Tumor suppression of novel anti-PD-1 antibodies mediated through CD28 costimulatory pathway.
Animals
Antineoplastic Agents, Immunological
/ immunology
CD28 Antigens
/ metabolism
CD8-Positive T-Lymphocytes
/ immunology
Epitopes
/ immunology
Humans
Jurkat Cells
Mice
NF-kappa B
/ metabolism
Neoplasms, Experimental
/ immunology
Programmed Cell Death 1 Receptor
/ immunology
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
19
12
2018
revised:
20
03
2019
accepted:
01
05
2019
pubmed:
28
5
2019
medline:
23
6
2020
entrez:
25
5
2019
Statut:
ppublish
Résumé
Classical antagonistic antibodies (Abs) targeting PD-1, such as pembrolizumab and nivolumab, act through blockade of the PD-1-PDL-1 interaction. Here, we have identified novel antagonistic anti-PD-1 Abs not blocking the PD-1-PDL-1 interaction. The nonblocking Abs recognize epitopes on PD-1 located on the opposing face of the PDL-1 interaction and overlap with a newly identified evolutionarily conserved patch. These nonblocking Abs act predominantly through the CD28 coreceptor. Importantly, a combination of blocking and nonblocking Abs synergize in the functional recovery of antigen-specific exhausted CD8 T cells. Interestingly, nonblocking anti-PD-1 Abs have equivalent antitumor activity compared with blocker Abs in two mouse tumor models, and combination therapy using both classes of Abs enhanced tumor suppression in the mouse immunogenic tumor model. The identification of the novel nonblocker anti-PD-1 Abs and their synergy with classical blocker Abs may be instrumental in potentiating immunotherapy strategies and antitumor activity.
Identifiants
pubmed: 31123083
pii: jem.20182359
doi: 10.1084/jem.20182359
pmc: PMC6605749
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
CD28 Antigens
0
Epitopes
0
NF-kappa B
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Banques de données
PDB
['4ZQK', '5GGS', '5GGR', '4Q9Q', '6HIG', '1DZB', '1MVU', '4M61']
SWISSPROT
['Q15116']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1525-1541Informations de copyright
© 2019 Fenwick et al.
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