CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement.
Cancer Immunol Res
; 8(6): 781-793, 2020 06.
Article
in En
| MEDLINE
| ID: mdl-32273279
ABSTRACT
Following the success of immune checkpoint blockade therapy against cancer, agonistic antibodies targeting T-cell costimulatory pathways are in clinical trials. The TNF superfamily of receptors (TNFRSF) members CD137 and OX40 are costimulatory receptors that stimulate T-cell proliferation and activation upon interaction with their cognate ligands. Activating CD137 and OX40 with agonistic mAbs stimulates the immune system due to their broad expression on CD4+ and CD8+ T cells and natural killer cells and has antitumor effects in preclinical models. Most TNFRSF agonist antibodies require crosslinking via Fcγ receptors (FcγR), which can limit their clinical activity. FS120 mAb2, a dual agonist bispecific antibody targeting CD137 and OX40, activated both CD4+ and CD8+ T cells in an FcγR-independent mechanism, dependent on concurrent binding. A mouse surrogate version of the bispecific antibody displayed antitumor activity in syngeneic tumor models, independent of T regulatory cell depletion and of FcγR interaction, but associated with peripheral T-cell activation and proliferation. When compared with a crosslink-independent CD137 agonist mAb, the FS120 surrogate induced lower liver T-cell infiltration. These data support initiation of clinical development of FS120, a first-in-class dual agonist bispecific antibody for the treatment of human cancer.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Killer Cells, Natural
/
Lymphocyte Activation
/
T-Lymphocytes, Regulatory
/
Colonic Neoplasms
/
Antibodies, Bispecific
/
Tumor Necrosis Factor Receptor Superfamily, Member 9
/
Receptors, OX40
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cancer Immunol Res
Year:
2020
Document type:
Article
Affiliation country:
United kingdom