Antibody-protein binding and conformational changes : identifying allosteric signalling pathways to engineer a better effector response
Numerous monoclonal antibodies have been developed successfully for the treatment of various diseases. Nevertheless, the development of biotherapeutic antibodies is complex, expensive, and time-consuming, and to facilitate this process, careful structural analysis beyond the antibody binding site is required to develop a more efficacious antibody. In this work, we focused on protein antigens, since they induce the largest antibody changes, and provide interesting cases to compare and contrast. The structures of 15 anti-protein antibodies were analysed to compare the antigen-bound/unbound forms. Surprisingly, three different classes of binding-induced changes were identified. In class (B1), the antigen binding fragment distorted significantly, and we found changes in the loop region of the heavy chain's constant domain; this corresponds well with expected allosteric movements. In class (B2), we found changes in the same loop region without the overall distortion. In class (B3), these changes did not present, and only local changes at the complementarity determining regions were found. Consequently, structural analysis of antibodies is crucial for therapeutic development. Careful evaluation of allosteric movements must be undertaken to develop better effector responses, especially during the transformation of these antibodies from small fragments at the discovery stage to full antibodies at the subsequent development stages.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
Scientific reports - 10(2020), 1 vom: 13. Aug., Seite 13696 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Al Qaraghuli, Mohammed M [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antibodies |
|---|
| Anmerkungen: |
Date Completed 11.01.2021 Date Revised 29.03.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41598-020-70680-0 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM313672857 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM313672857 | ||
| 003 | DE-627 | ||
| 005 | 20240329234239.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41598-020-70680-0 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1354.xml |
| 035 | |a (DE-627)NLM313672857 | ||
| 035 | |a (NLM)32792612 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Al Qaraghuli, Mohammed M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Antibody-protein binding and conformational changes |b identifying allosteric signalling pathways to engineer a better effector response |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.01.2021 | ||
| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Numerous monoclonal antibodies have been developed successfully for the treatment of various diseases. Nevertheless, the development of biotherapeutic antibodies is complex, expensive, and time-consuming, and to facilitate this process, careful structural analysis beyond the antibody binding site is required to develop a more efficacious antibody. In this work, we focused on protein antigens, since they induce the largest antibody changes, and provide interesting cases to compare and contrast. The structures of 15 anti-protein antibodies were analysed to compare the antigen-bound/unbound forms. Surprisingly, three different classes of binding-induced changes were identified. In class (B1), the antigen binding fragment distorted significantly, and we found changes in the loop region of the heavy chain's constant domain; this corresponds well with expected allosteric movements. In class (B2), we found changes in the same loop region without the overall distortion. In class (B3), these changes did not present, and only local changes at the complementarity determining regions were found. Consequently, structural analysis of antibodies is crucial for therapeutic development. Careful evaluation of allosteric movements must be undertaken to develop better effector responses, especially during the transformation of these antibodies from small fragments at the discovery stage to full antibodies at the subsequent development stages | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antibodies |2 NLM | |
| 650 | 7 | |a Antigens |2 NLM | |
| 700 | 1 | |a Kubiak-Ossowska, Karina |e verfasserin |4 aut | |
| 700 | 1 | |a Ferro, Valerie A |e verfasserin |4 aut | |
| 700 | 1 | |a Mulheran, Paul A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 10(2020), 1 vom: 13. Aug., Seite 13696 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2020 |g number:1 |g day:13 |g month:08 |g pages:13696 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-020-70680-0 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2020 |e 1 |b 13 |c 08 |h 13696 | ||