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Functional Antagonism of Human CD40 Achieved by Targeting a Unique Species-Specific Epitope.

Yamniuk AP, Suri A, Krystek SR, Tamura J, Ramamurthy V, Kuhn R, Carroll K, Fleener C, Ryseck R, Cheng L, An Y, Drew P, Grant S, Suchard SJ, Nadler SG, Bryson JW, Sheriff S
J Mol Biol 428 2860-79 (2016)
Related entries: 5dmi, 5ihl

Cited: 14 times
EuropePMC logo PMID: 27216500

Abstract

Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human CD40-specific epitope that is divergent in the CD40 of nonhuman primates. A similarly selected anti-cynomolgus CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications.

Articles - 5dmj mentioned but not cited (3)

  1. Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity. Yu X, Chan HTC, Fisher H, Penfold CA, Kim J, Inzhelevskaya T, Mockridge CI, French RR, Duriez PJ, Douglas LR, English V, Verbeek JS, White AL, Tews I, Glennie MJ, Cragg MS. Cancer Cell 37 850-866.e7 (2020)
  2. Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling. Bitra A, Doukov T, Wang J, Picarda G, Benedict CA, Croft M, Zajonc DM. J Biol Chem 293 1317-1329 (2018)
  3. Structural basis for recognition of Emi2 by Polo-like kinase 1 and development of peptidomimetics blocking oocyte maturation and fertilization. Jia JL, Han YH, Kim HC, Ahn M, Kwon JW, Luo Y, Gunasekaran P, Lee SJ, Lee KS, Kyu Bang J, Kim NH, Namgoong S. Sci Rep 5 14626 (2015)


Reviews citing this publication (4)

  1. OX40: Structure and function - What questions remain? Willoughby J, Griffiths J, Tews I, Cragg MS. Mol Immunol 83 13-22 (2017)
  2. Antigen recognition by single-domain antibodies: structural latitudes and constraints. Henry KA, MacKenzie CR. MAbs 10 815-826 (2018)
  3. Agonistic CD40 Antibodies in Cancer Treatment. Djureinovic D, Wang M, Kluger HM. Cancers (Basel) 13 1302 (2021)
  4. Concepts for agonistic targeting of CD40 in immuno-oncology. Richards DM, Sefrin JP, Gieffers C, Hill O, Merz C. Hum Vaccin Immunother 16 377-387 (2020)

Articles citing this publication (7)

  1. Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies. Yu X, Chan HTC, Orr CM, Dadas O, Booth SG, Dahal LN, Penfold CA, O'Brien L, Mockridge CI, French RR, Duriez P, Douglas LR, Pearson AR, Cragg MS, Tews I, Glennie MJ, White AL. Cancer Cell 33 664-675.e4 (2018)
  2. Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits. Park J, Selvam B, Sanematsu K, Shigemura N, Shukla D, Procko E. J Biol Chem 294 4759-4774 (2019)
  3. Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VL Single-Domain Antibodies from In Vitro Display Libraries. Henry KA, Kim DY, Kandalaft H, Lowden MJ, Yang Q, Schrag JD, Hussack G, MacKenzie CR, Tanha J. Front Immunol 8 1759 (2017)
  4. 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)
  5. Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients. Marken J, Muralidharan S, Giltiay NV. Arthritis Res Ther 23 5 (2021)
  6. Residue-Specific Message Encoding in CD40-Ligand. Sarode AY, Jha MK, Zutshi S, Ghosh SK, Mahor H, Sarma U, Saha B. iScience 23 101441 (2020)
  7. X-linked hyper-immunoglobulin M syndrome harboring a novel CD40-ligand gene mutation: a case report. Ramachandran R, Krishnan Y, Singh P, Kumar A, Mohanty A. Immunogenetics 75 191-194 (2023)


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