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Series GSE189359 Query DataSets for GSE189359
Status Public on Dec 20, 2021
Title Gene expression based outcome of CT-26 tumor in C57/BL6 mice after treatment with anti-PD-1 antibody, GITR-L, combination or Bispecific molecules
Organism Mus musculus
Experiment type Expression profiling by array
Summary Co-stimulatory receptors such as GITR play key roles in regulating the effector functions of T cells. Agonistic anti-GITR antibodies have been investigated as a cancer immunotherapy with demonstrated efficacy in pre-clinical models. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect which may be due to a suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a novel bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (anti-PD-1-GITR-L) that induces a PD-1-dependent and FcγR-independent GITR clustering, resulting in an enhanced activation, proliferation, and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1 directed GITR-L construct that has a different mechanism of action (MoA) than the co-administration of anti-PD-1 plus GITR-L and demonstrated a dose-dependent immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models. Combination of anti-PD-1-GITR-L with TGFβ inhibition or chemotherapy (gemcitabine), respectively, resulted in tumor remission in immunogenically cold and checkpoint blockade resistant mouse models. Dose-dependent correlations between target saturation and Ki67 and TIGIT up-regulation on memory T cells have been observed following a single dose of anti-PD-1-GITR-L bispecific in mice and non-human primates. Anti-PD-1-GITR-L thus represents a novel bispecific approach for directing GITR agonism for cancer immunotherapy.
 
Overall design 5 mice per treatment arm were treated using 3 doses of test agents on days 7, 9 and 11 after tumor inoculation (tumors approx 100mm3 day 7). Test articles are isotype control 0.3mg/kg, anti-muPD-1 0.3mg/kg, isotype-muGITR-L 0.43mg/kg, 1:1 combination (anti-muPD-1 0.3mg/kg plus isotype-muGITR-L 0.43mg/kg), and anti-muPD-1-muGITR-L bispecific 0.43mg/kg. FFPE samples collected days 8 and 10 for FFPE production of tumors and draining lymph nodes. RNA run on NanoString mouse PanCancer immune profiling panel C3400.
 
Contributor(s) Alvarez Jares HM, Rhodes S, Halliwill K
Citation(s) 35256819
Submission date Nov 22, 2021
Last update date Apr 19, 2022
Contact name Kyle Halliwill
E-mail(s) kyle.halliwill@gmail.com
Organization name Abbvie Inc
Street address 1500 Seaport Blvd
City Redwood City
State/province California
ZIP/Postal code 94063
Country USA
 
Platforms (1)
GPL30298 nCounter PanCancer Immune Profiling Panel [Mouse]
Samples (100)
GSM5699788 day 8 Isotype control mouse 1 Draining lymph node
GSM5699789 day 8 Isotype control mouse 2 Draining lymph node
GSM5699790 day 8 Isotype control mouse 3 Draining lymph node
Relations
BioProject PRJNA782648

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

Supplementary file Size Download File type/resource
GSE189359_combined_normalized_counts_2021-11-18.xlsx 577.3 Kb (ftp)(http) XLSX
GSE189359_raw_dln_counts_2021-11-18.xlsx 240.5 Kb (ftp)(http) XLSX
GSE189359_raw_tmr_counts_2021-11-18.xlsx 250.2 Kb (ftp)(http) XLSX
Processed data are available on Series record
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