13 with exceptionally high affinity and that tralokinumab is unable to displace IL-13 from IL-13Rα2. In contrast to this, tralokinumab is able to disrupt the IL-13/IL-13Rα1 and IL-13Rα1/IL-13/IL-4Rα complex. Furthermore, we demonstrate that whereas the IL-13/tralokinumab complex is unable to bind IL-13Rα2, any IL-13 that is not bound by tralokinumab (i.e., free IL-13) can be bound by IL-13Rα2 and subsequently internalized, regardless of the presence of tralokinumab. In summary, our study indicates that tralokinumab does not interfere with endogenous IL-13Rα2–mediated regulation of free IL-13. |
| first_indexed | 2024-03-11T21:54:28Z |
| format | Article |
| id | doaj.art-2a3b1111d3f942a1bb15d6b5cb88d644 |
| institution | Directory Open Access Journal |
| issn | 2667-0267 |
| language | English |
| last_indexed | 2024-03-11T21:54:28Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JID Innovations |
| spelling | doaj.art-2a3b1111d3f942a1bb15d6b5cb88d6442023-09-26T04:12:43ZengElsevierJID Innovations2667-02672023-09-0135100214Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 ComplexMaxim A.X. Tollenaere0Christina Mølck1Ian Henderson2Scott Pollack3Philip Addis4Helle Heibroch Petersen5Hanne Norsgaard6LEO Pharma A/S, Ballerup, Denmark; Correspondence: Maxim A.X. Tollenaere, LEO Pharma A/S, Industriparken 55, Ballerup 2750, Denmark.LEO Pharma A/S, Ballerup, DenmarkSygnature Discovery, Nottingham, United KingdomSygnature Discovery, Nottingham, United KingdomSygnature Discovery, Nottingham, United KingdomLEO Pharma A/S, Ballerup, DenmarkLEO Pharma A/S, Ballerup, DenmarkTralokinumab, a fully human mAb specifically targeting the IL-13 cytokine, has demonstrated clinical efficacy and safety in patients with moderate-to-severe atopic dermatitis. Tralokinumab binds IL-13 with high affinity, which prevents the interaction of IL-13 with IL-13Rα1 and subsequent signaling. Similarly, tralokinumab-bound IL-13 cannot bind to IL-13Rα2, a proposed decoy receptor that is reported to bind IL-13 with extraordinarily high affinity. It has however not been fully elucidated to what extent tralokinumab interferes with the endogenous regulation of IL-13 through IL-13Rα2. In this mechanistic study, we used biophysical, biochemical, and cellular assays to investigate the effect of tralokinumab on the interaction between IL-13 and IL-13Rα1 and IL-13Rα2, respectively, as well as the effects on IL-13Rα2–mediated IL-13 internalization. We demonstrate that IL-13Rα2 binds IL-13 with exceptionally high affinity and that tralokinumab is unable to displace IL-13 from IL-13Rα2. In contrast to this, tralokinumab is able to disrupt the IL-13/IL-13Rα1 and IL-13Rα1/IL-13/IL-4Rα complex. Furthermore, we demonstrate that whereas the IL-13/tralokinumab complex is unable to bind IL-13Rα2, any IL-13 that is not bound by tralokinumab (i.e., free IL-13) can be bound by IL-13Rα2 and subsequently internalized, regardless of the presence of tralokinumab. In summary, our study indicates that tralokinumab does not interfere with endogenous IL-13Rα2–mediated regulation of free IL-13.http://www.sciencedirect.com/science/article/pii/S2667026723000395 |
| spellingShingle | Maxim A.X. Tollenaere Christina Mølck Ian Henderson Scott Pollack Philip Addis Helle Heibroch Petersen Hanne Norsgaard Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex JID Innovations |
| title | Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex |
| title_full | Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex |
| title_fullStr | Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex |
| title_full_unstemmed | Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex |
| title_short | Tralokinumab Effectively Disrupts the IL-13/IL-13Rα1/IL-4Rα Signaling Complex but Not the IL-13/IL-13Rα2 Complex |
| title_sort | tralokinumab effectively disrupts the il 13 il 13rα1 il 4rα signaling complex but not the il 13 il 13rα2 complex |
| url | http://www.sciencedirect.com/science/article/pii/S2667026723000395 |
| work_keys_str_mv | AT maximaxtollenaere tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex AT christinamølck tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex AT ianhenderson tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex AT scottpollack tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex AT philipaddis tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex AT helleheibrochpetersen tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex AT hannenorsgaard tralokinumabeffectivelydisruptstheil13il13ra1il4rasignalingcomplexbutnottheil13il13ra2complex |