Science Pool

Download our presentation from Recovery of Biological Products XX titled “Turning the crank using a hybrid continuous purification platform” from Michelle Najera, Megan McClure, Shahbaz Gardezi and Beth Larimore. 

Learn how:

1. Process intensification solutions for monoclonal antibodies, Fc-fusion proteins and bispecific antibodies t ease liquid handling pain points.
2. Our J.CHO High Expression System is delivering perfusion permeate titers of over 2 g/L/d over 25 days.
3. Continuous capture chromatography significantly enhances resin utilization
4. Two tank virus inactivation steps can be developed with bench-scale models

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This poster describes the rapid conversion of an intensified fed-batch antibody manufacturing process to an integrated continuous biomanufacturing process using the Just-Evotec Biologics platform, resulting in several key project accomplishments: 

• Mitigation of upstream IFB challenges
• Significant productivity increase
• Short development time
• Minimal risk from changes in product quality

These results demonstrate that the rapid conversion of fed-batch processes for monoclonal antibodies to an integrated continuous biomanufacturing process can be achieved with a robust ICB platform. This supports the biotherapeutics industry’s need to quickly adapt to changing clinical and business circumstances.

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Biologics manufacturing typically uses engineered Chinese Hamster Ovary (CHO) cells to produce folded and glycosylated antibodies. Determining the optimum conditions to grow and maintain cell culture often requires considerable time and effort.

A quantitative understanding of cell metabolism through an analysis of cell culture metabolites can enable optimization growth conditions for improved titles or increased perfusion duration. Mass spectrometry is the optimum tool for metabolite measurement, however, transforming raw data into accurate quantitative measurement requires both expertise and extensive sample preparation.

In this poster we demonstrate the ability of simple sample preparation using universal calibrators and a novel machine learning algorithm to rapidly provide biological insight into bioprocessing samples taken from perfusion cell cultures.

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Continuous biomanufacturing arrives in Europe:

Nick Hutchinson, Head of Market Development at Just – Evotec Biologics, explains the benefits of this new approach, why the company’s new cGMP manufacturing facility, J.POD® Toulouse, France (EU), is the first of its kind in Europe and what this means for the industry.

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Autoimmune diseases (ADs) represent a significant challenge in healthcare, affecting millions worldwide. These conditions arise when the body's immune system mistakenly attacks healthy tissues, leading to chronic inflammation and tissue damage. While current treatments for ADs focus on immunosuppression, they often come with significant side effects and provide only symptomatic relief. In recent years, there has been growing interest in cell-based therapies, particularly CAR (chimeric antigen receptor) cell therapy, as a potential solution to address the underlying causes of ADs.  

Autoimmune diseases encompass a wide range of conditions, including rheumatoid arthritis, lupus, multiple sclerosis and inflammatory bowel disease, among others. Despite their diverse manifestations, these diseases share a common underlying pathology of immune dysregulation. In healthy individuals, the immune system is finely tuned to distinguish between self and non-self antigens, but in autoimmune disorders, this distinction becomes blurred, leading to an attack on the body's own tissues. 

CAR cell therapy offers a promising approach to treating ADs by depleting disease-driving immune cells and rebalancing immune homeostasis. CAR T cells, which are engineered to express synthetic receptors targeting antigens expressed on the surface of pathogenic cells, have shown remarkable success in treating certain cancers. Now, researchers are exploring the potential of CAR T cells and their counterparts, CAR iNK (natural killer) cells, in targeting the aberrant autoreactive cells implicated in autoimmune diseases to reset the immune sytsem¹. We believe that cell therapy approaches could provide long-lasting drug-free remission and potentially a curative treatment for AD patients.

Understanding CAR Therapeutics

CAR T cell therapy first emerged as a groundbreaking treatment modality for hematological malignancies, such as leukemia and lymphoma. Building on this clinical success, researchers have recently turned their attention to applying CAR cell therapy to treat autoimmune diseases. 

In the context of ADs, CAR T cells have been investigated for their ability to target autoreactive T cells or B cells. B cells, in particular, play a central role in many autoimmune disorders by producing autoantibodies and driving inflammation. One promising target for CAR cell therapy in ADs is the cell surface protein CD19. High-level expression of CD19 is maintained throughout the majority of B-cell differentiation stages. By targeting CD19-positive B cells, CAR T cells or CAR NK cells can selectively eliminate the autoreactive B cell populations responsible for driving autoimmune responses². 

A recent early clinical study showed promising results for using CD19 CAR T cell therapy to treat ADs. Patients with systemic sclerosis, severe Systemic Lupus Erythematosus (SLE), and idiopathic inflammatory myositis showed remission following therapy³. However, CAR NK cell therapy may be beneficial over CAR T cell therapy, particularly in ADs that have dysfunctional T cells. CAR T cell therapy may also result in side-effects such as GvHD (Graft-versus-host disease, worsening the AD symptoms), neurotoxicity, and cytokine release syndrome; CAR NK cell therapy may offer a safer alternative⁴. 

Despite the potential of CAR cell therapy in ADs, several challenges remain, including scalability, persistence, and off-target effects. Evotec's innovative approach to addressing these challenges involves the use of induced pluripotent stem cells (iPSCs) to generate allogeneic off-the-shelf CAR iNK cells with enhanced scalability and precision. iPSCs, reprogrammed from adult somatic cells, offer a potentially inexhaustible source of immune cells that can be genetically engineered and differentiated into various cell types to tackle a range of diseases.

iPSC-Derived CD19 CAR iNK Cells for Targeted B Cell Depletion

A study by researchers at Evotec investigated the performance of iPSC-derived CD19 CAR iNK cells as a novel therapeutic approach for ADs. Using Evotec’s validated GMP iPSC line, researchers produced genetically modified cells with a knock-in of CD19-CAR. The modified cells successfully differentiated into CD19 CAR iNK cells using a feeder-free 3D differentiation process, which could be confirmed by flow cytometry. The established protocol can ensure high purity and functionality of the resulting cells. Results showed that iNKs generated from the GMP iPSC line were homogenous and phenotypically comparable to blood-derived (BD) NK cells form healthy donors.  

Figure 1: Cytotoxicity against SLE patient B cells. NK killing assays of effector cells - iNK without CAR (WT), CD19 CAR iNK or healthy donor BD NK cells (BD-NK) co-cultured 1:1 (E:T) with SLE patient B cells, + 10μg/ml anti-CD20 antibody (Obinutuzumab (Obi)) or isotype control (Iso) (n=2). 

In vitro experiments demonstrated the cytotoxic effector function of CD19 CAR iNK cells in selectively targeting and eliminating CD19-positive B cells. Co-culture assays using patient-derived primary B cells from patients with SLE autoimmune disease, showed robust cytotoxicity of CD19 CAR iNK cells. The CD19 CAR iNK cells were more efficient than iNK cells without a CAR or BD NK cells in depleting the patient-derived primary B cells. These findings highlight the therapeutic potential of CD19 CAR iNK cells in treating ADs, offering a targeted and scalable alternative to conventional immunosuppressive therapies.

Evotec's Scalable Therapeutics Approach

Evotec's commitment to allogeneic cell therapy innovation is exemplified by its scalable therapeutics approach, which leverages cutting-edge technologies and infrastructure to develop next-generation therapies for ADs. Central to this approach is the use of iPSCs as a platform for generating CAR iNK cells with enhanced scalability and precision. By introducing CARs targeting CD19 into iPSCs and differentiating them into iNK cells, Evotec aims to create scalable and precise off-the-shelf therapies for ADs. 

Figure 2: Evotec’s pipeline to co-create iPSC-based cell therapeutics with partners in Inflammation & Immunology.

Evotec's end-to-end process for iPSC-based therapeutics encompasses differentiation, gene editing, preclinical and clinical development, ensuring the efficient generation and characterization of CAR iPSC-derived cells. By utilizing validated GMP iPSC lines and GMP-compatible differentiation protocols, Evotec ensures the safety and quality of its allogeneic cell therapy products, paving the way for clinical translation.

Figure 3: Evotec’s end-to-end process for iPSC-based therapeutics. 

The scalability of Evotec's approach enables the production of large quantities of CAR iNK cells, making them suitable for widespread use in treating ADs. Additionally, the precision of iPSC-derived CAR iNK cells allows for targeted and personalized therapies tailored to individual patients' needs, reducing the risk of off-target effects and enhancing treatment efficacy.

Future Potential with Evotec

Evotec's iPSC-derived CD19 CAR iNK cells represent a promising new approach to treating autoimmune diseases. By harnessing the power of iPSC and CAR technology, allogeneic cell therapy can help revolutionize the treatment landscape for ADs, offering patients a targeted, scalable and potentially curative alternative to conventional therapies. 

As research in this field continues to advance, Evotec remains at the forefront of allogeneic cell therapy innovation, driving the development of next-generation treatments for ADs (Figure 2). Evotec’s GMP-compliant production pipelines provides an efficient, reproducible, and scalable way to produce CAR iNK cells derived from iPSC for clinical development. With its commitment to precision medicine and scalable therapeutics, Evotec is well-positioned to meet the growing demand for effective and accessible off-the-shelf therapies for autoimmune diseases.

See more iPSC-based Cell Therapies for I&I Diseases

To discover more about this research, download our scientific poster

References: 

(1) Blache, U.; Tretbar, S.; Koehl, U.; Mougiakakos, D.; Fricke, S. CAR T Cells for Treating Autoimmune Diseases. RMD Open 2023, 9 (4), e002907. https://doi.org/10.1136/rmdopen-2022-002907.

(2) Jin, X.; Xu, Q.; Pu, C.; Zhu, K.; Lu, C.; Jiang, Y.; Xiao, L.; Han, Y.; Lu, L. Therapeutic Efficacy of Anti-CD19 CAR-T Cells in a Mouse Model of Systemic Lupus Erythematosus. Cell. Mol. Immunol. 2021, 18 (8), 1896–1903. https://doi.org/10.1038/s41423-020-0472-1.

(3) Müller Fabian; Taubmann Jule; Bucci Laura; Wilhelm Artur; Bergmann Christina; Völkl Simon; Aigner Michael; Rothe Tobias; Minopoulou Ioanna; Tur Carlo; Knitza Johannes; Kharboutli Soraya; Kretschmann Sascha; Vasova Ingrid; Spoerl Silvia; Reimann Hannah; Munoz Luis; Gerlach Roman G.; Schäfer Simon; Grieshaber-Bouyer Ricardo; Korganow Anne-Sophie; Farge-Bancel Dominique; Mougiakakos Dimitrios; Bozec Aline; Winkler Thomas; Krönke Gerhard; Mackensen Andreas; Schett Georg. CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-Up. N. Engl. J. Med. 2024, 390 (8), 687–700. https://doi.org/10.1056/NEJMoa2308917.

(4) Műzes, G.; Sipos, F. CAR-Based Therapy for Autoimmune Diseases: A Novel Powerful Option. Cells 2023, 12 (11), 1534. https://doi.org/10.3390/cells12111534.

Continuous biomanufacturing is reducing the cost of goods of biopharmaceuticals. Achieving continuous manufacturing requires expertise in equipment design.

Download the highlights of Andrea Isby's presentation at Repligen's DSP Workshop in Estonia from May 23rd, 2024 to learn more. 

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High-throughput screening methodologies have accelerated downstream development for monoclonal antibodies by enabling parallelized evaluation of chromatographic resins across a range of conditions. However, scientists must now interpret results in a meaningful and consistent way.

Learn how Just - Evotec Biologics' Downstream Data Browser automates visualization of high-throughput datasets, fits response surface statistical models, standardizes report results from a high-throughput screening method and facilitates comparison across molecules allowing the accelerated development of continuous biomanufacturing processes.

Read our poster to learn more

Inflammatory Bowel Disease (IBD) is the umbrella term for a group of diseases characterized by chronic, idiopathic and remitting inflammation of the gastrointestinal tract. Common symptoms include diarrhea, abdominal pain, and fatigue. However, extraintestinal manifestations such as inflammatory arthralgias/arthritides, primary sclerosing cholangitis (PSC), ocular or cutaneous involvement are often present and add to the complexity of the clinical picture.

The two most common forms of IBD are Crohn's disease and ulcerative colitis. Crohn's disease can cause inflammation anywhere in the gastrointestinal tract from the mouth to the anus, while ulcerative colitis is usually confined to the colon, where it can cause inflammation and ulceration. In about one in ten people, the two diseases cannot be clearly distinguished, and the condition is called indeterminate colitis. With approximately 6-8 million IBD patients worldwide (2 million in Europe and 1.5 million in North America), there is a huge unmet medical need.

IBD is an immune-mediated disease, but the exact causes are unknown. Crohn's disease, for example, involves a complex interplay of genetic predisposition, immune dysregulation, environmental influences, and microbial factors.

This complexity poses many challenges for drug development, as exemplified by the recent failure of a drug approved for ulcerative colitis that failed in late-stage clinical trials for Crohn's disease. The important lesson here is the need for proper patient stratification.

With its multimodal approach and patient stratification tools, Evotec is well positioned to develop innovative medicines. The Company is focused on development of IBD medicines through in-house research and through collaborations. Evotec’s strategy is modality agnostic, utilizing Evotec’s entire scope of technology platforms - from small molecules to biologics as well as iPSC-based cell therapies.

The Evotec approach

Drug discovery at Evotec always starts with patient data. Evotec's drug discovery efforts are based on its proprietary panOmics approach and a proprietary portfolio of molecular patient databases (E.MPD). panOmics combines both data generation and analysis platforms to industrialize OMICs data generation and AI/ML-based omics data analysis. Based on proprietary molecular patient data, panOmics fundamentally improves the understanding of disease processes, in vitro and in vivo disease modeling, identification of novel high value targets, biomarker discovery and patient selection.

Another integral aspect of drug development at Evotec is precision medicine. For this approach, Evotec has developed a comprehensive patient stratification toolbox via its panOmics-driven diagnostic approach – EVOgnostic.  

Therefore, IBD patients are an integral part of a pilot study in which Evotec is performing plasma and metabolomic analyses on samples from autoimmune disease patients to combine these clinical data with experimental data and data science approaches to identify potentially novel biomarker signatures.

Evotec aims to develop medicines that allow an early intervention and or, ideally, a cure for patients suffering from IBD. Evotec is engaged in several drug discovery programs tackling various aspects of IBD such as restoration of epithelial barrier function, modulation of inflammation, or resolution of intestinal fibrosis. Depending on the different aspects of the disease. Evotec’s experts are engaged in the IBD community and you can see our recent poster summarizing our IBD activities here. 

Selected collaborations

Evotec also is constantly seeking to enhance its capabilities through strategic investments and collaborations. For example, in 2022 it invested in IMIDomics Inc., a company focused on immune-mediated inflammatory diseases (IMIDs). IBD constitutes a large part of IMIDs. The aim is to jointly develop and use IMIDomics' Precision Discovery™ Engine. This technology enables a deep understanding of how inflammatory diseases work in patients. It applies a combination of clinical and computational expertise to clinical data and biological samples from more than 17,000 patients in a biobank, generating proprietary biomolecular signatures. 

With the Crohn's & Colitis Foundation, Evotec is advancing drug discovery for two novel IBD drug targets originating from academic research. The targets address fibrosis, the excessive accumulation of scar tissue in the intestinal wall, and the restoration of intestinal barrier function in IBD to reduce the increased intestinal permeability and chronic intestinal inflammation often seen in IBD patients.

Efficacy models in IBD

Another challenge in IBD is the lack of adequate animal models. While more than two dozen mouse and rat models of colitis have been developed and implemented, the multifactorial etiology and highly heterogeneous manifestations of the disease have prevented the development of a model that fully represents the pathophysiology of human IBD and related complications. Each mouse model has its strengths in elucidating the pathogenesis of colonic inflammation, fibrosis, or CAC, but each has a self-limiting nature and shows marked variability in drug development. While these IBD models cannot fully recapitulate the disease features commonly seen in humans (genetic and environmental influences, gut microbiota interactions, etc.), they have led to the identification of three key elements for disease etiology: T lymphocytes (T cells) mediate chronic intestinal inflammation; intestinal inflammation is initiated and maintained by certain commensal intestinal bacteria; the onset and severity of the disease is largely dependent on the genetic background.

Therefore, Evotec has carefully selected several preclinical models that recapitulate key aspects of IBD: inflammation, leukocyte trafficking, breakdown of epithelial barrier integrity, T cell-mediated injury. These models are routinely used and complemented by the current gold standard: the T cell transfer model of chronic colitis. This mouse model best reflects the clinical pathology observed in IBD and dissects the initiation, induction, and regulation of T cell-mediated immunopathology. 

In summary, Evotec is advancing breakthrough solutions for IBD using the most advanced technologies and platforms available. The Company's primary focus is on precision medicine and leading-edge approaches with the goal of providing tailored, effective, and minimally invasive treatments by taking into account the unique characteristics of each patient.

Download our poster from the IBD Innovate Conference

IBD is a collective term for a range of clinical phenotypes caused by chronic, idiopathic and remitting inflammation of gastrointestinal tract. Crohn’s disease and ulcerative colitis are the two most common forms. Despite many advancements in the treatment of IBD, there remains a high unmet medical need to provide patients with an early intervention of highly effective therapy, preferably with curative potential. 

Evotec is currently engaged in several drug discovery programs tackling various aspects of the disease such as restoration of epithelial barrier function, modulation of inflammation and intestinal fibrosis.

Given the heterogeneity of the disease, we actively invest into efforts leading to increased disease understanding and stratification of patients based on the disease endotypes.

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Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0] hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.

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