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

Abstract

Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha and elicits an anti-tumor response via immune effector activity. Recent studies from a global phase 3 trial in ovarian cancer patients treated with carboplatin/taxane plus farletuzumab found that the tumor-produced CA125 protein can suppress farletuzumab function via perturbing its engagement to the activating Fc-γ receptors CD32a (FCGR2A) and CD16a (FCGR3A). Previous reports have indicated that naturally occurring polymorphisms in both of these receptors may play a role in their ability to engage therapeutic antibodies and elicit an optimal immune response via antibody-dependent cellular cytotoxicity (ADCC). In light of the importance of farletuzumab ADCC function for optimal tumor cell killing, we evaluated the frequency of FCGR2A-131H/R and FCGR3A-158V/F polymorphisms in 461 consenting patients from this global clinical study and their association with clinical outcome to placebo versus farletuzumab treatment. Here, we show that farletuzumab has enhanced binding to FCGR3A-158V high-affinity receptor and has an enhanced clinical outcome in patients with low baseline CA125 levels and at least 1 high-affinity allele of FCGR2A or FCGR3A.

Tumor‐shed antigen CA125 blocks complement‐mediated killing via suppression of C1q‐antibody binding

“…Of the commercial IgG1‐type antibodies, rituximab showed significant inhibition of C1q binding in the presence of CA125, while pertuzumab did not. Previous studies have shown that CA125 does not bind pertuzumab nor does it affect its ability to engage with CD16a, therefore further supporting the finding that CA125 direct antibody binding perturbs the ability of C1q engagement and subsequent CDC activity . Daudi cells have been reported to be susceptible to the CDC‐mediated killing by rituximab in vitro .…”

“…In light of our observed farletuzumab‐mediated CDC suppression and the previous reports that CA125 can affect ADCC by direct antibody binding , we determined if other circulating antibodies were capable of binding CA125. First, total purified human IgM and IgG1 from serum of healthy volunteers were tested for their ability to bind CA125.…”

“…Previous studies found that CA125 can bind to a subset of IgG1 antibodies and consequently inhibit their interaction with CD16a and CD32a Fc‐γ receptors . Cancer cells are known to develop multiple mechanisms to avoid CDC and impair the efficacy of therapeutic mAbs by producing membrane complement regulatory proteins including CD59, decay accelerating factor and membrane cofactor protein .…”

“…only CA125 appeared to correlate with clinical outcome. Patients with low CA125 serum levels showed a 7.7 month improvement in PFS as compared to placebo control ( p < 0.0005) suggesting that high concentrations of soluble CA125 in the tumor microenvironment may be sufficient to suppress immune‐effector activity, including CDC . To address this possibility, we used patient serum containing varying endogenous levels of CA125 as a surrogate for soluble CA125 in the tumor microenvironment of these patients.…”

“…A clinical trial testing farletuzumab plus standard‐of‐care chemotherapy in patients with recurrent ovarian cancer found that a subset of patients with low serum levels (less than or equal to three times the upper limit of normal) of the CA125 tumor‐shed antigen had improved progression‐free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108) as compared to placebo control . Additional studies have also reported the effect of CA125 level to clinical outcome, and these effects were reported to be in part a result of direct CA125 binding to the (FAB’) 2 domain of a subset of IgG1‐type mAbs that in turn reduced engagement with the high and low affinity Fc‐γ activating receptors CD16a and CD32a . The pharmacologic activity of farletuzumab as well as that of a number of other therapeutic mAbs is mediated in part through antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity (CDC) .…”