A pilot clinical study of the therapeutic antibody against canine PD-1 for advanced spontaneous cancers in dogs

Abstract

Inhibition of programmed death 1 (PD-1), expressed on activated T cells, can break through immune resistance and elicit durable responses in human melanoma as well as other types of cancers. Canine oral malignant melanoma is one of the most aggressive tumors bearing poor prognosis due to its high metastatic potency. However, there are few effective treatments for the advanced stages of melanoma in veterinary medicine. Only one previous study indicated the potential of the immune checkpoint inhibitor, anti-canine PD-L1 therapeutic antibody in dogs, and no anti-canine PD-1 therapeutic antibodies are currently available. Here, we developed two therapeutic antibodies, rat-dog chimeric and caninized anti-canine PD-1 monoclonal antibodies and evaluated in vitro functionality for these antibodies. Moreover, we conducted a pilot study to determine their safety profiles and clinical efficacy in spontaneously occurring canine cancers. In conclusion, the anti-canine PD-1 monoclonal antibody was relatively safe and effective in dogs with advanced oral malignant melanoma and other cancers. Thus, our study suggests that PD-1 blockade may be an attractive treatment option in canine cancers.

Cross-Reactivity and Functionality of Approved Human Immune Checkpoint Blockers in Dogs

“…Moreover, a canine study with the humanized anti-CCR4 antibody mogamulizumab showed depletion of regulatory T cells that remained consistent throughout the study, indicating that the potential development of ADA did not impair functionality for extended treatment timeframes [ 39 ]. In a recent study testing chimeric and caninized anti-PD-1 antibodies for treatment of dog cancer patients, the appearance of ADAs against the caninized version did not result in the reduction of the antibody availability in circulation for at least two weeks [ 16 ]. In neither case were severe side-effects detected.…”

“…In light of our results, we expect that efficacy tests in cancer-bearing dogs are feasible with atezolizumab. Our in vitro results and in vivo studies using canine specific chimeric antibodies targeting the PD-1/PD-L1 axis [ 16 , 17 ] suggest that also in dogs, not all patients will benefit from atezolizumab monotherapy. In humans, it is well-established that only certain types of cancers are responsive to ICIs alone [ 41 ].…”

“…The PD-1/PD-L1 axis is currently the most frequently targeted immune checkpoint in immunooncology and the number one choice for combinatorial immunotherapeutic approaches [ 3 ]. In vitro and in vivo studies report increased PD-1/PD-L1 expression in canine cancers and successful targeting of these checkpoints in patient dogs [ 16 , 17 ]. Yet, commercially available antibodies for veterinary medicine are missing.…”

“…Moreover, increased expression of PD-1 has been shown on canine T cells [ 9 , 12 , 14 ], as well as PD-L1 on canine antigen presenting cells (APCs) [ 10 , 12 ], and tumor cells [ 10 , 12 , 13 , 15 ]. However, to our knowledge, only two interventional studies in canine tumor patients have been published to date, showing some degree of success with anti-PD-L1 and anti-PD-1 antibodies [ 16 , 17 ]. Despite these promising results, no canine-specific ICIs for use in veterinary practice are commercially available.…”

Spontaneously occurring canine cancer as a relevant animal model for developing novel treatments for human cancers

“…IFN-γ has also been shown to enhance PD-L1 expression in canine tumor cell lines [86,91,93]. However, only our group [94] and Maekawa et al [95,96] have reported clinical trials using these antibody drugs in cancer-bearing dogs. The first clinical trial for this indication was conducted by the Hokkaido University group.…”