Found 1 Presentation For Request "987P"
987P - A new therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy
- Toshifumi Obonai (Kawasaki, Japan)
Abstract
Background
CD73 is expressed on certain types of leukocytes and tumor cells and is known as a poor prognostic factor in patients. CD73 catalyzes conversion of extracellular adenosine monophosphate (AMP) to adenosine (Ado) which accumulates in the tumor microenvironment (TME). Ado suppresses immune activation through Ado receptors, allowing tumors to escape from the host immune system. Suppressing CD73 activity provokes T-cell activation and reverses immune suppression exerted by Ado. Thus, the inhibition of CD73 by anti-CD73 antibodies may provide potent cancer immunotherapy options.
Methods
We performed a large screen of anti-human CD73 mouse antibodies, and two clones were humanized using human IgG1 framework with Fc silent. Binding activity was confirmed by flow cytometry (FCM) and surface plasmon resonance. T-cell proliferation was observed using human PBMC with CD3/CD28-agonistic beads and the antibodies in the presence of ATP. Internalization of CD73 was assessed by immunocytochemistry and FCM. Anti-tumor effect was investigated with immune-humanized mouse model (xenogenic grafted MDA-MB-231 in human CD34+ cell-engrafted NSG mice) and human CD73 knock-in mouse (subcutaneous MC38-hCD73 in hCD73 konck-in Mice).
Results
Humanized anti-CD73 antibody (BP1200) binds to both human and cynomolgus CD73 expressing on cell surface with KD value of 0.2 nM. BP1200 blocked AMP hydrolysis by CD73 on cell surface with an inhibition rate like benchmark antibody. BP1200 was internalized into T lymphocytes besides tumor cell lines by binding to CD73. BP1200 enhanced T-cell proliferation several folds compared to competitive antibody and increased cytokines production. Finally, we examined the anti-tumor effect with humanized immune system mice and human CD73 knock-in mice. In both model mice, BP1200 augmented the effect of anti-PD-1 immunotherapy on tumor growth.
Conclusions
BP1200 is a humanized anti-CD73 antibody that attenuates the AMP hydrolysis activity of CD73. By blocking AMP hydrolysis, BP1200 ameliorates adenosine mediated immunosuppressive TME and activates T-cell activity. The combination of BP1200 and immunocheckpoint antibody for cancer treatment will be a promising regimen in clinical practice.
Legal entity responsible for the study
BrightPath Biotherapeutics Co., Ltd.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.