Prevention and management of complications in pelvic exenteration.

Pelvic exenteration is widely recognised as the gold standard of care for locally advanced tumours of the pelvis. Surgery in pursuit of curative resection comes at the cost of significant morbidity. Perioperative complications are commonplace with the majority managed without further surgical intervention. Boundaries of resection are expanding, resulting in increasing incidence of excision of major vascular structures and bone. Optimisation of patients is paramount prior to such significant surgical insult. Specialist centres with designated multidisciplinary teams should be used whenever possible. Addressing anaemia and nutrition play a significant role in prehabilitation. Intra-operatively consideration should be given to prevention of empty pelvis syndrome, perineal reconstruction, safe control of vascular structures and minimising risk of fistulae. Post-operative complications are common however employment of enhanced recovery protocols, minimally invasive surgery and opiate sparing analgesia protocols may in time lead to improvements for patients. Enteric fistulae and urine leak remain the most devastating and risk reduction strategies should be employed. Early recognition and aggressive management of complications is essential.

Consistent manufacturing and quality control of a highly complex recombinant polyclonal antibody product for human therapeutic use.

The beneficial effect of antibody therapy in human disease has become well established mainly for the treatment of cancer and immunological disorders. The inherent monospecificity of mAbs present limitations to mAb therapy which have become apparent notably in addressing complex entities like infectious agents or heterogenic endogenous targets. For such indications mixtures of antibodies comprising a combination of specificities would convey more potent biological effect which could translate into therapeutic efficacy. Recombinant polyclonal antibodies (rpAb) consisting of a defined number of well-characterized mAbs constitute a new class of target specific antibody therapy. We have developed a cost-efficient cell banking and single-batch manufacturing concept for the production of such products and demonstrate that a complex pAb composition, rozrolimupab, comprising 25 individual antibodies can be manufactured in a highly consistent manner in a scaled-up manufacturing process. We present a strategy for the release and characterization of antibody mixtures which constitute a complete series of chemistry, manufacturing, and control (CMC) analytical methods to address identity, purity, quantity, potency, and general characteristics. Finally we document selected quality attributes of rozrolimupab based on a battery of assays at the genetic-, protein-, and functional level and demonstrate that the manufactured rozrolimupab batches are highly pure and very uniform in their composition.

Development of mass spectrometry based techniques for the identification and determination of compositional variability in recombinant polyclonal antibody products.

Recombinant polyclonal antibodies are a new class of protein biologics, combining a defined number of target-specific antibodies, developed for therapeutic use across various indications. Development, manufacture, and release of recombinant polyclonal antibodies as well characterized biological products have required development of new chemistry, manufacturing, and control (CMC) technologies. Sym001 is a recombinant polyclonal antibody product containing 25 unique antibodies specific for the Rhesus D antigen. Sym001 drug substance is manufactured using a single batch technology, Sympress. Here, we describe the development of two novel mass spectrometry based methods that allows identification of individual antibodies in the Sym001 drug substance, through the determination of unique marker peptides or antibody light chains. The two methods provide an unambiguous identification of the 25 unique antibodies comprised in the Sym001 drug substance. Furthermore, the light chain liquid chromatography-mass spectrometry (LC-MS) method has been developed to allow the determination of the relative distribution of the 25 antibodies. The light chain LC-MS method has demonstrated linearity, specificity, precision, and accuracy, thus qualifying it for use in the quality control of recombinant polyclonal antibodies for human use. The development of such quantitative methods is central for the development and quality control of additional therapeutic recombinant polyclonal antibody products.