This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.

The use of hyper-immune bovine colostrum as a human therapeutic platform is an emerging technology with potential to deliver the efficacy of antibody therapeutics with the convenience and safety of oral or topical application. It is necessary to understand how the bovine immune system responds to immunization with foreign proteins, both in terms of the serum antibody response and the transfer of antigen-specific antibodies into the colostrum to enable efficient large-scale production of therapeutic antibodies. We have immunized 25 cows with recombinant human tumor necrosis factor (rhTNF) and measured the levels of rhTNF-specific antibodies in the serum and colostrum of these animals. We observed a decline of 84±9% in serum IgG1 concentrations in the final weeks of pregnancy that presumably reflects rapid transport of IgG1 into colostrum. The serum IgG2 levels remained constant, such that the serum IgG1 to IgG2 ratio was 1:20 at parturition. We observed substantial animal-to-animal variability in the levels of anti-rhTNF antibodies in both serum and colostrum samples. In particular, a subset of 4 cows had extraordinarily high colostral anti-rhTNF antibody production. Only a weak correlation was found between the peak serum anti-rhTNF activity and the colostral anti-rhTNF activity in these animals. The 4 cows with high colostral anti-rhTNF activities trended toward higher serum IgG1 loss relative to average colostral anti-rhTNF producers, but this difference was not statistically significant in this small sample. The high-anti-rhTNF-producing cows also exhibited a greater proportion of rhTNF-specific antibodies that bound to bovine IgG1- and IgG2-specific detection antibodies relative to the total anti-rhTNF immunoglobulin population. This finding suggests that the isotype distribution of the anti-rhTNF response is varied between individuals and genetic or environmental factors may increase the yield of antigen-specific colostral antibodies.

Bovine colostral antibodies, purified from cow’s milk produced immediately after calving, have enhanced resistance to degradation by intestinal proteases relative to antibodies from human or bovine serum, making them of particular interest as orally administered therapeutic agents. However, the basis of this resistance is not well defined. We evaluated the stability of AVX-470, a bovine colostral anti-tumor necrosis factor (TNF) polyclonal antibody used in early clinical studies for treatment of ulcerative colitis, using conditions that mimic the human small intestine. AVX-470 was degraded ~3 times more slowly than human IgG antibodies or infliximab (a monoclonal mouse-human chimeric IgG). Bovine IgG1 antibodies, the primary component of AVX-470, were slowly cleaved to F(ab’)2 fragments. In contrast, bovine IgG2 and human IgG1 antibodies were cleaved rapidly into Fab and smaller fragments, pointing to specific regions where additional stability might be gained. Infliximab was modified to incorporate the sequences from these regions, including the bovine IgG1 hinge region and a predicted disulfide bonding motif linking the upper hinge region, the CH1 domain and the light chain. This infliximab-bovine IgG1 chimera (bovinized infliximab) retained the antigen binding and neutralization activity of the wild-type sequence but was degraded 9-fold more slowly than the unmodified infliximab. This remarkable increase in stability with as few as 18 amino-acid substitutions suggest that this “bovinization” process is a means to enable oral delivery of proven therapeutic antibodies, as well as novel antibodies to targets that have been previously inaccessible to therapies delivered by injection.

Background Clinical workflows require the ability to synthesize and act on existing and emerging patient information. While offering multiple benefits, in many circumstances electronic health records (EHRs) do not adequately support these needs. Objectives We sought to design, build, and implement an EHR-connected rounding and handoff tool with real-time data that supports care plan organization and team-based care. This article first describes our process, from ideation and development through implementation; and second, the research findings of objective use, efficacy, and efficiency, along with qualitative assessments of user experience. Methods Guided by user-centered design and Agile development methodologies, our interdisciplinary team designed and built Carelign as a responsive web application, accessible from any mobile or desktop device, that gathers and integrates data from a health care institution's information systems. Implementation and iterative improvements spanned January to July 2016. We assessed acceptance via usage metrics, user observations, time–motion studies, and user surveys. Results By July 2016, Carelign was implemented on 152 of 169 total inpatient services across three hospitals staffing 1,616 hospital beds. Acceptance was near-immediate: in July 2016, 3,275 average unique weekly users generated 26,981 average weekly access sessions; these metrics remained steady over the following 4 years. In 2016 and 2018 surveys, users positively rated Carelign's workflow integration, support of clinical activities, and overall impact on work life. Conclusion User-focused design, multidisciplinary development teams, and rapid iteration enabled creation, adoption, and sustained use of a patient-centered digital workflow tool that supports diverse users' and teams' evolving care plan organization needs.