Enhanced complement-mediated cytotoxicity by EGFR-directed monoclonal antibodies in the therapy of solid tumors.

• Applicant: Professorin Dr. Stefanie Derer
• Subject Area: Hematology, Oncology
• Term: from 2011 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 196263374

The complement system constitutes the first-line defense against invading pathogens in in-nate immunity but can also be recruited by tumor targeting antibodies to eliminate tumor cells. Epidermal growth factor receptor (EGFR) targeting antibodies constitute a major treatment option for colorectal or head and neck tumor patients. In the background of high expression of complement-regulatory proteins (CRP) on solid tumor cells as well as of the fact that single EGFR targeting IgG1 antibodies lack the capacity to trigger efficient complement-dependent cytotoxicity (CDC), strategies have been implemented in the course of the expiring funding period to improve either the intrinsic capacity of antibodies to initiate the complement cascade or to interfere with tumor cells` resistance mechanisms. In short, as EGFR is also expressed on normal healthy tissues, we generated a CDC-optimized antibody targeting the tumor-specific EGFR variant III. Furthermore, we established an IgG3 isotype switch variant of the EGFR targeting antibody cetuximab encompassing superior C1q but low C4b or C3b binding capacities and therefore only potent CDC activity against tumor cells expressing low levels of the complement-regulatory protein CD55. Hence, we aim to further investigate tumor-specific CDC enhancing approaches to take advantage of the powerful anti-tumoral effector functions of the complement system. For this purpose, we would like to improve C4b and/or C3b binding to the CH1 domain of IgG3 EGFR antibodies to exploit initial strong C1q binding to the antibody. To reduce CD55 dependency of anti-EGFR-IgG3, we aim to target CRP-specific siRNAs to tumor cells via coupling to the generated EGFRvIII targeting antibody. Finally, both strategies shall be combined to solely sensitize tumor cells for anti-EGFR-IgG3 triggered complement activation. Furthermore, the expression levels of CRP shall be determined in different tumor entities and related to the CDC activity of anti-EGFR-IgG3. Based on these findings, CRP expression levels might be established as potential predictors for efficient complement activation by anti-EGFR IgG3. In summary, in the proposed follow-up project we aim to extend development of tumor-specific strategies with an increased cytotoxic potential for the EGFR-targeted antibody-based tumor therapy.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Thomas Valerius