Site-Specific Conjugation of Monomethyl Auristatin E to Anti-CD30 Antibodies Improves Their Pharmacokinetics and Therapeutic Index in Rodent Models.

Antibody-drug conjugates (ADCs) have demonstrated clinical benefits that have led to the recent FDA approval of KADCYLA and ADCETRIS. Most ADCs that are currently in clinical use or development, including ADCETRIS, are produced by chemical conjugation of a toxin via either lysine or cysteine residues, inevitably leading to heterogeneous products with variable drug-to-antibody ratios (DARs). Here, we describe the in vitro and in vivo characterization of four novel ADCs that are based on the anti-CD30 antibody cAC10, which has the same polypeptide backbone as ADCETRIS, and compare the results with the latter. Bacterial transglutaminase (BTG) was exploited to site-specifically conjugate derivatives of monomethyl auristatin E (all comprising a cleavable linker) to the glutamine at positions 295 and 297 of cAC10, thereby yielding homogeneous ADCs with a DAR of 4. In vitro cell toxicity experiments using two different CD30-positive cell lines (Karpas 299 and Raji-CD30(+)) revealed comparable EC50 values for ADCETRIS (1.8 ± 0.4 and 3.6 ± 0.6 ng/mL, respectively) and the four cAC10-based ADCs (2.0 ± 0.4 to 4.9 ± 1.0 ng/mL). Quantitative time-dependent in vivo biodistribution studies (3-96 h p.i.) in normal and xenografted (Karpas 299 cells) SCID mice were performed with a selected (125)I-radioiodinated cAC10 ADC and compared with that of (125)I-ADCETRIS. The chemo-enzymatically conjugated, radioiodinated ADC showed higher tumor uptake (17.84 ± 2.2% ID/g 24 h p.i.) than (125)I-ADCETRIS (10.5 ± 1.8% ID/g 24 h p.i.). Moreover, (125)I-ADCETRIS exhibited higher nontargeted liver and spleen uptake. In line with these results, the maximum tolerated dose of the BTG-coupled ADC (>60 mg/kg) was significantly higher than that of ADCETRIS (18 mg/kg) in rats. These results suggest that homogeneous ADCs display improved pharmacokinetics and better therapeutic indexes compared to those of chemically modified ADCs with variable DARs.

[Potentially inappropriate prescriptions for the elderly: a study of health insurance reimbursements in Southeastern France]. / Prescriptions médicamenteuses potentiellement inadaptées chez les personnes âgées : une étude en Provence-Alpes-Côte d'Azur à partir des données de remboursements de l'Assurance maladie.

BACKGROUND: This study conducted in the region of Provence-Alpes-Côte d'Azur (PACA) sought to assess the feasibility of constructing and using indicators of potentially inappropriate prescriptions for the elderly from health insurance reimbursement data. We present and discuss different indicators of inappropriate prescriptions for people aged 70 years or older (at-risk prescriptions, dangerous or at-risk coprescriptions, absence of necessary coprescriptions) and reports their prevalence in PACA. METHODS: The indicators were constructed from the French list of inappropriate prescriptions, national agency guidelines, and the advice of experts in the field. The indicators selected were applied to the databases of the PACA Salaried Workers' Health Insurance Fund for 2008 for all recipients aged 70 years or older and compared according to age, sex, chronic disease status, and, after standardization for age and sex, according to district of residence. RESULTS: In January 2009, 500,904 recipients aged 70 years or older were identified in the data base of the Salaried Workers' Health Insurance Fund, 60.8% of whom were women and 52.1% of whom had approved coverage for a chronic disease. The potentially inappropriate prescriptions most frequently observed here, in decreasing order, were: prescription of an NSAID without the coprescription of gastric protection (28.1%); long-term benzodiazepine treatment (21.5%); prescription of long half-life benzodiazepine (14.9%), and long-term treatment with NSAIDs (11.6%). Overall, the prevalence of each increased significantly with age and was higher among women and people with chronic diseases. Significant variations were also observed between the different districts of PACA. CONCLUSION: Our results confirm that a substantial proportion of elderly people receive potentially inappropriate prescriptions. They also suggest that health insurance reimbursement data could be used in some prescription domains for monitoring trends in the potentially inappropriate prescriptions in the populations of various territories, provided that specific limitations are considered.