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A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency.

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Chodorge M, Züger S, Stirnimann C, Briand C, Jermutus L, Grütter MG, Minter RR
OpenAccess logo Cell Death Differ 19 1187-95 (2012)
Cited: 41 times
EuropePMC logo PMID: 22261618

Abstract

Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general.

Articles - 3thm mentioned but not cited (5)

  1. A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency. Chodorge M, Züger S, Stirnimann C, Briand C, Jermutus L, Grütter MG, Minter RR. Cell Death Differ 19 1187-1195 (2012)
  2. Comparing domain interactions within antibody Fabs with kappa and lambda light chains. Toughiri R, Wu X, Ruiz D, Huang F, Crissman JW, Dickey M, Froning K, Conner EM, Cujec TP, Demarest SJ. MAbs 8 1276-1285 (2016)
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  2. The promise and challenges of immune agonist antibody development in cancer. Mayes PA, Hance KW, Hoos A. Nat Rev Drug Discov 17 509-527 (2018)
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  6. CD95 Structure, Aggregation and Cell Signaling. Levoin N, Jean M, Legembre P. Front Cell Dev Biol 8 314 (2020)
  7. Harnessing co-stimulatory TNF receptors for cancer immunotherapy: Current approaches and future opportunities. Waight JD, Gombos RB, Wilson NS. Hum Antibodies 25 87-109 (2017)
  8. Should development of Alzheimer's disease-specific intravenous immunoglobulin be considered? Loeffler DA. J Neuroinflammation 11 198 (2014)
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  12. 4-1BB immunotherapy: advances and hurdles. Singh R, Kim YH, Lee SJ, Eom HS, Choi BK. Exp Mol Med (2024)
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  2. High-throughput functional screening for next-generation cancer immunotherapy using droplet-based microfluidics. Wang Y, Jin R, Shen B, Li N, Zhou H, Wang W, Zhao Y, Huang M, Fang P, Wang S, Mary P, Wang R, Ma P, Li R, Tian Y, Cao Y, Li F, Schweizer L, Zhang H. Sci Adv 7 eabe3839 (2021)
  3. TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity. Medler J, Nelke J, Weisenberger D, Steinfatt T, Rothaug M, Berr S, Hünig T, Beilhack A, Wajant H. Cell Death Dis 10 224 (2019)
  4. FAS system deregulation in T-cell lymphoblastic lymphoma. Villa-Morales M, Cobos MA, González-Gugel E, Álvarez-Iglesias V, Martínez B, Piris MA, Carracedo A, Benítez J, Fernández-Piqueras J. Cell Death Dis 5 e1110 (2014)
  5. Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity. Daburon S, Devaud C, Costet P, Morello A, Garrigue-Antar L, Maillasson M, Hargous N, Lapaillerie D, Bonneu M, Dechanet-Merville J, Legembre P, Capone M, Moreau JF, Taupin JL. PLoS One 8 e54000 (2013)
  6. Monovalent IgG4 molecules: immunoglobulin Fc mutations that result in a monomeric structure. Wilkinson IC, Fowler SB, Machiesky L, Miller K, Hayes DB, Adib M, Her C, Borrok MJ, Tsui P, Burrell M, Corkill DJ, Witt S, Lowe DC, Webster CI. MAbs 5 406-417 (2013)
  7. Quantitative analysis of cell surface antigen-antibody interaction using Gaussia princeps luciferase antibody fusion proteins. Kums J, Nelke J, Rüth B, Schäfer V, Siegmund D, Wajant H. MAbs 9 506-520 (2017)
  8. A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity. Vargas JG, Wagner J, Shaikh H, Lang I, Medler J, Anany M, Steinfatt T, Mosca JP, Haack S, Dahlhoff J, Büttner-Herold M, Graf C, Viera EA, Einsele H, Wajant H, Beilhack A. Front Immunol 13 888274 (2022)
  9. Crystal structure of CD27 in complex with a neutralizing noncompeting antibody. Teplyakov A, Obmolova G, Malia TJ, Gilliland GL. Acta Crystallogr F Struct Biol Commun 73 294-299 (2017)
  10. A Shorter Route to Antibody Binders via Quantitative in vitro Bead-Display Screening and Consensus Analysis. Mankowska SA, Gatti-Lafranconi P, Chodorge M, Sridharan S, Minter RR, Hollfelder F. Sci Rep 6 36391 (2016)
  11. TRAIL-based tumor sensitizing galactoxyloglucan, a novel entity for targeting apoptotic machinery. Aravind SR, Joseph MM, George SK, Dileep KV, Varghese S, Rose-James A, Balaram P, Sadasivan C, Sreelekha TT. Int J Biochem Cell Biol 59 153-166 (2015)
  12. Affinity maturation of an TpoR targeting antibody in full-length IgG form for enhanced agonist activity. Yang Z, Du M, Wang W, Xin X, Ma P, Zhang H, Lerner RA. Protein Eng Des Sel 31 233-241 (2018)
  13. CD40- and CD95-specific antibody single chain-Baff fusion proteins display BaffR-, TACI- and BCMA-restricted agonism. Nelke J, Medler J, Weisenberger D, Beilhack A, Wajant H. MAbs 12 1807721 (2020)
  14. Reducing affinity as a strategy to boost immunomodulatory antibody agonism. Yu X, Orr CM, Chan HTC, James S, Penfold CA, Kim J, Inzhelevskaya T, Mockridge CI, Cox KL, Essex JW, Tews I, Glennie MJ, Cragg MS. Nature 614 539-547 (2023)
  15. Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering. Heckel F, Turaj AH, Fisher H, Chan HTC, Marshall MJE, Dadas O, Penfold CA, Inzhelevskaya T, Mockridge CI, Alvarado D, Tews I, Keler T, Beers SA, Cragg MS, Lim SH. Commun Biol 5 229 (2022)
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  17. FasL Is Required for Osseous Healing in Extraction Sockets in Mice. Apaza Alccayhuaman KA, Heimel P, Lee JS, Tangl S, Strauss FJ, Stähli A, Matalová E, Gruber R. Front Immunol 12 678873 (2021)
  18. Lipid- and polyion complex-based micelles as agonist platforms for TNFR superfamily receptors. Gilbreth RN, Novarra S, Wetzel L, Florinas S, Cabral H, Kataoka K, Rios-Doria J, Christie RJ, Baca M. J Control Release 234 104-114 (2016)
  19. Possible mechanisms of Leukoagglutinin induced apoptosis in human cells in vitro. Kochubei T, Kitam V, Maksymchuk O, Piven O, Lukash L. Cell Biol Int 40 1313-1319 (2016)
  20. Antibody engineering of a cytotoxic monoclonal antibody 84 against human embryonic stem cells: Investigating the effects of multivalency on cytotoxicity. Klement M, Zheng J, Liu C, Tan HL, Wong VV, Choo AB, Lee DY, Ow DS. J Biotechnol 243 29-37 (2017)
  21. Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer. Mondal T, Gaur H, Wamba BEN, Michalak AG, Stout C, Watson MR, Aleixo SL, Singh A, Condello S, Faller R, Leiserowitz GS, Bhatnagar S, Tushir-Singh J. Cell Death Differ 30 2408-2431 (2023)
  22. Respiratory syncytial virus-approved mAb Palivizumab as ligand for anti-idiotype nanobody-based synthetic cytokine receptors. Ettich J, Wittich C, Moll JM, Behnke K, Floss DM, Reiners J, Christmann A, Lang PA, Smits SHJ, Kolmar H, Scheller J. J Biol Chem 299 105270 (2023)


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