INHIBITORS OF CHI3L1 AND THEIR USES
Although the therapy of Human epidermal growth factor receptor-2 (HER2) positive breast cancer is mainly based on the use of Trastuzumab and Pertuzumab, still 20% of these tumors are resistant to these two drugs, presenting poor clinical prognosis and low patient survival. For these reasons is extremely important to understand how resistance to Trastuzumab and Pertuzumab treatment is maintained. The mechanism of action of the two antibodies is based on the enhancement of antibody dependent cytotoxicity (ADCC) by NK cells. An impairment of NK cell ADCC activity could be a potential mechanism of resistance to HER2 targeted therapy. The aim of our method is to provide a novel therapeutic approach in particular in patients that do not respond or are resistant to common therapies.
The method shows how the diseases progression to Trastuzumab treatment is correlated with the capacity of sera from progressive disease (PD) patients to impair healthy NK cell ADCC. We found that CHI3L1 levels are increased in sera of PD patients compared with complete remission (CR) patients and healthy controls (Fig. 2). Recombinant CHI3L1 protein is able to inhibit Trastuzumab mediated NK cells ADCC in vitro. The inhibition can be reverted by adding two different neutralizing ligands of CHI3L1, a specific monoclonal antibody and the soluble form of its receptor interleukin 13 receptor alpha 2 (IL13ra2) (Fig. 3).
- Breast cancer treament.
- The antibody can be administrated in patients in combination with other treatments, in particular with antibodies capable to neutralize other receptors involved in tumor growth or angiogenesis.