Development and Validation of a Specific and Sensitive Anti-Drug Antibody Assay for Abelacimab That Avoids False Positive Results Due to Factor XI Interference

Abelacimab is a fully human IgG1 monoclonal antibody that has dual activity against the inactive zymogen Factor XI (FXI) and the activated Factor XI (FXIa). Clinical trials for this investigational product are ongoing. As part of the initial assessment of abelacimab safety and efficacy, an anti-drug antibody (ADA) assay was validated and implemented in two single ascending dose studies conducted in the United States and Japan in healthy subjects. In those studies, ADA positive results were detected in up to 31.1% of subjects. There was no apparent impact on PK, PD, or development of immunogenicity-adverse events in study subjects who were ADA positive relative to those who were ADA negative in either study. Further, the rates of ADA positive subjects seemed inconsistent with a single administration of a fully human IgG1 monoclonal antibody therapeutic. Given the homodimeric structure of FXI, it appeared that the ADA assay was returning false positive results due to cross-linking through FXI. To address this issue, a novel ADA assay, following the 3-tiered approach of screening, confirmation, and titer determination was developed and validated. The assay was shown to be sensitive, specific, and did not show false positive interference by FXI. Two subsequent clinical trials (ANT-003 A randomized, subject- and investigator-blinded, placebo-controlled study conducted in healthy subjects and in obese, but otherwise healthy, subjects aged 18 to 60 years of age and ANT-004 A randomized, subject- and investigator-blinded, placebo-controlled, multiple ascending dose study in patients with atrial fibrillation (AF) or atrial flutter aged 18 to 85 years old with a CHA 2DS 2-VASc risk score of 0-1 for men and 1-2 for women and in whom the use of an anticoagulant for stroke prevention was not planned for the duration of the trial) showed no treatment-emergent ADA responses from either trial. The screen positive rate from the two studies was approximately 5% with no screen positive samples confirmed as positive indicating that the new assay format successfully addressed the false positive issue, and that the sensitivity was appropriately set to achieve the FDA-recommended 5% false positive rate for ADA assays. Disclosures Cullen: Anthos Therapeutics, Inc: Consultancy. Freedholm: Anthos Therapeutics, Inc: Current Employment, Current holder of stock options in a privately-held company.

Evaluation of MEDI8852, an Anti-Influenza A Monoclonal Antibody, in Treating Acute Uncomplicated Influenza

ABSTRACT We evaluated MEDI8852, a human IgG1 monoclonal antibody that binds a highly conserved influenza A hemagglutinin stalk epitope, in outpatients with uncomplicated influenza A infection. A total of 126 subjects aged 18 to 65 years were enrolled during the 2015 to 2016 Northern and 2016 Southern Hemisphere seasons. Subjects with symptom onset ≤5 days before dosing were randomized to four cohorts: 750 mg (cohort 1) or 3,000 mg (cohort 2) MEDI8852 (single intravenous infusion) plus 75 mg oseltamivir, placebo plus 75 mg oseltamivir (cohort 3), and 3,000 mg MEDI8852 alone (cohort 4). Subjects were monitored through day 10 for solicited influenza symptoms, day 28 for adverse events (AEs), and day 101 for serious AEs and AEs of special interest. Nasopharyngeal samples were collected through day 7 for confirmation of influenza A infection, viral shedding, and oseltamivir and MEDI8852 susceptibility. Slightly more AEs were reported in subjects receiving MEDI8852 (cohorts 1, 2, and 4 combined: 39/93, 41.9%) than oseltamivir only (cohort 3: 10/32, 31.3%). Most AEs were mild or moderate. The most common AE was bronchitis (11/93, 11.8%; 1/32, 3.1%). The median (range) decrease in viral shedding (log10 virus genome copies/ml) was similar between the two groups (−3.58 [−6.2. 0.5]; −3.43 [−5.9, 0.9]). Genotypic analyses found a limited number of hemagglutinin and neuraminidase amino acid changes between viruses isolated before and after therapy; however, none appeared within a known oseltamivir-resistant site or MEDI8852-binding region. The safety profile of MEDI8852 supports its continued development for treatment of patients hospitalized with influenza A infection. (This study has been registered at ClinicalTrials.gov under identifier NCT02603952.)

Activity of insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic refractory adrenocortical carcinoma.

4639 Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancywithout an available effective systemic chemotherapy. IGF-R2 overexpression leading to the activation of the IGF1R/mTOR pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), was combined with temsirolimus on the basis of preclinical data. Methods: Patientsreceived cixutumumab, 3-6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Results: Twenty-six patients were enrolled (13 [50%] men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug-related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolemia (31%), hypertriglyceridemia (35%), and hyperglycemia (31%). Eleven of 26 patients (42%) achieved stable disease (SD) > 6 months (duration range = 6 to 21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. Conclusions: Cixutumumab combined with temsirolimus was well tolerated and more than 40% of patients achieved prolonged SD. This study was supported by R21CA13763301A1 (AN), U01CA62461 (RK), and U01CA62487 (PL).