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1.  A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma 
Summary
Purpose
Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody–drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Ley) antigen, conjugated to doxorubicin. Ley is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Ley-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients.
Experimental design
Sixty-two patients with recurrent or metastatic NSCLC expressing Ley, one or two prior chemotherapy regimens, and PS ≤ 2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life.
Results
Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A.
Conclusions
SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.
doi:10.1016/j.lungcan.2006.05.020
PMCID: PMC3715069  PMID: 16934909
Immunoconjugate; Targeted therapy; NSCLC; Lewis Y; SGN-15; Monoclonal antibody
2.  FTSite: high accuracy detection of ligand binding sites on unbound protein structures 
Bioinformatics  2011;28(2):286-287.
Motivation: Binding site identification is a classical problem that is important for a range of applications, including the structure-based prediction of function, the elucidation of functional relationships among proteins, protein engineering and drug design. We describe an accurate method of binding site identification, namely FTSite. This method is based on experimental evidence that ligand binding sites also bind small organic molecules of various shapes and polarity. The FTSite algorithm does not rely on any evolutionary or statistical information, but achieves near experimental accuracy: it is capable of identifying the binding sites in over 94% of apo proteins from established test sets that have been used to evaluate many other binding site prediction methods.
Availability: FTSite is freely available as a web-based server at http://ftsite.bu.edu.
Contact: vajda@bu.edu; midas@bu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr651
PMCID: PMC3259439  PMID: 22113084
3.  Robust Identification of Binding Hot Spots Using Continuum Electrostatics: Application to Hen Egg-White Lysozyme 
Journal of the American Chemical Society  2011;133(51):20668-20671.
Binding hot spots, protein regions with high binding affinity, can be identified by using X-ray crystallography or NMR spectroscopy to screen libraries of small organic molecules that tend to cluster at such hot spots. FTMap, a direct computational analogue of the experimental screening approaches, uses 16 different probe molecules for global sampling of the surface of a target protein on a dense grid and evaluates the energy of interaction using an empirical energy function that includes a continuum electrostatic term. Energy evaluation is based on the fast Fourier transform correlation approach, which allows for the sampling of billions of probe positions. The grid sampling is followed by off-grid minimization that uses a more detailed energy expression with a continuum electrostatics term. FTMap identifies the hot spots as consensus clusters formed by overlapping clusters of several probes. The hot spots are ranked on the basis of the number of probe clusters, which predicts their binding propensity. We applied FTMap to nine structures of hen egg-white lysozyme (HEWL), whose hot spots have been extensively studied by both experimental and computational methods. FTMap found the primary hot spot in site C of all nine structures, in spite of conformational differences. In addition, secondary hot spots in sites B and D that are known to be important for the binding of polysaccharide substrates were found. The predicted probe–protein interactions agree well with those seen in the complexes of HEWL with various ligands and also agree with an NMR-based study of HEWL in aqueous solutions of eight organic solvents. We argue that FTMap provides more complete information on the HEWL binding site than previous computational methods and yields fewer false-positive binding locations than the X-ray structures of HEWL from crystals soaked in organic solvents.
doi:10.1021/ja207914y
PMCID: PMC3244821  PMID: 22092261

Results 1-3 (3)