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A phase I, first-in-human study of ARGX-110, a monoclonal antibody targeting CD70, a receptor involved in immune escape and tumor growth in patients with solid and hematologic malignancies.
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2014
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Clinical ImmunologyImmunodeficienciesImmunologyImmune RegulationPathologyImmunodominanceImmunoeditingImmunologic MechanismCd4 T Cell ResponsesImmunotherapeuticsImmunotherapyCd70+ CellsTumor ImmunologyTumor ImmunityImmune EscapeRadiation OncologyMonoclonal AntibodyMolecular OncologyAutoimmune DiseaseTumor GrowthImmune SurveillanceAutoimmunityT Cell ImmunityCancer ImmunosurveillanceEnhanced AdccImmune Checkpoint InhibitorMedicine
3023 Background: Distribution of CD70, a TNF superfamily receptor involved in transient, rapid-onset immune response, is normally restricted to subsets of T-, B-, and dendritic cells. It is chronically over-expressed in patients with malignancies in whom it mediates tumor growth and immune escape. ARGX-110, a monoclonal IgG1 SIMPLE Antibody glyco-engineered for enhanced ADCC (POTELLIGENT), is undergoing Phase 1 testing (ClinicalTrials.gov Identifier: NCT01813539). Methods: As of December 2013, 19 patients (median age: 56 years; prior chemo: 82%; prior biologics/TKIs: 29%) with > 10% tumor cells staining positive for CD70 by immunohistochemistry were treated at 0.1, 1, 5, and 10 mg/kg IV q3 weeks; n = 6, 5, 3, and 5) and received a total of 82 cycles (median = 4; range 1-11). Results: The most common drug-related adverse events (AE) observed in 14 patients were: infusion-related reaction (26%), fatigue (21%) and diarrhea (16%). Drug-related Grade 3 AEs (hypoxia, anorexia, fatigue) were observed in 2 patients. No immune-related AE was observed. Pharmacokinetics were dose-linear (T 1/2 = 11 days). Saturated target-mediated clearance (Ctarget) was observed as of 1 mg/kg. ADCC and depletion of circulating CD70+ cells (qPCR) were demonstrated in all patients. Complement-derived cytotoxicity (CDC) was maximal at > 0.1 mg/kg. Circulating Tregswere reduced by ≥ 50% in most patients treated at the highest doses. One CR (in blood) was confirmed in a patient with stage IVA (T2NxM0B2) Sézary syndrome. Five patients maintained SD for > 6 months (RCC, parotid, myoepithelial, platinum-resistant ovarian, mesothelioma). Conclusions: Based on the clinical and immunological parameters an intermediate dose level of 2 mg/kg is being studied. Full results will be presented. Clinical trial information: NCT01813539. Dose 0.1 mg/kg 1 mg/kg 5 mg/kg 10 mg/kg PK (Ctarget) Not saturated Saturated Saturated Saturated ADCC Yes Yes Yes Yes CDC Not saturated Maximal Maximal Maximal CD70 qPCR 70% ↓ 61%↓ 72%↓ NA B-cell count Stable Stable Stable Stable T-cell count Stable Stable Stable Stable