Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-γ receptor engagement

Abstract

Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin-taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low serum CA125 levels treated with farletuzumab demonstrated improvements in progression free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108) as compared to placebo. Farletuzumab’s pharmacologic activity is mediated in part through ADCC. Here we show that CA125 inhibits ADCC by directly binding to farletuzumab that in turn perturbs Fc-γ receptor engagement on effector cells.

FCGR2A and FCGR3A Genotypes Correlate with Farletuzumab Response in Patients with First-Relapsed Ovarian Cancer Exhibiting Low CA125

“…ELISAs were carried out as previously described [Kline et al, 2017]. Briefly, corresponding antigens (farletuzumab [IgG 1 ], panitumumab [IgG2a], and IgM) were diluted to 5 μg/mL in 0.05 M carbonate buffer pH 9.5 and immobilized on polystyrene plates overnight at 4 ° C. Plates were washed with 0.05 M PBS, pH 7.2, and blocked with 5% BSA in PBS for 1 h at room temperature.…”

“…Biological rolling assays (BRA) were carried out as previously described using Chinese hamster ovary (CHO-K1) cells cotransfected with an expression construct producing the FcεR and the FCGR3A-158F/FCGR3A-158V receptors or FCGR2A-131R/ FCGR2A-131H receptors [Kline et al, 2017]. Briefly, U-bottom microplates were coated overnight with 10 μg/mL farletuzumab or pertuzumab (control isotype) in 0.2 M bicarbonate buffer, pH 9.4, at 4 ° C. Wells were washed and blocked with 200 μL PBS/1% BSA for 1 h at room temperature.…”

“…However, a prespecified subgroup analysis within the statistical analysis plan in patients with low (no greater than 3 times the upper limit of normal [ ≤ 3× ULN]) CA125 tumor-shed antigen levels revealed that high-dose farletuzumab plus SOC had improved PFS and overall survival over placebo plus SOC (hazard ratio [HR] = 0.49; p = 0.0028 and HR = 0.44, p = 0.0108, respectively). Recent molecular studies have found that the tumor-shed antigen CA125 is able to directly bind to farletuzumab and suppress its ability to engage with FCGR3A, and to a lesser extent FCGR2A, and in turn suppress their mediated ADCC activity by natural killer or other immune Fc-γ receptor-expressing cells [Kline et al, 2017].…”

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

“…Unfortunately, each of these agents exhibited only modest singleagent activity and neither demonstrated meaningful efficacy over chemotherapy alone when evaluated as part of combination regimens in advanced-stage EOC in Phase III trials [47,48]. However, subset analysis of both studies showed subpopulations responding to each agent [49,50]. …”

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“…The fact that these cultures maintain the production of TSAs makes tumoroids useful to better understand the effects TSAs have on tumor immune suppression. Recently, Kline et al have shown that the CA125 TSA is immunosuppressive to antibody-based tumor therapies [32]. This system will enable better understanding of how the alternative immunosuppressive mechanism can affect the growth and stasis of tumors in the presence of of a given patient's immune system.…”