Morphotek, Inc., a subsidiary of Eisai Inc., has entered into a collaborative research agreement with University of Wisconsin-Madison (UW-Madison) to elucidate the immunosuppressive effects of the CA125 tumour antigen on the investigational monoclonal antibody farletuzumab.

Farletuzumab is a humanized monoclonal antibody (mAb) that binds to folate receptor alpha (FRA), a cell-surface protein highly expressed in ovarian carcinoma but largely absent from normal tissue. Previously published work by researchers at UW-Madison showed that the human CA125 tumour antigen may potentially suppress immune-mediated killing of macrophages and natural killer (NK) cells by suppressing their antibody-dependent cellular cytotoxicity (ADCC) function.

ADCC is an immune-mediated cell-killing process inherent to macrophages and NK cells that is activated through the engagement of mAbs bound to cell-surface tumor antigens. Farletuzumab is an investigational mAb that targets tumor cells through binding the cell surface-expressed FRA and mediates tumor cell killing in part by ADCC. CA125 is a secreted protein highly over-expressed by the majority of ovarian cancers. Previous independent studies suggest that one of CA125’s pro-tumor functions is to enable tumors to avoid immune-mediated killing by the patient’s own immune system.

The collaboration will initially investigate the immune status of primary macrophage and NK cells derived from the blood of ovarian cancer patients with varying levels of CA125. In addition, the collaboration will test whether the farletuzumab-mediated killing of ovarian cancer cells using patient-derived immune cells is affected by tumor-derived CA125.

“We are excited to enter this collaboration with researchers at the University of Wisconsin-Madison in this innovative field of CA125-mediated immune suppression,” stated Luigi Grasso, Ph.D., chief scientific officer of Morphotek.

“Our efforts to understand the mechanisms by which tumors evolve to evade immune surveillance, including ADCC suppression, will continue to enable us to develop novel therapeutic agents and innovative clinical designs to overcome these mechanisms and potentially aid patients with malignancies over-expressing CA125.”

As ADCC is an important mechanism of action of farletuzumab, higher levels of CA125 may potentially disrupt the ability of farletuzumab to elicit an ADCC response, thereby lowering its anti-FRA-mediated tumor-killing potential. To potentially minimise the effect of CA125-based suppression of ADCC in patients, Morphotek recently initiated a clinical research study in platinum-sensitive ovarian cancer patients with low CA125 levels. The double-blind, randomized, controlled study is designed to prospectively evaluate the clinical effects observed in the previously conducted phase 3 trial in the pre-specified subset of patients treated with farletuzumab exhibiting low CA125 levels.