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Evaluation of nanobody-based biologics targeting purinergic checkpoints in tumor models in vivo
Mélanie Demeules1, Allan Scarpitta1, Romain Hardet1
1University of Rouen, INSERM, U1234, Pathophysiology Autoimmunity and Immunotherapy (PANTHER), Normandie Univ, Rouen, France.
Abstract:
Adenosine triphosphate (ATP) represents a danger signal that accumulates in injured tissues, in inflammatory sites, and in the tumor microenvironment. ATP promotes tumor growth but also anti-tumor immune responses notably via the P2X7 receptor. ATP can also be catabolized by CD39 and CD73 ecto-enzymes into immunosuppressive adenosine. P2X7, CD39 and CD73 have attracted much interest in cancer as targets offering the potential to unleash anti-tumor immune responses. These membrane proteins represent novel purinergic checkpoints that can be targeted by small drugs or biologics. Here, we investigated nanobody-based biologics targeting mainly P2X7, but also CD73, alone or in combination therapies. Blocking P2X7 inhibited tumor growth and improved survival of mice in cancer models that express P2X7. P2X7-potentiation by a nanobody-based biologic was not effective alone to control tumor growth but enhanced tumor control and immune responses when used in combination with oxaliplatin chemotherapy. We also evaluated a bi-specific nanobody-based biologic that targets PD-L1 and CD73. This novel nanobody-based biologic exerted a potent anti-tumor effect, promoting tumor rejection and improving survival of mice in two tumor models. Hence, this study highlights the importance of purinergic checkpoints in tumor control and open new avenues for nanobody-based biologics that may be further exploited in the treatment of cancer.
Insights
Nanobody biologics targeting purinergic checkpoints like P2X7 and CD73 show promise in cancer therapy. Blocking these targets can inhibit tumor growth and enhance anti-tumor immunity, offering new treatment strategies.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Adenosine triphosphate (ATP) acts as a danger signal in the tumor microenvironment, influencing both tumor growth and anti-tumor immunity via the P2X7 receptor.
- CD39 and CD73 ecto-enzymes catabolize ATP into immunosuppressive adenosine, contributing to immune evasion in tumors.
- P2X7, CD39, and CD73 are identified as novel purinergic checkpoints with therapeutic potential in cancer.
Purpose of the Study:
- To investigate the efficacy of nanobody-based biologics targeting P2X7 and CD73, alone or in combination therapies, for cancer treatment.
- To explore the potential of targeting purinergic checkpoints to modulate anti-tumor immune responses and control tumor progression.
Main Methods:
- Development and evaluation of nanobody-based biologics targeting P2X7 and CD73 in preclinical cancer models.
- Assessment of therapeutic effects, including tumor growth inhibition, survival improvement, and immune response modulation.
- Investigation of combination therapies involving nanobodies and chemotherapy (oxaliplatin).
Main Results:
- Blocking P2X7 with nanobodies inhibited tumor growth and improved survival in relevant cancer models.
- P2X7 potentiation using nanobodies, while ineffective alone, enhanced tumor control and immune responses when combined with oxaliplatin.
- A bispecific nanobody targeting PD-L1 and CD73 demonstrated potent anti-tumor effects, promoting tumor rejection and improving survival in two tumor models.
Conclusions:
- Purinergic checkpoints (P2X7, CD73) play a critical role in tumor immune evasion and progression.
- Nanobody-based biologics targeting these purinergic checkpoints represent a promising therapeutic strategy for cancer.
- Combination therapies involving nanobodies offer enhanced anti-tumor efficacy and open new avenues for cancer treatment development.
