Prof. Dr. Kerstin Otte
Prof. Dr. Kerstin Otte is a trained biologist from the Phillipps-University of Marburg, Germany and received her PhD in 1998 from the SL-University in Uppsala, Sweden. After a postdoctoral fellowship at the Gurdon-Institute in Cambridge, UK she gained industry experience for more than seven years at Graffinity Pharmaceuticals and LION Bioscience in Heidelberg, Germany. In 2006 she was appointed full professor at the University of Applied Sciences in Biberach. Kerstin Otte has extensive research experience in areas of basic and applied molecular and cell biology. Currently she has focused her research on cell line development for the production of biopharmaceuticals working closely with both academic and industrial collaborators to advance our understanding of cellular production.
microRNAs to enhance production of biopharmaceuticals
Biopharmaceuticals are highly complex biological drugs like antibodies for cancer therapy which are mainly produced by eukaryotic cell lines. Optimized and tailored mammalian production hosts are needed for the synthesis of regular and bispecific antibodies as well as other bispecific immunotherapeutics which are frequently difficult to express.
In contrast to classical cell engineering strategies like overexpression or knockout of single genes, our laboratory focuses on the development of micoRNAs as versatile tools to optimize production cells. MicroRNAs constitute an important class of non-coding RNAs in mammals. Individual miRNAs control entire cellular pathways without adding translational burden to cells and are able to beneficially influence bioprocess relevant characteristics like cell proliferation, apoptosis, protein production or protein glycosylation. For identification of candidate miRNAs we performed a whole miRnome screen by transiently introducing miRNA mimics into Chinese hamster ovary (CHO) - production cells. A remarkable number of impactful miRNAs were identified to affect bioprocess relevant pathways. Bioinformatic strategies complemented with molecular analysis enabled for the identification of specific miRNA target genes and underlying molecular mechanisms of action within in CHO production cells. Our comprehensive miRNA research led to the generation of a ‘miRNA target catalog' providing an avenue for next-generation CHO cell engineering.
Identification of intracellular production bottlenecks of monoclonal antibodies
The optimization of production processes for therapeutic antibodies is a continuing challenge with some antibodies appearing to be more difficult to produce. Additionally, with the advance of more complex biological formats such as bispecific antibodies or fusion proteins, mammalian expression systems often show low performance with cell lines displaying inferior product titers or insufficient product quality. Described determining factors may be accumulation or haltering of heterologous proteins within the different cellular compartments and thereby disturbing transport or secretion. Therefore, we developed a streamlined high-throughput compatible fluorescence microscopy based methodology optimized for CHO production cells tracing the recombinant protein traveling through the distinct cellular compartments of the secretory pathway. Using this technology, haltering organelles can be visualized as for example the endoplasmic reticulum, where massive protein accumulation and morphology changes compromise sufficient protein processing and secretion. Our research further addresses the underlying molecular mechanisms using electron microscopy, biochemical as well as transcriptomic analyses covering intracellular aggregation, inefficient antibody processing/assembly and cellular adaptation processes. The mechanistic understanding of molecular pathways will enable rational approaches to overcome cellular production bottlenecks.
Investigations on pro-apoptotic microRNAs in cancer
The development and progression of cancer can be ascribed to imbalances in gene regulation leading to aberrant cellular behavior. The loss of microRNAs exhibiting tumor-suppressive function has been demonstrated to be often causative for uncontrolled cell proliferation, migration or tissue infiltration. Therefore, the installation of de novo tumor suppressive function by using pro-apoptotic miRNAs might be a promising therapeutic approach.
This prompted us to perform a microRNA screen for pro-apoptotic functions in human cancer cell lines which led to the discovery of novel apoptosis inducing microRNAs. Focusing on ovarian and colorectal cancer cell lines, analysis of endogenous expression of individual miRNAs and dissection of molecular pathways by ectopic miRNA expression will unravel the regulation of miRNA induced pro-apoptotic signaling pathways. These findings can finally present starting points for miRNAs to be developed for future therapeutic applications as well as for cancer diagnostics and prognosis.
Invited conference presentations