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A sugar engineered non-fucosylated anti-CD40 antibody, SEA-CD40, with enhanced immune stimulatory activity alone and in combination with immune checkpoint inhibitors.
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2015
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Clinical ImmunologyImmunologyImmune RegulationImmunodominanceImmunologic MechanismAntigen ProcessingImmunotherapeuticsCd4 T Cell ResponsesImmune SystemImmunotherapySynthetic ImmunologyImmune Stimulatory ActivityImmune Checkpoint InhibitorsTumor ImmunityHuman Cd40Antibody EngineeringNon-fucosylated Anti-cd40 AntibodyMedicineImmunoengineeringImmune SurveillanceT Cell ImmunityHumoral ImmunityCell BiologyMolecular ImmunologyImmune Cell DevelopmentImmunomodulationSurrogate AntibodyMouse Cd40Immunological Biomarkers
3074 Background: SEA-CD40 is a non-fucosylated, humanized IgG1 monoclonal antibody directed against human CD40. It is derived from dacetuzumab, a humanized IgG1 previously developed for B-lineage malignancies. Antibody glycosylation is essential for Fc receptor-mediated activity and nonfucosylated antibodies may show improved efficacy via increased binding to FcγRIIIa (CD16). Methods: Enhanced functionality of SEA-CD40 was determined through FcγRIIIa binding, immune activation, and induction of antigen-specific T-cells Results: While SEA-CD40 and the parent antibody dacetuzumab bind to CD40 with similar affinity, the non-fucosylated SEA-CD40 has a higher affinity for both low (158F) and high (158V) affinity FcγRIIIa. The consequence of enhanced SEA-CD40/FcγRIIIa binding is potent ADCC activity and improved agonistic signaling to antigen presenting cells (APCs). SEA-CD40 treatment of human PBMCs elicits a robust immune response consisting of proinflammatory cytokine production, APC maturation and up-regulation of co-stimulatory receptors on APCs with activity at antibody concentrations as low as 10 ng/ml. Utilizing a surrogate antibody against mouse CD40, the immune stimulatory properties of nonfucosylated anti-CD40 were confirmed in vivo in syngeneic tumor models. SEA-CD40 induction of antigen specific T-cells was assessed using human peripheral blood mononuclear cells (PBMCs) exposed to the M1 influenza antigen. SEA-CD40 stimulated the expansion of influenza specific T-cells and elevated their production of IFNγ. Likewise, SEA-CD40 also stimulated T-cell proliferation and IFNγ production in PBMCs from melanoma, pancreatic, or breast cancer patients in response to a mixture of the tumor-associated antigens MAGE-A1/A3. Interestingly, antigen-specific T-cell responses to both the influenza and tumor antigens were enhanced in the presence of blocking antibodies to CTLA4 or PD1. Conclusions: These observations demonstrate the potential of combining the non-fucosylated agonistic SEA-CD40 with immune check point inhibitors to generate more effective adaptive antitumor immune responses.