CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients

Abstract

The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-γ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (∼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.

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

“…The finding that CA125 does not bind or affect the ability of C1q binding to the humanized pertuzumab mAb, which shares significant amino acid homology to other humanized mAbs within the framework and Fc regions, including farletuzumab, suggests that the critical region(s) for CA125 binding may lie within the CDRs. This is supported by the reports that (FAB’) 2 fragments from farletuzumab and amatuximab were able to bind CA125 but not a fragment containing the Fc domain . These data were consistent with the ability of CA125 to bind all farletuzumab isotype chimeras shown in Fig.…”

“…for farletuzumab in relapsed ovarian cancer and the anti‐mesothelin antibody amatuximab in first‐line mesothelioma . While CA125 has been identified as a biomarker for tumor presence, its steady‐state levels have been reported by several independent groups not to simply reflect tumor bulk or burden, whereby small tumor lesions have been shown to produce high levels of CA125 while in other instances large bulky tumor expressed little to no CA125 .…”

Block‑Removed Immunoglobulin Technology to enhance rituximab effector function by counteracting CA125‑mediated immunosuppression

“…We have previously reported that CA125 interacts with RTX and reduces its interaction with the complement factor C1q, leading to reduced CDC activity ( 19 ). Because CA125 has been reported to also inhibit ADCC activity ( 13 , 15 ), we hypothesized that CA125 could also affect RTX-mediated ADCC and thus investigated this hypothesis. The results demonstrated that CA125 significantly reduced RTX's ADCC activity against the CD20-positive Daudi cells ( Fig.…”

“…Up to 37% of FL patients have elevated CA125 serum levels (11); however, despite its prevalence in FL and other cancers, the role of CA125 in tumor biology and immunity has been only recently elucidated. Previous clinical evidence suggested that high levels of serum CA125 have a negative impact on the effectiveness of the experimental therapeutic antibodies farletuzumab and amatuximab (13)(14)(15). Similar to RTX, the modes of action of farletuzumab and amatuximab include ADCC and CDC (16)(17)(18).…”

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

“…A subsequent randomized, placebo-controlled phase II trial (ARTEMIS, NCT02357147) was prematurely terminated, with no new clinical trials on amatuximab initiated since. It has been noted that amatuximab may bind to MUC16 in the sera of patients, potentially reducing its ADCC activity [99,101,102].…”