PD-1/L1 axis blockade shows durable responses and extended overall survival across cancer types in a subset of patients. Tumour Necrosis Factor Receptor (TNFR) superfamily activation is also being tested clinically to improve patient responses. Current interventions using therapeutic CD137 agonists to activate T cells are limited by adverse safety effects and poor efficacy as monotherapies. The generation of a bispecific agonist of CD137 following PD-L1 crosslinking allows a greater therapeutic window with improved safety and efficacy.
An anti-CD137/PD-L1 mAb2 was generated by introducing a CD137-binding specificity into the Fc-region of a human IgG1 targeting PD-L1 mAb. FcgR binding was decreased by introducing a LALA mutation. Binding characterisation was assessed and in vitro activity measured in a mouse primary OT-1 CD8+ T cell assay. The anti-tumour activity and PK/PD of anti-CD137/PD-L1 mAb2 was tested in mouse tumour models.
An anti-CD137/PD-L1 mAb2 was developed, which binds to mouse PD-L1 enabling CD137 agonism (in vitro EC50: 3 pM in primary antigen-specific OT-1 assay). The mAb2 significantly reduced tumour growth in 3 syngeneic mouse tumour models (MC38, CT26 and B16-F10) with dose-dependent inhibition seen in CT26, resulting in a significant survival benefit at concentrations of 0.3 mg/kg or above. This growth inhibition was coincident with increases in tumour and peripheral activated CD8 T cells. Liver pharmacology was minimal as defined by histopathology.
We report intra-tumoural and peripheral PD changes leading to an increase in the proliferative CD8+ T cell response following dosing with an anti-CD137/PD-L1 bispecific mAb2. These changes were dose dependent and coincident with tumour growth inhibition. In in vitro T cell activation assays the bispecific was superior to control antibodies and relevant combinations. Minimal liver pharmacology and no toxicity was observed with the anti-CD137/PD-L1 mAb2 unlike with other monoclonal antibodies targeting CD137. This warrants the development of a first-in-class anti-human CD137/PD-L1 bispecific antibody with a novel mode of action and improved therapeutic index for the treatment of human cancer.
The authors.
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