Targeting CD73 in the tumor microenvironment with MEDI9447

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• CD73 is an ectoenzyme that generates adenosine, a potent immunosuppressive molecule in the tumor microenvironment.
• Adenosine suppresses lymphocyte function and promotes tumor growth.
• Targeting CD73 offers a novel strategy for cancer immunotherapy.

Purpose of the Study:

• To evaluate MEDI9447, a novel human monoclonal antibody targeting CD73, as a potential cancer immunotherapy.
• To investigate the immune-modulatory effects of MEDI9447 in vitro and in vivo.
• To assess the efficacy of MEDI9447 as a monotherapy and in combination with anti-PD-1 antibodies.

Main Methods:

• In vitro assays measuring CD73 ectonucleotidase activity and lymphocyte suppression.
• In vivo studies using mouse syngeneic tumor models to assess tumor growth inhibition and immune cell infiltration.
• Combination studies with MEDI9447 and anti-PD-1 antibodies in human cells and mouse models.

Main Results:

• MEDI9447 potently inhibits CD73 ectonucleotidase activity.
• MEDI9447 reverses adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro.
• MEDI9447 inhibits tumor growth in vivo and alters myeloid and lymphoid cell populations within the tumor microenvironment, including increasing CD8(+) effector cells and activated macrophages.
• Combination therapy with MEDI9447 and anti-PD-1 antibodies demonstrated additive activity.

Conclusions:

• MEDI9447 is a potent inhibitor of CD73 with significant immune-regulatory effects.
• MEDI9447 demonstrates potential as a novel cancer immunotherapy agent, both as a monotherapy and in combination with other immunotherapies.
• Phase I clinical trials are underway to evaluate the safety and efficacy of MEDI9447 in cancer patients.