PMID- 36997299
OWN - NLM
STAT- MEDLINE
DCOM- 20230802
LR  - 20240322
IS  - 1440-1711 (Electronic)
IS  - 0818-9641 (Print)
IS  - 0818-9641 (Linking)
VI  - 101
IP  - 7
DP  - 2023 Aug
TI  - Mutation of the TGN1412 anti-CD28 monoclonal antibody lower hinge confers 
      specific FcgammaRIIb binding and retention of super-agonist activity.
PG  - 657-662
LID - 10.1111/imcb.12646 [doi]
AB  - The agonistic action of several immunomodulatory monoclonal antibodies (mAbs) 
      requires both target antigen binding and clustering of this mAb:target complex by 
      the Fcs interacting with Fcgamma receptors (FcgammaRs), in particular FcgammaRIIb, on 
      neighboring bystander cells. Fc mutations were made in the immunoglobulin G4 
      (IgG4)-based TGN1412 anti-CD28 mAb to define the role of FcgammaR interactions in its 
      "super-agonist" activity. The dual mutation, IgG4-ED(269,270) AA, ablated 
      interaction with all human FcgammaRs and agonistic action was consequentially lost, 
      confirming the FcgammaR dependence on the action of TGN1412. The IgG4 lower hinge 
      region (F(234) L(235) G(236) G(237) ) was modified by L(235) E mutation (F(234) 
      E(235) G(236) G(237) ), a mutation commonly used to ablate FcgammaR binding, 
      including in approved therapeutic mAbs. However, rather than ablating all FcgammaR 
      binding, IgG4-L(235) E conferred specific binding to FcgammaRIIb, the inhibitory Fc 
      receptor. Furthermore, in combination with the core hinge-stabilizing mutation 
      (IgG4-S(228) P, L(235) E), this mutation increased affinity for FcgammaRIIb compared 
      with wild-type IgG4. In addition to having FcgammaRIIb specificity, these engineered 
      TGN1412 antibodies retained their super-agonistic ability, demonstrating that 
      CD28- and FcgammaRIIb-specific binding are together sufficient for agonistic 
      function. The FcgammaRIIb-specific nature of IgG4-L(235) E has utility for 
      mAb-mediated immune agonism therapies that are dependent on FcgammaRIIb interaction 
      and of anti-inflammatory mAbs in allergy and autoimmunity that harness FcgammaRIIb 
      inhibitory signaling.
CI  - (c) 2023 The Authors. Immunology & Cell Biology published by John Wiley & Sons 
      Australia, Ltd on behalf of the Australian and New Zealand Society for 
      Immunology, Inc.
FAU - Chenoweth, Alicia M
AU  - Chenoweth AM
AD  - Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
AD  - Department of Immunology and Pathology, Central Clinical School, Monash 
      University, Melbourne, VIC, Australia.
FAU - Esparon, Sandra
AU  - Esparon S
AD  - Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
FAU - Wines, Bruce D
AU  - Wines BD
AD  - Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
AD  - Department of Immunology and Pathology, Central Clinical School, Monash 
      University, Melbourne, VIC, Australia.
AD  - Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 
      Australia.
FAU - Schuurman, Janine
AU  - Schuurman J
AD  - Genmab, Utrecht, The Netherlands.
FAU - Labrijn, Aran F
AU  - Labrijn AF
AUID- ORCID: 0000-0001-9239-8439
AD  - Genmab, Utrecht, The Netherlands.
FAU - Hogarth, P Mark
AU  - Hogarth PM
AD  - Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
AD  - Department of Immunology and Pathology, Central Clinical School, Monash 
      University, Melbourne, VIC, Australia.
AD  - Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 
      Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230428
PL  - United States
TA  - Immunol Cell Biol
JT  - Immunology and cell biology
JID - 8706300
RN  - POO0DOD3AS (TGN-1412)
RN  - 0 (Receptors, IgG)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Antibodies, Monoclonal)
SB  - IM
MH  - Humans
MH  - *Receptors, IgG/metabolism
MH  - *Immunoglobulin G
MH  - Antibodies, Monoclonal/therapeutic use
MH  - Mutation/genetics
PMC - PMC10952187
OTO - NOTNLM
OT  - CD28 super-agonism
OT  - antibody Fc engineering
OT  - cytokine release syndrome
OT  - inhibitory FcR
OT  - monoclonal antibody therapeutics
COIS- The authors declare Alicia Chenoweth, Bruce Wines, Sandra Esparon and P Mark 
      Hogarth are inventors on a PCT application: "Modified immunoglobulin with 
      affinity for FcgammaRIIb and method of use thereof" owned by the Burnet Institute.
EDAT- 2023/03/31 06:00
MHDA- 2023/08/02 06:42
PMCR- 2024/03/20
CRDT- 2023/03/30 21:13
PHST- 2023/03/24 00:00 [revised]
PHST- 2022/12/27 00:00 [received]
PHST- 2023/03/28 00:00 [accepted]
PHST- 2023/08/02 06:42 [medline]
PHST- 2023/03/31 06:00 [pubmed]
PHST- 2023/03/30 21:13 [entrez]
PHST- 2024/03/20 00:00 [pmc-release]
AID - IMCB12646 [pii]
AID - 10.1111/imcb.12646 [doi]
PST - ppublish
SO  - Immunol Cell Biol. 2023 Aug;101(7):657-662. doi: 10.1111/imcb.12646. Epub 2023 
      Apr 28.