Bypassing the immunosuppressive effects of CA125/MUC16 via re-engineered rituximab (NAV-006) to improve its antitumor activity in vivo

TL;DR

A modified version of rituximab, NAV-006, was developed to overcome the immune-suppressing effects of CA125/MUC16, improving its effectiveness in treating lymphoma in mice.

Contribution

NAV-006 is a re-engineered rituximab variant that bypasses CA125/MUC16's immunosuppressive effects, showing improved antitumor activity in vivo.

Findings

NAV-006 showed enhanced CDC and ADCC activities unaffected by CA125/MUC16.

NAV-006 demonstrated improved in vivo antitumor activity in a human lymphoma model.

CA125/MUC16 suppressed the immune effector functions of newer antibody-based treatments like obinutuzumab and tafasitamab.

Abstract

The monoclonal antibody rituximab functions through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) and is used to treat non-Hodgkin’s lymphoma. Elevated serum CA125/MUC16 levels, present in some follicular lymphoma patients, have been shown to correlate with reduced efficacy of rituximab. Previous studies revealed that CA125/MUC16 binds to rituximab, diminishing its CDC and ADCC. A rituximab variant, NAV-006, was engineered to counteract CA125/MUC16’s immunosuppressive effects. NAV-006 demonstrated enhanced CDC and ADCC activities and was unaffected by CA125/MUC16. In the present study, NAV-006 showed improved in vivo antitumor activity compared to rituximab in a human lymphoma model with reconstituted CA125/MUC16. Additionally, CA125/MUC16 bound to newer antibody-based lymphoma treatment agents, including obinutuzumab and tafasitamab, suppressing their immune effector functions. Bispecific antibodies mosunetuzumab and glofitamab also exhibited reduced cytotoxicity in the presence of CA125/MUC16. These findings suggest that NAV-006 could improve therapeutic efficacy in B-cell lymphomas, particularly in patients with elevated CA125/MUC16 levels.

Statement of Significance: Multiple recent studies have highlighted the immunosuppressive impact of MUC16/CA125 on antibodies immune effector function including rituximab (RITUXAN®). The present study presents data related to the engineering of a variant of rituximab that can escape MUC16/CA125 immunosuppressive effects resulting in improved efficacy in vivo.

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