Validation of a Proprietary Deterioration Index Model and Performance in Hospitalized Adults.

Importance: The Deterioration Index (DTI), used by hospitals for predicting patient deterioration, has not been extensively validated externally, raising concerns about performance and equitable predictions. Objective: To locally validate DTI performance and assess its potential for bias in predicting patient clinical deterioration. Design, Setting, and Participants: This retrospective prognostic study included 13 737 patients admitted to 8 heterogenous Midwestern US hospitals varying in size and type, including academic, community, urban, and rural hospitals. Patients were 18 years or older and admitted between January 1 and May 31, 2021. Exposure: DTI predictions made every 15 minutes. Main Outcomes and Measures: Deterioration, defined as the occurrence of any of the following while hospitalized: mechanical ventilation, intensive care unit transfer, or death. Performance of the DTI was evaluated using area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Bias measures were calculated across demographic subgroups. Results: A total of 5 143 513 DTI predictions were made for 13 737 patients across 14 834 hospitalizations. Among 13 918 encounters, the mean (SD) age of patients was 60.3 (19.2) years; 7636 (54.9%) were female, 11 345 (81.5%) were White, and 12 392 (89.0%) were of other ethnicity than Hispanic or Latino. The prevalence of deterioration was 10.3% (n = 1436). The DTI produced AUROCs of 0.759 (95% CI, 0.756-0.762) at the observation level and 0.685 (95% CI, 0.671-0.700) at the encounter level. Corresponding AUPRCs were 0.039 (95% CI, 0.037-0.040) at the observation level and 0.248 (95% CI, 0.227-0.273) at the encounter level. Bias measures varied across demographic subgroups and were 14.0% worse for patients identifying as American Indian or Alaska Native and 19.0% worse for those who chose not to disclose their ethnicity. Conclusions and Relevance: In this prognostic study, the DTI had modest ability to predict patient deterioration, with varying degrees of performance at the observation and encounter levels and across different demographic groups. Disparate performance across subgroups suggests the need for more transparency in model training data and reinforces the need to locally validate externally developed prediction models.

Development of a novel affinity chromatography resin for platform purification of bispecific antibodies with modified protein a binding avidity.

There is strong interest in the production of bispecific monoclonal antibodies that can simultaneously bind two distinct targets or epitopes to achieve novel mechanisms of action and efficacy. Regeneron's bispecific technology, based upon a standard IgG, consists of a heterodimer of two different heavy chains, and a common light chain. Coexpression of two heavy chains leads to the formation of two parental IgG impurities, the removal of which is facilitated by a dipeptide substitution in the Fc portion of one of the heavy chains that ablates Fc Protein A binding. Therefore, the affinity capture (Protein A) step of the purification process must perform both bulk capture and high resolution of these mAb impurities, a task current commercially available resins are not designed for. Resolution can be further impaired by the ability of Protein A to bind some antibodies in the variable region of the heavy chain (VH ). This article details development of a novel Protein A resin. This resin combines an alkali stable ligand with a base matrix exhibiting excellent mass transfer properties to allow high capacity single step capture and resolution of bispecific antibodies (bsAbs) with high yields. The developed resin, named MabSelect SuRe™ pcc, is implemented in GMP production processes for several bsAbs. © 2018 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 34:650-658, 2018.

Purification of monoclonal antibodies from clarified cell culture fluid using Protein A capture continuous countercurrent tangential chromatography.

Recent studies using simple model systems have demonstrated that continuous countercurrent tangential chromatography (CCTC) has the potential to overcome many of the limitations of conventional Protein A chromatography using packed columns. The objective of this work was to optimize and implement a CCTC system for monoclonal antibody purification from clarified Chinese Hamster Ovary (CHO) cell culture fluid using a commercial Protein A resin. Several improvements were introduced to the previous CCTC system including the use of retentate pumps to maintain stable resin concentrations in the flowing slurry, the elimination of a slurry holding tank to improve productivity, and the introduction of an "after binder" to the binding step to increase antibody recovery. A kinetic binding model was developed to estimate the required residence times in the multi-stage binding step to optimize yield and productivity. Data were obtained by purifying two commercial antibodies from two different manufactures, one with low titer (∼ 0.67 g/L) and one with high titer (∼ 6.9 g/L), demonstrating the versatility of the CCTC system. Host cell protein removal, antibody yields and purities were similar to those obtained with conventional column chromatography; however, the CCTC system showed much higher productivity. These results clearly demonstrate the capabilities of continuous countercurrent tangential chromatography for the commercial purification of monoclonal antibody products.