EXTON, Pa., July 11, 2017 /PRNewswire/ -- Morphotek®, Inc., a subsidiary of Eisai Inc., announced today that a publication entitled "Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc receptor engagement" was published in the journal Oncotarget as a priority paper. This publication addresses a potential mechanism by which tumor-produced CA125 may negatively affect pharmacologic activity of farletuzumab, an investigational drug in clinical development for ovarian cancer. The work highlights the ongoing preclinical studies done to assess observations from a completed Phase 3 clinical trial (NCT00849667) in 1,100 patients with first relapsed platinum-sensitive ovarian cancer, which did not achieve its primary statistical endpoint of improved progression-free survival (PFS) in the intent-to-treat population (HR 0.86, p = 0.076), but showed in a prespecified subgroup analysis that patients (n=290) with low baseline levels of CA125 had improvements in PFS (HR 0.49, p = 0.0028) and overall survival (OS) (HR 0.44, p = 0.0108)1 when treated with 2.5mg/kg farletuzumab as compared to placebo control. The authors show that CA125 is able to bind directly to farletuzumab, and while not affecting its ability to bind to its target on cells, is perturbed so that the antibody can no longer engage with the CD16a Fc-receptor on lymphocytic effector cells that are required to engage immune-effector cell killing, a process called antibody dependent cellular cytotoxicity (ADCC).
ADCC is a function used by several commercial and experimental-stage therapeutic antibodies to target the host's immune system to destroy tumor cells that are bound by the antibody2. Farletuzumab has been shown in previous in vivo preclinical studies to utilize immune-effector activities including ADCC and complement mediated cytotoxicity (CDC) to kill target cells, as well as induce an intracellular death program called autophagy3-5. While the relationship of these pathways on optimal tumor cell killing is still being studied, evidence has shown that removal of at least one of these components results in significantly diminished farletuzumab anti-tumor activity3,4. These data now support the scientific relationship between CA125 levels and potential clinical outcomes of patients when treated with farletuzumab. To address this hypothesis, the effects of CA125 on farletuzumab pharmacologic activity when combined with standard of care chemotherapy are being further investigated in a clinical trial currently recruiting patients with low serum CA125 (NCT02289950).
About Morphotek Morphotek®, Inc., a subsidiary of Eisai Inc., is a clinical-stage biotechnology company focused on developing novel classes of biological-based products to treat cancer, inflammatory and infectious diseases. Our mission is to develop novel, targeted therapies that attack underlying disease pathways and overcome the immunosuppressive effects by tumors on immune-mediated experimental therapies. Our diverse pipeline includes clinical-stage monoclonal antibodies to lead targets folate receptor alpha, mesothelin and endosialin, as well as antibody drug conjugates and bispecific antibodies to undisclosed targets in preclinical development. Our mission is supported by the proprietary cutting-edge technologies in antibody engineering, manufacturing and screening optimization platforms, along with our expertise in developing diagnostics to support patient selection and therapeutic strategy. For more information, please visit www.morphotek.com.
About Eisai Inc. At Eisai Inc., human health care (hhc) is our goal. We give our first thought to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs.
Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US and follow us on Twitter and LinkedIn.
Vergote I, et.al. A randomized, double-blind, placebo-controlled, phase III study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J. Clin. Oncol. 2016; 34:2271-2278.
Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nature Reviews Drug Discovery 2007; 6:349-356.
Wen Y, et.al. Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer. Clin. Cancer Res. 2015; 21:448-459.
Lin JM, et.al. The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity. Cancer Biol. Ther. 2013; 14:1032-1038.
Ebel, W., Routhier, E., Foley, B., Jacob, S., McDonough, J., Patel, R., Turchin, H., Chao, Q., Old, L.J., Phillips, M., Nicolaides, N.C., Sass, P.M., and Grasso, L. Preclinical Evaluation of MORAb-003, A Humanized Monoclonal Antibody Antagonizing Folate Receptor-Alpha. Cancer Immun 7:6-14, 2007.