Recombinant antibodies and their derivatives are increasingly being used as therapeutic agents. Clinical applications of antibodies often require large amounts of highly purified molecules, sometimes for multiple treatments. The development of very efficient expression systems is essential to the full exploitation of the antibody technology. Production of recombinant protein in the milk of transgenic dairy animals is currently being tested as an alternative to plasma fractionation for the manufacture of a number of blood factors (human antithrombin, human alpha-1-antitrypsin, human serum albumin, factor IX). The ability to routinely yield mg/ml levels of antibodies and the scale-up flexibility make transgenic production an attractive alternative to mammalian cell culture as a source of large quantities of biotherapeutics. The following review examines the potential of transgenic expression for the production of recombinant therapeutic antibodies.

Purified plasma derived human albumin has been available as a therapeutic product since World War II. However, cost effective recombinant production of albumin has been challenging due to the amount needed and the complex folding pattern of the protein. In an effort to provide an abundant source of recombinant albumin, a herd of transgenic cows expressing high levels of rhA in their milk was generated. Expression cassettes efficiently targeting the secretion of human albumin to the lactating mammary gland were obtained and tested in transgenic mice. A high expressing transgene was transfected in primary bovine cell lines to produce karyoplasts for use in a somatic cell nuclear transfer program. Founder transgenic cows were produced from four independent cell lines. Expression levels varying from 1-2 g/l to more than 40 g/l of correctly folded albumin were observed. The animals expressing the highest levels of rhA exhibited shortened lactation whereas cows yielding 1-2 g/l had normal milk production. This herd of transgenic cattle is an easily scalable and well characterized source of rhA for biomedical uses.

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Background and aims Biosimilars used in multiple rheumatic conditions offer the potential for cost savings. We present the outcomes of a service evaluation of switching rheumatic patients established on originator etanercept (Enbrel) to biosimilar Benepali, using a managed switching programme funded through a novel fi xed price incentivisation model. Methods Evaluation outcomes included savings in drug acquisition costs, patient-reported side effects, adverse events, patient outcomes and patient experience. Results A total of 154 patients on Enbrel were identifi ed for switching. A total of 113 patients (43 had rheumatoid arthritis, 43 had axial spondyloarthritis and 27 had psoriatic arthritis) were switched from originator etanercept to Benepali from August 2016 to March 2017. The Royal Berkshire NHS Foundation Trust had the highest percentage of switches in the Thames Valley in this period. There was no increased incidence of side effects before and after switch. Drug acquisition costs were decreased by £95,000 with an overall reduction in prescribing costs of £186,000 for the local health economy. Conclusions A managed switching programme from originator etanercept to biosimilar Benepali, using a novel fi xed price model, delivers signifi cant cost savings and investment in clinical services while maintaining similar patient-reported outcomes and good patient experience.

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A retrospective study was performed on all patients with clinical suspicion of a pancreatic cancer over a seven-month period. Diagnostic scans of the pancreas were obtained in 87% of the patients. Of 112 patients with a successful ultrasound study, 97 had adequate clinical or surgical follow up. The ultrasound examination was abnormal in 16 of 17 pancreatic cancer patients, yielding a positive predictive value of 84%. Most patients had distant spread at this time. The negative predictive value was 99%, sensitivity was 94%, specificity 96%. This study does nt suggest that ultrasound leads to an earlier diagnosis of pancreatic cancer. However, because the symptoms of the disease are common in the elderly, ultrasound allows reliable exclusion of this disease in a noninvasive way.

Transgenic mice were produced by microinjection of a DNA construct composed of the bovine kappa-casein (kappa-CN) cDNA under the control of the goat beta-CN 5' promoter elements and 3' flanking regions into pronuclear-stage embryos. The gene construct targeted the expression of bovine kappa-CN RNA to the mammary gland and secretion of bovine kappa-CN in the milk. In the three lines studied (BC-7, BC-31 and BC-67) the transgene was stably integrated and propagated as a Mendelian locus. Expression of the bovine protein in lactating mice from the three transgenic lines was demonstrated by northern and western blots. In ten different tissues analysed by northern blotting, expression was confined to the mammary gland of lactating transgenic mice from line BC-7, with low-level expression also observed in the salivary gland of lines BC-31 and BC-67. Transgene expression in the mammary gland paralleled normal casein gene expression during lactation and was not observed in virgin females. The level of bovine kappa-CN mRNA expression on day 10 of lactation in hemizygous transgenic females in relation to endogenous mRNA of whey acid protein (WAP) gene expression was 14%, 69%, and 127% in lines BC-7, BC-31 and BC-67, respectively. No association between transgene copy number and expression was observed. The bovine kappa-CN concentration in milk on day 10 of lactation ranged from 0.94 to 3.85 mg of protein per ml of milk. The bovine kappa-CN expressed in mouse milk had the same molecular mass and immunoactivity with polyclonal antibodies as did kappa-CN from bovine milk. A high degree of variation in the production of bovine kappa-CN within each of the transgenic lines was observed.

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