Background Ovarian cancer remains the most lethal gynecologic malignancy to date and thus represents a substantial health challenge. The introduction of monoclonal antibodies (mAbs) has revolutionized treatment of various types of cancer, but patients with ovarian cancer have yet not benefitted. Natural killer (NK) cells contribute significantly to antibody-dependent cellular cytotoxicity (ADCC), a key factor for success of mAb treatment, and many efforts presently aim to enhance this important antibody function by modifying the Fc moiety. B7-H3 (CD276) is highly expressed in many tumor entities whereas expression on healthy tissue is rather limited, making it a promising target for immunotherapy. Here, we report on an Fc-optimized B7-H3 antibody for treatment of ovarian cancer.
Methods We generated a chimeric B7-H3-mAb containing a Fc part with amino acid substitutions (S239D/I332E) to increase affinity for CD16-expressing NK cells (8H8-SDIE). The efficacy of 8H8-SDIE against ovarian cancer cells was tested in various in vitro assays, including analysis of NK cell activation, degranulation, cytokine release and cytotoxicity.
Results Our analyses demonstrate that various ovarian cancer cell lines exhibit high B7-H3 expression levels. Furthermore, functional analysis revealed that 8H8-SDIE triggers profound NK cell functions such as activation, degranulation and secretion of IFNg, resulting in potent tumor cell lysis.
Conclusions Our data emphasize the potential of 8H8-SDIE as a novel immunotherapeutic option for treatment of ovarian cancer.
Ethics Approval The study was approved by IRB (ethics committee of the Faculty of Medicine of the Eberhard Karls Universitaet Tuebingen and of the University Hospital Tuebingen) and was conducted in accordance with the Declaration of Helsinki; reference number 13/2007V.
Consent Human material was collected after obtaining written informed consent of patients/participants.
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