Science Pool

The 11^th edition of our Drug Discovery Update (DDup) is dedicated to biotherapeutics discovery and development with a focus on artificial intelligence and machine learning and its opportunity in transforming antibody discovery.

In this edition, it covers:

• an introduction to antibodies including:
  • an overview of monoclonal antibodies as therapeutic agents
  • a history of antibody drug discovery platforms
• how Just - Evotec Biologics are exploiting artificial intelligence and machine learning to generate a novel humanoid antibody library biased towards highly desirable features
• a description of the process from idea to IND and beyond for antibody discovery and development
• facts and figures on the market for therapeutic antibodies
• an overview of function-focused antibody (FFmab) screening
• an interviews with the experts

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Stable expression of recombinant protein therapeutics in CHO cells often relies on random or semi-random genomic integration events which results in a widely heterogenous cell population. This leads to significant effort in clone screening during cell line development in order to identify clones with high expression, growth and product quality. 

In this publication, we focus on:

• the development of two targeted integration systems that express high levels of recombinant protein in CHO cells by: 
  • the installation of rationally designed piggyBac-based chromosomal landing pads
  • the use of site specific recombinases including PhiC31 and CRE 
• demonstration of the functional integration of several donor vectors encoding various therapeutic proteins including two monoclonal antibodies and one Fc-fusion molecule

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Loss of heart myocardium is considered to be an irreversible process which can eventually lead to heart failure. Adult cardiomyocytes divide at a rate of less than 1% per year and no cardiac stem or progenitor cell type contribute significantly to the replacement of lost myocytes. One approach being pursued to replace lost heart muscle and regenerate the heart is the use of stem cell-derived cardiomyocytes.

In this publication, we focus on an in-depth review of the use of human pluripotent stem-cell derived cardiomyocytes in heart regeneration including:

• a background to cardiac regeneration and the approaches used to address this
• preclinical research and achievements in the use of cell therapy and stem cell-derived cardiomyocytes for the replacement of lost heart muscle 
• an overview of existing open questions such as how the technology works, the duration of effect, patient selection, immunological issues and how to reduce risk
• a summary of the clinical trials currently ongoing in this field

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Dendritic Cells (DCs) are very efficient antigen-presenting cells and have long been considered as attractive candidates for cancer immunotherapy. They are obtained from the patient and loaded in vitro with tumour antigens and additional maturation stimuli and subsequently, infused back into the patient. However, after more than 200 clinical trials involving thousands of patients, clinical responses have been disappointing so far.

While the treatment is safe and well-tolerated and often elicits anti-tumour immunity in both patients with advanced stages of disease and those with minimal residual disease following tumour resection, only a minority of patients demonstrates objective response rates. There are several reasons why the results are disappointing, and while scientists have been able to address problems such as active immune suppression and evasion mechanisms of the tumour, some DC therapy-related aspects contributing to the limited clinical efficacy of DC therapy remain to be solved: the choice of the antigen, the method of loading, and, above all, the type of DCs used. Access to the full spectrum of DCs is limited and many subsets known to be very effective simply are not accessible as they can be derived from the patients only in very low quantities.

As a result, sentiment has switched to approaches viewed as more promising, such as checkpoint inhibitors or chimeric antigen receptor (CAR)-T cells.

Exciting advances with iPSCs

However, thanks to the recent advances made with induced pluripotent stem cells (iPSCs) interest in these vaccines has been renewed. iPSCs can be induced to produce dendritic cells and this provides an opportunity for the rational design of DC vaccines displaying additional functionality via genetic engineering technologies. As iPSCs also open up the possibility for the mass production of large numbers of high-quality iPSC-derived DCs, it is now possible to design next generation DC vaccines from engineered DCs.

Moreover, iPSCs also allow for the production of DC subsets that are not accessible as yet for therapeutic development because sufficient quantities could not be obtained. Examples are DCs facilitating anti-viral responses and a certain subset called CD141+ specialised on cross-presentation of antigens. The CD141+ subset, which is found in very low abundance in vivo, is of particular interest for cancer therapy as it induces optimal cytotoxic T lymphocyte (CTL) responses. Thanks to iPSC, these subsets now can be produced under cGMP conditions in bulk quantities.

Off-the-shelf cancer vaccines?

All in all, these advances may provide the opportunity to design off-the-shelf DC products suitable for cancer vaccines.

Evotec therefore has invested in British immune oncology company OXvax Ltd., a spin-out from the University of Oxford focused on the development of an advanced next-generation dendritic cell vaccine platform for the treatment of solid cancers. The company is pioneering the use of iPSCs as a novel source of CD141+ dendritic cells (DC) and is based on intellectual property from the Fairchild laboratory at the Sir William Dunn School of Pathology. OXvax’s technology addresses, among others, the low cross-presentation and the T-cell activation problems of past DC-based cancer treatments. The platform enables the manufacture at scale of an off-the-shelf, highly potent vaccine which addresses the major limitations that have frustrated cancer vaccine development in the past. If the approach is successful in oncology, it can also be expanded to other therapeutic areas, e.g. viral infections.

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Learn more about Human iPSC-Derived Mixed CNS Cells and their advantages including:

• Highly physiological neural networks
• Long term synchronous network activity
• Suitable as seizure liability mode

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Learn more about the advantages of human iPSC-derived cardiomyocytes including:

• Predictive and physiological cell model
• Applicable for drug development, preclinical research, and cardiac safety assessment
• Quantity, consistency and efficiency for HTS

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Learn more about in Vitro iPSC research services at Evotec including:

• Robust differentiation protocols or adaptation of client protocols
• High-quality production of iPSC-derived cells at large scale
• Disease-relevant phenotypic read-outs for exploratory research and compound profiling/HTS
• Proprietary iPSC patent portfolio in tissue and disease modeling

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Learn more about Multi-Omic Analysis of Induced Biotherapeutic Protein Production in CHO Cells Reveals Substantial Shifts in Energy Allocation in this presentation from PEGS Boston - Optimizing Protein Expression from May 2021. 

In this presentation, we focus on:

• Experimental design
• Data processing and analysis in transcriptomics
• Multivariate 'omic analysis
• CHO clone screenings

For more than a decade, Evotec has been closing strategic R&D collaborations in the area of induced pluripotent stem cells (iPSC), both with academic and industry partners.

The scope ranges from broad, long-term alliances to targeted research-driven collaborations. These partnerships support Evotec’s growing iPSC activities, strengthen the capabilities, and thus comprise a strong foundation for success within Evotec’s iPSC Lighthouse.

A brief overview of key references for iPSC partnerships is provided below.

Industry partnerships

In 2006, Evotec and CHDI Foundation, Inc. (“CHDI”) closed a strategic collaboration to advance drugs for the treatment of Huntington´s disease. The partnership builds on Evotec’s integrated neuroscience platform and its iPSC platform, among others, and was extended in 2018.

In 2016, Evotec and Celgene (now Bristol Myers Squibb) signed a broad R&D collaboration to develop disease-modifying treatments for neurodegenerative disorders based on Evotec's unique iPSC platform. The platform allows for systematic drug screening in patient-derived disease models. The partnership was expanded to include additional cell lines in 2018 and new cell types in 2019. Following the acquisition of Celgene by Bristol Myers Squibb, the agreement with Evotec was again expanded to further broaden the number of cell lines in 2020.

In 2020, Evotec formed an alliance with Sartorius and Curexsys to advance an iPSC-based exosome approach. The collaboration combines Evotec’s iPSC platform with Curexsys’ proprietary exosome isolation technology, while Sartorius will support Curexsys in setting up a GMP-compliant and scalable manufacturing platform.

Scientific collaborations

The first iPSC partnership was a collaboration with the Harvard Stem Cell Institute ('HSCI') in 2013 to identify compounds which prevent or halt the loss of motor neurons, a key symptom of amyotrophic lateral sclerosis ('ALS').

In 2017, Evotec entered into a research collaboration with the Center for Regenerative Therapies TU Dresden ("CRTD") to discover novel small molecule candidates for retinal diseases. Gola of the collaboration is to combine CRTD's expertise in stem cell-based retinal disease modelling with Evotec´s iPSC technology platform to generate promising drug candidates for potential clinical development.

In 2018, Evotec and Centogene signed an agreement for a global drug discovery collaboration to develop novel small molecules in rare hereditary metabolic diseases, which are generated by a joint high-throughput platform.

The collaboration was expanded into Gaucher´s disease in 2020, leveraging Evotec’s iPSC platform and broad drug discovery and development capabilities and Centogene´s proprietary rare disease platform, including iPSC lines, to generate novel treatment approaches for this orphan drug indication.

In 2021, Evotec and the Medical Center Hamburg-Eppendorf (“UKE”) signed a partnership for the development of a novel, innovative first-in-class cell therapy based on Engineered Heart Tissue for the treatment of heart failure. The goal is to produce human, clinical-grade heart muscle cells (cardiomyocytes) for implantation.

Evotec is continuously looking to expand its iPSC portfolio through industry and academic partnerships both within existing disease areas but also to expand into new disease areas. Reach out to us for questions around collaborations and partnerships.

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