An immunoadhesin therapy for glioblastoma targeting CD97

Effective treatment of glioblastomaGBMthe most common and most lethal human brain tumorrepresents one of the most formidable challenges in oncologyDespite the use of surgeryradiation therapy and chemotherapythe prognosis for patients with GBM remains poorIt is the infiltrative nature of these tumors that eliminates the possibility of curative surgical resectionConventional DNA damaging chemotherapies may exhibit limited duration of efficacy because GBM cells are proficient at repairing DNA damageleading to drug resistanceCDis a cell surface protein that is significantly upregulated in GBM and overexpression confers an invasive phenotype to glioblastoma cells and is associated with decreased survival of GBM patientsBecause of thisCDis an attractive therapeutic target for GBMThe extracellular region of CDcontains binding sites for a number of cellular ligandsone of which is CDthe decay accelerating factor for complementalso known as DAFWe have produced fusions of human DAF with human IgGFc and have demonstrated a strong neutralizing interaction between DAF Fc and CDwith resulting inhibition of GBM migration in culture and a profound antibody dependent cellular cytotoxicityADCCreaction against GBM cellsWe therefore propose developing DAF Fc as a GBM therapyWe will produceusing our plant expression systemadditional forms of DAF Fcmodified to have improved ADCC activity and be retained more efficiently in the brainWe will evaluate the ability of these DAFFc variants to bind to purified CDand CDexpressing GBM cellsand to kill GBM cells in ADCC assaysWe will also compare the ability of the DAF Fc variants to inhibit GBM cell migrationproliferationcomplement activationand angiogenesisWe will compare the in vivo activity of DAF Fc variants against patient derived human glioblastoma intracranial xenografts in immunodeficient miceas well as verify the lack of toxicity of DAF Fc treatmentWe anticipate that these studies will validate our hypothesis regarding the impact of CDon GBM biology and will eventually impact the poor prognosis faced by patients with this devastating cancer Effective treatment of glioblastomaGBMthe most common and most lethal human brain tumorrepresents one of the most formidable challenges in oncologyCDa cellsurface protein that is significantly upregulated in GBM is an attractive therapeutic targetBased on strong preliminary data showing that decay accelerating factorDAFfused to IgG Fc binds to CDon GBM cellsinhibits tumor growthmigration and invasivenessand promotes ADCCwe propose developing DAF Fc as a GBM therapy