CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients.

Abstract

The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-γ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (∼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.

• Authors: Nicholas C Nicolaides, Charles Schweizer, Elizabeth B Somers, Wenquan Wang, Shawn Fernando, Erin N Ross, Luigi Grasso, Raffit Hassan, J Bradford Kline
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 19 Issue 7 Pg. 622-630 (07 03 2018) ISSN: 1555-8576 [Electronic] United States
• PMID: 29652548 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• CA-125 Antigen
• FCGR2A protein, human
• GPI-Linked Proteins
• MUC16 protein, human
• Membrane Proteins
• RNA, Small Interfering
• Receptors, IgG
• Pemetrexed
• amatuximab
• Mesothelin
• Cisplatin

Topics

• Aged
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• CA-125 Antigen (blood, genetics, immunology, metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Clinical Trials, Phase II as Topic
• Female
• GPI-Linked Proteins (antagonists & inhibitors, immunology, metabolism)
• Gene Knockdown Techniques
• Humans
• Lung Neoplasms (blood, drug therapy, mortality, pathology)
• Male
• Membrane Proteins (blood, genetics, immunology, metabolism)
• Mesothelin
• Mesothelioma (blood, drug therapy, mortality, pathology)
• Mesothelioma, Malignant
• Middle Aged
• Pemetrexed (pharmacology, therapeutic use)
• Pleural Neoplasms (blood, drug therapy, mortality, pathology)
• Progression-Free Survival
• RNA, Small Interfering (metabolism)
• Receptors, IgG (immunology, metabolism)