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An anti-PD-1–GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy

Journal Article · · Nature Cancer
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  1. AbbVie, Redwood City, CA (United States)
  2. Calico Labs, San Francisco, CA (United States)
  3. Seattle Genetics, San Francisco, CA (United States)
  4. Atomwise, San Francisco, CA (United States)
  5. Bristol Myers Squibb, Redwood City, CA (United States)
  6. Bolt Biotherapeutics, Inc., Redwood City, CA (United States)
  7. Sanofi, Cambridge, MA (United States)
  8. Univ. of Naples Federico II (Italy)
  9. AbbVie, Inc., Chicago, IL (United States)
  10. AbbVie Bioresearch Center, Worcester, MA (United States)
  11. Northwestern Univ., Evanston, IL (United States); Univ. of California, Berkeley, CA (United States)
  12. Oxford Biotherapeutics, San Jose, CA (United States)
  13. Good Therapeutics, Inc., Seattle, WA (United States)
+ Show Author Affiliations
Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to 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 bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in 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 demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1–GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1863029
Journal Information:
Nature Cancer, Journal Name: Nature Cancer Journal Issue: 3 Vol. 3; ISSN 2662-1347
Publisher:
SpringerCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (1)

Additional file 1 of GITR and TIGIT immunotherapy provokes divergent multicellular responses in the tumor microenvironment of gastrointestinal cancers dataset January 2023

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Related Subjects

60 APPLIED LIFE SCIENCES
antibody therapy
cancer
cancer immunotherapy
drug development