A Generic Approach for Miniaturized Unbiased High-Throughput Screens of Bispecific Antibodies and Biparatopic Antibody-Drug Conjugates.

The toolbox of modern antibody engineering allows the design of versatile novel functionalities exceeding nature's repertoire. Many bispecific antibodies comprise heterodimeric Fc portions recently validated through the approval of several bispecific biotherapeutics. While heterodimerization methodologies have been established for low-throughput large-scale production, few approaches exist to overcome the bottleneck of large combinatorial screening efforts that are essential for the identification of the best possible bispecific antibody. This report presents a novel, robust and miniaturized heterodimerization process based on controlled Fab-arm exchange (cFAE), which is applicable to a variety of heterodimeric formats and compatible with automated high-throughput screens. Proof of applicability was shown for two therapeutic molecule classes and two relevant functional screening read-outs. First, the miniaturized production of biparatopic anti-c-MET antibody-drug conjugates served as a proof of concept for their applicability in cytotoxic screenings on tumor cells with different target expression levels. Second, the automated workflow enabled a large unbiased combinatorial screening of biparatopic antibodies and the identification of hits mediating potent c-MET degradation. The presented workflow utilizes standard equipment and may serve as a facile, efficient and robust method for the discovery of innovative therapeutic agents in many laboratories worldwide.

Effectiveness of an educational intervention to increase knowledge and reduce use of risky behaviors associated with cumulative trauma in office workers.

OBJECTIVE: This pilot project assessed the effectiveness of an intervention to increase knowledge and reduce risky behaviors related to cumulative trauma disorders (CTD) in office workers. STUDY DESIGN: All 124 employees from the administrative offices of a health maintenance organization were invited to participate. Subjects were followed across time using an identification number. Data were collected via questionnaire in June 1994 (pretest1) (N=84), August 1994 (pretest II) (N= 63) and September 1995 (posttest) (N=40). The yearlong intervention focused on functional activities to prevent CTD. RESULTS: of chi-square analyses for the 40 subjects who completed all surveys indicated this intervention significantly increased overall knowledge of CTD (p =.002). Significant changes in self-reported hand/wrist (p =.016) and neck/shoulder (p =.003) posture were also found. CONCLUSIONS: This study is a first step in identifying effective educational interventions to increase knowledge and reduce risk factors related to CTD in office workers.