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Published on: June 15, 2019
Tumor-shed antigen CA125 blocks complement-mediated killing via suppression of C1q-antibody binding
J Bradford Kline1, Shawn Fernando1, Erin N Ross1
1Morphotek Inc., Exton, PA, USA.
Abstract:
C1q-engagement with IgG and IgM type antibodies is the initiating step of classical complement-mediated immunity. The tumor shed antigen CA125 has been reported to have immunosuppressive effects on host tumor responses as well as commercially approved and experimental monoclonal antibody (mAb)-based therapeutic agents. To better understand this effect, molecular and cellular studies were carried out testing the ability of CA125 to perturb the classical complement pathway. Here, we show that patient-derived CA125 inhibits IgG1, IgG3, and IgM-mediated complement-dependent cytotoxicity (CDC) by perturbing antibody-Fc interaction with the C1q complement-initiating protein only in those mAbs that are directly bound by CA125. This mechanism was found to impact naturally generated IgM antibodies as well as experimental and clinically approved mAbs, such as farletuzumab and rituximab, respectively. These data support a role for CA125 in humoral immune suppression and as a potential mechanism by which tumors may possibly avoid host immune responses.
Insights
Tumor antigen CA125 suppresses the classical complement pathway by blocking antibody interaction with C1q. This immune evasion mechanism affects various antibodies, including therapeutic monoclonal antibodies (mAbs).
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Classical complement activation is initiated by C1q binding to antibodies (IgG, IgM).
- Tumor antigen CA125 is known to possess immunosuppressive properties.
- CA125's impact on complement-mediated immunity, particularly with therapeutic antibodies, requires elucidation.
Purpose of the Study:
- To investigate how CA125 affects the classical complement pathway.
- To determine if CA125 can interfere with antibody-dependent complement activation.
Main Methods:
- Molecular and cellular assays were performed to test CA125's effect on complement activation.
- Studies focused on the interaction between CA125, antibodies (IgG1, IgG3, IgM), and the C1q protein.
- The impact on complement-dependent cytotoxicity (CDC) was assessed for various antibodies, including therapeutic monoclonal antibodies (mAbs).
Main Results:
- Patient-derived CA125 was shown to inhibit IgG1, IgG3, and IgM-mediated CDC.
- This inhibition occurs by disrupting the antibody-Fc interaction with C1q, specifically when CA125 binds directly to the antibody.
- The mechanism affects naturally occurring IgM antibodies and clinically used mAbs like rituximab and experimental ones like farletuzumab.
Conclusions:
- CA125 plays a role in humoral immune suppression.
- CA125 may enable tumors to evade host immune responses by interfering with complement activation.
- Understanding this interaction is crucial for developing effective antibody-based cancer therapies.
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