Probody therapeutics are antibodies that can be broken by enzymes. They bind only to tumor cells, leaving healthy cells intact and therefore minimizing side effects. They do this by “masking” the antibody to reduce its binding to PD-L1 found on healthy cells. When in the tumor microenvironment, CX-072 can become “unmasked” by tumor-specific proteins.
How CX-072 works
CX-072 is a recombinant antibody prodrug composed of a monoclonal antibody directed against the tumor-associated antigen PD-L1 masked by a small protein. The masking protein can also block formation of new tumors. Because it minimizes binding to PD-L1 in normal, healthy tissues it has fewer side effects.
Normally when PD-L1 binds to PD-1, the T-cell receives a signal that reduces cytokine production and suppresses the proliferation of T-cells. Tumor cells use this interaction to avoid detection and inhibit the immune system’s response to turn against them.
CX-072 stabilizes the masked antibody in circulation. As it reaches the tumor site, the small protein mask is broken by enzymes associated with the tumor. These highly concentrated enzymes and are aberrantly activated in tumors; in normal, healthy tissues, they are inactive and found only at low concentrations.
As the monoclonal antibody becomes unmasked, it binds to PD-L1, which is also overexpressed in some cancer cells. This prevents the binding to and activation of its receptor called programmed cell death 1 (PD-1) on T-cells. That lets T-cells recognize and attack cancer cells.
CX-072 in clinical trials
A Phase 1/2 study (NCT03013491), PROCLAIM-CX-072, is now recruiting participants to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of intravenous CX-072 as a single treatment or in combination with Yervoy (ipilimumab) or Zelboraf (vemurafenib) in people with advanced or recurrent solid tumors or lymphomas.
The primary objective is the number of participants who experience a dose-limiting toxicity at various levels when given multiple doses of CX-072 as a single treatment or in combination with Yervoy or Zelboraf in 28 days. Secondary objectives include the percentage of participants who experience anti-cancer activity after two years when given multiple doses of CX-072 as a single treatment or in combination. The study aims to enroll 150 participants and finish by December 2021, with a primary objective measure expected by December 2019.
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