DOP07 IMP761, a novel anti-LAG-3 agonist antibody for the treatment of auto-immune diseases

Blockade of the immune checkpoints PD-1 and LAG-3 using antagonist antibodies is currently investigated for many indications in immuno-oncology. Deficiencies in the PD-1 and LAG-3 pathways have been linked to the development of auto-immune diseases. Auto-immune T cells chronically stimulated by the same self-peptide at site of inflammation tend to express exhaustion markers such as PD-1 or LAG-3, therefore making these two markers prime targets for treating the root cause of T-cell–based auto-immunity. To date, no therapeutic immune checkpoint agonist antibody targeting PD-1 or LAG-3 has been developed to downmodulate the activation of these self-antigen specific T cells. We here describe the first agonist anti-LAG-3 antibody (IMP761) and its immunosuppressive properties on human T cells in vitro and in a delayed-type hypersensitivity non-human primate model in vivo. Flow cytometry staining was used to show the capacity of IMP761 to bind and to inhibit CD8 T cells activation and proliferation in response to a foreign antigen peptide pool using activation marker staining and CFSE-based dilution assay. Eighteen cynomolgus macaques received BCG vaccines before being challenged by intradermal injection of tuberculin. Twelve animals received one subcutaneous injection of IMP761 (six at 0.03 mg/kg, six at 0.3 mg/kg) and six animals received PBS as control. A second tuberculin challenge was then performed. Skin biopsies were performed to monitor T-cell infiltration by immunofluorescence staining. IMP761 circulating concentration was measured by ELISA. The 13E2 LAG-3-specific hybridoma cells were selected in functional assays for their ability to suppress human peptide-specific T-cell responses. The murine Ig sequences were then humanised, giving IMP761. IMP761 was able to bind to activated CD8 T cells with an average IC50 of 34.25 ng/ml (range: 17.7–54.6 ng/ml) and to inhibit human CD8 T-cell activation and proliferation. In the cynomolgus macaque studies, median maximum IMP761 concentrations monitored were 165.6 and 1367 ng/ml for the 0.03 and 0.3 mg/kg injected groups, respectively. There was a significant inhibition of CD3-positive T cells infiltration in the skin biopsy in both IMP761 injected groups compared with the PBS group. The 0.3 mg/kg dose was able to decrease CD8 T-cell infiltration. IMP761 is the first LAG-3-specific product candidate that can inhibit antigen-specific T-cell–mediated immune responses in vitro and in vivo, for the treatment of auto-immune diseases.