Chan and Belmar et al. developed an anti-PD-1–GITR-L bispecific, in which anti-PD-1 is used to enhance GITR clustering and NF-κB signaling to T cells to improve the functioning of GITR agonism. The bispecific showed a dose-specific antitumor efficacy in various mouse models, with increases in effector and memory T cells and decreases in Tregs in the tumor microenvironment. Treatment was safe, improved outcomes, and induced immune memory. A similar mode of action and safety profile was found in nonhuman primates.
ABSTRACT: 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.
Author Info: (1) AbbVie Redwood City, Redwood City, CA, USA. (2) AbbVie Redwood City, Redwood City, CA, USA. (3) AbbVie Redwood City, Redwood City, CA, USA. (4) AbbVie Redwood City, Redwood Cit
Author Info: (1) AbbVie Redwood City, Redwood City, CA, USA. (2) AbbVie Redwood City, Redwood City, CA, USA. (3) AbbVie Redwood City, Redwood City, CA, USA. (4) AbbVie Redwood City, Redwood City, CA, USA. (5) Calico Labs, South San Francisco, CA, USA. (6) AbbVie Redwood City, Redwood City, CA, USA. (7) AbbVie Redwood City, Redwood City, CA, USA. (8) AbbVie Redwood City, Redwood City, CA, USA. (9) AbbVie Redwood City, Redwood City, CA, USA. (10) Seattle Genetics, South San Francisco, CA, USA. (11) AbbVie Redwood City, Redwood City, CA, USA. (12) Atomwise, San Francisco, CA, USA. (13) Bristol Myers Squibb, Redwood City, CA, USA. (14) Bolt Biotherapeutics, Inc., Redwood City, CA, USA. (15) Sanofi, Cambridge, MA, USA. (16) AbbVie Redwood City, Redwood City, CA, USA. (17) AbbVie Redwood City, Redwood City, CA, USA. (18) AbbVie Redwood City, Redwood City, CA, USA. (19) AbbVie Redwood City, Redwood City, CA, USA. (20) University of Naples Federico II, Naples, Italy. (21) AbbVie Redwood City, Redwood City, CA, USA. (22) AbbVie Redwood City, Redwood City, CA, USA. (23) AbbVie Redwood City, Redwood City, CA, USA. (24) AbbVie Redwood City, Redwood City, CA, USA. (25) AbbVie Redwood City, Redwood City, CA, USA. (26) AbbVie, Inc., North Chicago, IL, USA. (27) AbbVie, Inc., North Chicago, IL, USA. (28) AbbVie, Inc., North Chicago, IL, USA. (29) AbbVie Bioresearch Center, Worcester, MA, USA. (30) AbbVie, Inc., North Chicago, IL, USA. (31) AbbVie, Inc., North Chicago, IL, USA. (32) AbbVie, Inc., North Chicago, IL, USA. (33) AbbVie Bioresearch Center, Worcester, MA, USA. (34) AbbVie Bioresearch Center, Worcester, MA, USA. (35) Former Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA. California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA. (36) AbbVie Redwood City, Redwood City, CA, USA. (37) Oxford Biotherapeutics, San Jose, CA, USA. (38) AbbVie Redwood City, Redwood City, CA, USA. (39) Good Therapeutics, Inc., Seattle, WA, USA. (40) Calico Labs, South San Francisco, CA, USA. (41) AbbVie Redwood City, Redwood City, CA, USA. hamsell.alvarezjares@abbvie.com.
