Improvement of Biophysical Properties and Affinity of a Human Anti-L1CAM Therapeutic Antibody through Antibody Engineering Based on Computational Methods.

The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity and mechanism of action in human cholangiocarcinoma xenograft models. In the present study, we aimed to improve the biophysical properties of Ab417. We designed 20 variants of Ab417 with reduced aggregation propensity, less potential post-translational modification (PTM) motifs, and the lowest predicted immunogenicity using computational methods. Next, we constructed these variants to analyze their expression levels and antigen-binding activities. One variant (Ab612)-which contains six substitutions for reduced surface hydrophobicity, removal of PTM, and change to the germline residue-exhibited an increased expression level and antigen-binding activity compared to Ab417. In further studies, compared to Ab417, Ab612 showed improved biophysical properties, including reduced aggregation propensity, increased stability, higher purification yield, lower pI, higher affinity, and greater in vivo anti-tumor efficacy. Additionally, we generated a highly productive and stable research cell bank (RCB) and scaled up the production process to 50 L, yielding 6.6 g/L of Ab612. The RCB will be used for preclinical development of Ab612.

Missing effect of glutamine supplementation on the surgical outcome after pancreaticoduodenectomy for periampullary tumors: a prospective, randomized, double-blind, controlled clinical trial.

BACKGROUND: The effect of glutamine (Gln) supplementation in patients undergoing a major operation has not been conclusively established. This study was designed to elucidate the effect of Gln supplementation on the surgical outcome after a pancreaticoduodenectomy (PD) for periampullary tumors. METHODS: A prospective, randomized, double-blind, and controlled clinical trial was undertaken for patients who underwent a classical PD or a pylorus-preserving PD for periampullary tumors. The Gln and control groups received isonitrogenous amino acid, with a 0.2 g/kg per day Gln regimen administered to the Gln group. The surgical outcome was compared in light of length of postoperative hospital stay, nutritional and chemical profiles, and complication rate between the Gln and control groups. RESULTS: Sixty of the consecutive 143 patients who were admitted to undergo operation for periampullary tumors were enrolled in our study; 32 were in the Gln group and 28 in the control group. The two groups were comparable prior to and during the operation. The median length of the postoperative hospital stay and the postoperative nutritional and chemical profiles were not different between two groups. The overall and PD-related complication rates of the Gln group (37.5% and 25.0%) and the control group (28.6% and 14.3%) were not statistically different. CONCLUSIONS: No significant beneficial effect of Gln supplementation with a low-dose parenteral regimen was demonstrated on the surgical outcome after a PD for periampullary tumors. Therefore, we should be prudent in using Gln as a routine pharmacologic supplement to the standard nutrition in patients who undergo major operations.