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Series GSE144473 Query DataSets for GSE144473
Status Public on Jan 30, 2020
Title Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an FcγR-dependent manner, displaying an intermediate level of activity between two clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared to validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well-tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that display an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
 
Overall design Given the recent insights into the function of TNFR agonist antibodies that implicate epitope, affinity, and IgG subclass (16, 20–24) as critical features, an opportunity exists for novel CD137 agonists to achieve differentiated therapeutic activity and improved safety profile. Here we describe the discovery and preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that displays a favorable and well-differentiated efficacy-safety profile that is attributed to a unique epitope, optimized affinity, and FcγR-dependent activity.
 
Contributor(s) Eskiocak U, Guzman W, Wolf B, Cummings C, Milling L, Wu H, Ophir M, Lambden C, Bakhru P, Gilmore DC, Ottinger S, Liu L, McConaughy WK, He SQ, Wang C, Leung CL, Lajoie J, Carson IV WF, Zizlsperger N, Schmidt MM, Anderson AC, Bobrowicz P, Schuetz TJ, Tighe R
Citation(s) 32161196
Submission date Jan 29, 2020
Last update date Apr 13, 2020
Contact name Vijay Kuchroo
Organization name Brigham & Women's Hospital
Department Neurology
Lab Kuchroo
Street address 60 Fenwood Road
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (3)
GSM4288895 Tumor Control
GSM4288896 Tumor CTX-471-AF
GSM4288897 Tumor 3H3
Relations
BioProject PRJNA603752
SRA SRP245870

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE144473_RAW.tar 132.1 Mb (http)(custom) TAR (of TAR)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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