Our agenda is expertly curated by an experienced team of producers with an expansive global network.
The Festival of Biologics is your opportunity to hear from industry leaders, global regulators and world-renowned academics at the forefront of innovation. Join us for 3 days of cutting-edge insights into the latest industry developments.
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Innovation and adapted regulations and policies will come to play a pivotal role in addressing challenges and expanding access across healthcare systems globally. At Sandoz, we strongly believe that next-generation drug delivery approaches can meet the growing needs of new and increasingly complex biosimilars. And, that these in turn will provide more affordable treatment options for more patients and contribute to the overall sustainability of the global healthcare system through crucial cost savings.
Digital transformation is driving change in biopharmaceutical companies of every size. With the steady increase in laboratory automation, growing data stores across all modalities including multi-specifics, cell and gene therapies, and RNA therapeutics are being leveraged for AI/ML approaches. Multiple digital solutions need to be connected and structured into robust data streams so that companies can seamlessly access, analyze, integrate, report, and model data for R&D projects. We will discuss emerging lessons showing how biopharma and biotech companies are connecting every part of data and analytics ecosystems to extract maximum value, reduce effort duplication, and implement AI/ML approaches.
Global patient demand for biological medicines continues to grow driven by an increasing burden of cancers, infectious disease, immunological and neurological disorders. The World Economic Forum reports medicine supply challenges are being faced around the world leading to medicine shortages. Companies manufacturing biologics must have resilient supply chains that can be adapted to circumstances such as meeting the needs of niche markets, addressing the threat of pandemics, and controlling the costs of new medicines.
FUJIFILM Diosynth Biotechnologies is fostering trusting partnerships with clients by executing its strategy of building a global network of modular-designed large-scale and single-use facilities through an aligned production platform. This will allow customers to ramp up production rapidly and transfer processes at unprecedented speed. To support clients further we have developed an innovative single-use continuous biomanufacturing platform providing even more agility and with the potential to improve product quality while reducing medicine production costs.
Early-stage antibody discovery requires efficient and comprehensive approaches to identify promising candidates with optimal developability characteristics. This presentation explores the integration of a bioinformatics platform that combines next-generation sequencing (NGS) analysis tools with machine learning algorithms to optimize various aspects of antibody developability.
The PipeBio Bioinformatics Platform serves as a centralized hub for processing and analyzing NGS data, enabling researchers to efficiently handle large volumes of sequencing information. Through sophisticated algorithms and pipelines, the platform offers automated solutions for data quality control, sequence annotation, and identification of antibody candidates. Leveraging the power of NGS analysis, researchers can quickly identify potential candidates and gain insights into the diversity and repertoire of antibody sequences.
Furthermore, the integration of machine learning tools within the bioinformatics platform enhances the optimization of antibody developability. By training models on datasets encompassing diverse developability attributes, machine learning algorithms can predict key characteristics such as stability, solubility, and immunogenicity. These predictive models enable researchers to prioritize and select antibody candidates with improved developability profiles, increasing the chances of success in subsequent stages of development.
The presentation will highlight the practical implementation and benefits of this integrated bioinformatics platform. Case studies and real-world examples will showcase how the platform has expedited early-stage antibody discovery by efficiently processing NGS data and utilizing machine learning to optimize developability characteristics.
Multi-attribute method (MAM) using mass spectrometric detection and quantitation of biopharmaceutical quality attributes is used extensively in biopharmaceutical development and increasingly for cGMP testing. At Symphogen numerous challenges associated with conventional trypsin-based MAM workflows have been evaluated and addressed. Here the progression and maturation of an automated MAM workflow will be presented, with emphasis on - often overlooked - challenges and how these have been addressed. Topics covered in this presentation include solubility of hydrophobic peptides, chromatographic peak tailing/carry-over of challenging peptides, missed cleavages, and acid-catalyzed deamidation.
Success in antibody discovery requires flexibility and risk mitigation. ADS’ fit-for-purpose antibody discovery strategies are empowered by the combinatorial and somatic diversity produced by the suite of AlivaMab® Mouse strains and enhanced through ADS’ unique capabilities for recovering and interrogating an immune repertoire. Case studies featuring ADS strategies for rapidly identifying diverse antibody panels against challenging targets from AlivaMab Mice will be presented.
Genetic immunization unlocks a vast pool of highly diverse, high-affinity antibodies beyond conventional protein immunization. Our approach combines cutting-edge immunization strategies, single B cell screening platforms, and Gator Bio's biolayer interferometry to generate and characterize best-in-class anti-idiotypic antibodies (anti-IDs). This presentation illustrates that these technologies efficiently identify a robust panel of high-affinity anti-IDs that are ideal for pharmacokinetic applications.
Increasing pipelines and the vision to computational design drives the evolution of Developability towards higher throughput technologies. Show casing two enabling technologies: HT Intact Mass & Peptide Mapping Analysis.
The presence of inactive, empty capsids in potentially large quantities is one of the main challenges in AAV production. Quantifying the ratio of empty / full AAV capsids is currently challenging – existing methods are not quick and simple enough to be employed throughout the process. Mass photometry is an easy-to-use bioanalytical technology that measures the empty-full AAV capsid ratio in minutes using minimal sample amounts and without the need of sample preparation. Circumventing the requirement of large capital expense and skilled operators, it can be employed throughout the development and manufacturing processes. Here, we present the mass photometry instrument dedicated to the challenges of AAV characterization, SamuxMP, and the coming software to enable its use in GMP regulated environments.
The Apollo™X expression system and associated technologies provide robust and versatile solutions that are compatible with a diverse range of biotherapeutics, such as bispecific and Fc-fusion molecules. We demonstrate that the system has the ability to express these proteins efficiently. The inherent complexity of these molecules means that product quality assessments during developmentcan be challenging. FUJIFILM Diosynth Biotechnologies has developed methods to support this analysis which allows a streamlined development process.
Mass photometry, an analytical technology for biomolecular characterization, measures the mass of single particles in solution. The TwoMP is an easy-to-use instrument that can measure the mass and relative abundance of particles between 30 kDa and 5 MDa, with little sample. With mass photometry is possible to study antibody-antigen interactions, quantify small-molecule induced changes to complex formation, assess sample purity and more.
Indeed, not all proteins are created equal and some behave better than others. To triage lead therapeutic candidates to identify those with favorable biophysical properties, ATUM has created a suite of assays that can be used to limit the risk of choosing to develop a molecule that may pose future difficulties during development. This presentation will describe the suite of assays as we as provide examples of how it was used in various case studies.
Mammalian display libraries can be interrogated consecutively for manufacturability and specificity. Similarly, libraries secreting antibodies are a perfect match for microfluidics-assisted high throughput function first screens. The versatility and options arising from combinations of these emerging technologies will be discussed.
Oncolytic virus (OV) are one the most promising anticancer biotherapy. They have been studied for more than 70 years, but yet oncolytic virotherapy has a limited role for advanced cancer patients, with in regular use in the clinic as an approved treatment. OVs are rapidly moving towards the forefront of modern medicines, but much remains to be elucidated regarding their efficacy and implantation in patients with hard-to-treat tumors. During this lecture, we will discuss on new experimental models, technological approaches or computational modelling strategies, to better select patients or to devise new therapeutic combos to bring virotherapy to the next level, with a focus on pancreatic adenocarcinoma.
Modern discovery of biological molecules is a data-driven process where machine learning is playing an increasingly important role. Discovery and development derived data is heterogeneous and ever-changing, which contributes to the challenges with making sure that the full value of your data can be extracted. Bionamic is a game changing system that is designed to increase traceability and efficiency in this process. It can serve data to any existing models and track the result, while also transforming your discovery projects into well-organised datasets ready for the next generation of AI powered tools.
Senior Representative, Veraxa
CRS is one of the major safety liabilities associated with treatment with T cell engaging therapies in the clinic, including CAR-T cells and T cell engagers. A series of in vitro and in vivo preclinical studies were conducted to gain a better understanding on the biological mechanisms inducing CRS, providing new avenues for the mitigation of the same.
Generative models, such as inverse folding and protein language models, are becoming essential tools for exploring protein mutational space to identify biologics with enhanced therapeutic properties. In the context of antibodies, the primary objectives are to improve molecular affinity and biophysical characteristics. However, the extent to which these models can offer valuable insights with limited or zero experimental data remains unclear. This talk will evaluate the utility, limitations, and potential strategies for effectively employing these models in the antibody engineering process
Oxidation is a common posttranslational modification in proteins that can have an impact on a drugs potency, efficacy or safety. In this talk the approach is outlined how a proteins liability for oxidation is identified as part of the developability assessment. The integration of in-silico analysis during early candidate selections is outlined and the experimental confirmation during late phase development described based on a case study using different protein formats.
MCLA-129 is a full-length, IgG Biclonics® binding to EGFR and c-MET, capable of overcoming c-MET-dependent EGFR TKI resistance mechanisms following ligand-induced signaling. MCLA-129 is glycoengineered to enhance its Fc mediated ADCC and ADCP activity thus allowing it to inhibit tumor growth independent of EGFR or c-MET signaling. MCLA-129 holds promise as a potential treatment option for NSCLC and other solid tumors.
OmniAb’s platforms on Antibody Discovery and Screening Technologies enable the discovery of next generation therapeutic antibodies/binders by harnessing the Biological Intelligence™ of our proprietary transgenic animals. While OmniChicken®, OmniRat® and OmniMouse® have been genetically engineered to generate monoclonal antibodies with human sequences to facilitate discovery of human therapeutic candidates, OmniFlic® (transgenic Rat) and OmniClic® (transgenic Chicken) have been engineered to generate bispecific antibodies through a common light chain approach. OmniTaur™ is a platform inspired by cow antibodies and leverages their unique structural attributes to tackle complex targets such as Ion channels and Transporters. Antibody Discovery at OmniAb is effectively complemented by our Antigen Design and Development platform with demonstrated success at producing functional complex antigens including GPCRs, Ion Channels and Transporters along with proprietary B-cell screening platforms that effectively mine next-generation sequencing datasets with custom algorithms to identify fully human antibodies with superior performance and developability characteristics. With 3 approved products, 24 programs in the Clinic and 270+ programs in Discovery, OmniAb platforms have been leveraged over the years by our partners across modalities to create life-saving therapeutics.
The development of effective bi-specific antibody therapies for oncological patients, despite a few key breakthroughs, remains a daunting challenge for biopharma. An astonishing fraction (88%) phase I clinical trials fail to progress further, resulting in substantial financial setbacks, wasted time for drug developers and reduced hope for patients in need.
A primary contributor to this high attrition rate is the limited ability to predict clinical efficacy based on currently employed in vitro and in vivo assays, such as cell killing and cytokine release assays.
Recently, a novel key biomarker emerged in the form of cell avidity (CA), which has established itself as a superior predictor of in vivo efficacy when compared to conventional killing or cytokine secretion assays. (References: Larson et al. 2022, Nature; Chockley et al. 2023, Nature Biotechnology; Leick et al. 2022, Cancer Cell; Katsarou et al. 2021, Science Translational Medicine).
Cell avidity is defined by the sum of molecular interactions that occur at the cell-cell interface between a T cell and tumor cell. This is the key factor in determining the functional outcome and controlling tumor growth in both in vivo and clinical settings.
Our innovative service solution enables biopharma customers to access this new biological marker, allowing them to rank their Cell Engagers constructs based on their avidity, all at high throughput.
By leveraging this invaluable service, drug developers can gain a comprehensive understanding of the intricate interactions between engager molecules and target cells, facilitating the selection of the most efficacious CE candidates for seamless progression into IND filings.
This transformative approach has the potential to revolutionize immuno-oncology drug development, offering a promising avenue to increase the success rate of CE-based therapies and, ultimately, improve patient outcomes.
Owing to their remarkable capabilities to recognise two antigens simultaneously, bispecific antibodies (bsAbs) have continued to be a major trend in the biopharmaceutical sector in recent years. The increasing complexity of bsAbs presents a unique set of analytical challenges compared to monoclonal antibodies. Through concrete case studies, in this talk we provide insight on what analytical obstacles have been encountered and how these were navigated during the development of bsAbs.
An end-to-end generative AI platform for drug discovery including:
(1) Supporting basic information search;
(2) Target identification;
(3) De novo molecule design and optimization
Bio-Rad’s Pioneer Antibody Discovery Platform includes one of the largest Fab libraries ever made. The library contains over 2x10^11 unique human antibody sequences and has been extensively optimized for Fab selection and for IgG developability. In combination with the proprietary SpyDisplay selection platform and with the TrailBlazer modular antibody technology, Pioneer enables rapid identification and characterization of a diverse set of lead candidates. We will also introduce SpyLock, a novel approach for generation and early screening of bispecific antibodies with unprecedented speed and throughput.
As automation gains more and more traction in cell biology applications, Automata has been working on system designs for everything from basic cell line maintenance to on-demand assay ready cell plates. Automation of cell line development opens up the door to not just address those challenges of scaling throughput but also the possibility of layering in additional analytics for deeper datasets, earlier in the process.
Sincethe FDA approval of an NK-cell based cancer immunotherapy, the heterogeneity of primary NK-cell populations is becoming increasingly interesting. How can we shed light on these individual cell-characteristics in bulk analyses? Functional single cell experiments hold the solution, offering the user to monitor various properties of the killing events during an NK killing assay.
Current advancements aid high-throughput cell population analysis, but there is an urgent need for single cell studies in near in vivo conditions without stress, allowing to isolate cells of interest.
Enter ARRALYZE, a digital cell biology platform meeting these needs via miniaturized glass-well arrays. Cells are dispensed into micro-sized wells on a slide, imaged for analysis and isolated alive for downstream study. Coculturing various cell types is possible, making the technique ideal for immune cell assays.
A concrete example of how these assays are conducted will be presented in the talk. We believe the technology is valuable for immunology, therapeutic antibodies, and immunotherapy participants.
The theoretical antibody sequence space is immense and beyond the interrogation by ordinary wet-lab means. Deep learning has established its superiority in fields where high-dimensional big data is involved. We demonstrate the potential of deep learning to explore the whole antibody sequence space and find therapeutic candidates with superior efficacy and developability.
During this session, Christelle Dagoneau will present a unique platform concept which integrates the discovery, development, and manufacture of biologics in innovative and easily deployable production facilities called J.POD. She will particularly describe how Just-Evotec Biologics’ cutting-edge AI/ML protein design technologies combined with industry-leading intensified continuous bioprocess can help de-risk and accelerate biotherapeutics development from lead generation through IND to BLA while offering cost-effective and truly flexible clinical and commercial supply solutions.
At Lightcast we are developing a novel, programmable microfluidic platform that allows precise and highly flexible control of individual microdroplets using software-generated light patterns. Our massively parallel capability will enable higher screening capacity, allowing rare events to be detected such as antibodies for challenging targets. Every droplet is software-indexed, allowing monoclonal cells to be tracked and imaged at various timepoints. By merging droplets containing different cell types, reporters and /or other reagents, we can perform complex workflows with stepwise assays and sequential readouts with a level of flexibility beyond what is currently possible. Within the drug development space this has the potential to both accelerate functional characterisation and shorten optimisation time in Antibody Discovery and T-Cell workflows. Furthermore, as droplets remain individually addressable throughout, live cells of interest can be rapidly dispensed for downstream assays, such as clonal outgrowth and genomic or transcriptomic analysis.
It is becoming widely accepted that chain ratio balancing is critical for the robust high titer manufacturing of multispecific antibodies with good product quality. This talk will focus on the application for the Leap In Transposase cell lined development platform for addressing this challenge. Specifically, how the platform can be used to systematically and predictively vary the relative ratio of individual proteins in both 3 and 4 chain multispecific antibodies and the effects this can have on both titer and assembly. In addition to giving an overview of the platform a number of case studies will be presented
The attention-based mechanism introduced by AlphaFold1 (DeepMind) in the field of protein structure prediction has revolutionized Structural Biology studies. For the first time the quality of the predicted models were comparable to experimental structures in most cases, this provided scientists with an alternative to experimental structures to conduct refinement studies or to guide the interpretation of experimental data2. Specialised predictors have been developed to address specific classes of structures. Antibodies are a predominant class of therapeutics utilised effectively in multiple disease states, the paratope of the antibody which contacts the target consists of regions of non-conserved flexible loops. This inherent flexibility increased the complexity of structure prediction especially when using methods that rely on sequence alignments and secondary structure predictions. In this study we present for the first time a study to benchmark the quality of predicted antibody structures produced by several structure predictors, employing proprietary datasets from our internal database that the selected structure prediction tools could not have been trained on and are therefore blind. This resulted in the generation of an optimised structure prediction pipeline including analysis reports, annotation and correction of errors generated in the models to employ during antibody discovery and development workflows. The pipeline was used to predict the entire Observed Antibody Space Paired sequence database generating ~1.4M structures that will be used for the development of Machine Learning algorithms to build Antibody De Novo Design approaches.
Cancer is a tissue disease where heterogeneous tumor cells, stromal cells and immune cells form a dynamic ecosystem that evolves to support tumor expansion and ultimately tumor spread. The complexity of this system is the main obstacle to treat cancer. The study of the tumor ecosystem and its cell-to-cell communications is thus essential to enable an understanding of tumor biology, to define new biomarkers, and to identify new therapeutic routs and targets.
To understand the workings of the tumor ecosystem, highly multiplexed image information of tumor tissues is essential. Such multiplexed images will reveal which cell types are present in a tumor, their functional states, and how they interact together. To enable multiplexed tissue imaging, we developed imaging mass cytometry (IMC), a novel imaging modality that uses metal isotopes as reporters and currently allows to visualize over 50 antibodies and DNA probes simultaneously with subcellular resolution. In the near future, we expect that over 100 markers can be visualized. We applied IMC for the analysis of breast cancer samples in a quantitative manner. To extract biological meaningful data and potential biomarkers from this dataset, we developed a novel computational pipeline called histoCAT geared for the interactive and automated analysis of large scale, highly multiplexed tissue image datasets. Our analysis reveals a surprising level of inter and intra-tumor heterogeneity and identify new diversity within known human breast cancer subtypes as well as a variety of stromal cell types that interact with them.
In summary, our results show that IMC provides targeted, high-dimensional analysis of cell types, cell states and cell-to-cell interactions within the tumor ecosystem. Spatial relationships of complex cell states of cellular assemblies can be inferred and potentially used as biomarkers. We envision that IMC will enable a systems biology approach to understand and diagnose disease and to guide treatment.
We have previously shown that a periplasmic screening assay that links protein aggregation to bacterial susceptibility to b-lactam antibiotics is a powerful screen for protein re-design using directed evolution (Ebo et al. (2020) Nat Commun 11:1816). This talk will describe two novel iterations of this assay that firstly allows the aggregation of 1000s of variants to be assessed simultaneously and secondly, by introduction of an additional orthogonal screen, the ability to select for both aggregation resistance and target affinity.
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High throughput comprehensive characterization of antibody effector activity in the development of antibody-based therapeutics
In monoclonal antibody (mAb) drug development, it is common practice for the emphasis to be placed on the affinity of the antigen-binding region for its target, often relegating the Fc region's role to a secondary consideration in delivering desired safety and efficacy. Typically, the Fc region is considered late in the mAb design process, selected from a constrained library based on a pre-determined desired functional profile. However, recent research suggests that further optimization of Fc function can result in safer and more efficacious mAb products. To support this this paradigm shift, we have developed an industrialized high throughput poly functional profiling platform that provides comprehensive, high-throughput analysis of antibody effector activity. This platform is designed to evaluate the functional properties of antibody therapeutics by utilizing a set of up to 12 assays that measure antigen-specific antibody effector functions . Beyond the breadth of functions analyzed, three factors set our platform apart: 1) a capacity for high-throughput testing - thousands of mAbs can be processed in a single batch – which enables early phase hit-to-lead screening; 2) all the assays are antigen-specific and immune complex driven, and thus more faithfully replicate in vivo function than typical Fc receptor binding assays that are performed without antigen; and 3) assays are carried out in accordance with internationally recognized quality guidelines for robust and reproducible results, having been used to analyze tens of thousands of samples and qualified to support IND and BLA filings. By strategically characterizing Fc effector activities, developers can enhance the overall therapeutic efficacy and safety of mAb products.
Forimtamig is a GPRC5DxCD3 T-cell engaging bispecific antibody (TCB) that redirects T cells totarget and eliminate cells expressing GPRC5D, including malignant plasma cells. We have developedsimple QSP model that represents the mechanism of action of Forimtamig in the context of multiplemyeloma disease. The model is part of the Clinical Pharmacology strategy to inform dose and schedule decisions. In this talk we will present model development and calibration results.
Biotherapeutics represent one of the fastest growing segments in the pharmaceutical market. They are used in a broad range of treatments for various disease areas such as cancer, inflammation, cardiovascular, autoimmune and neurologic diseases. The increasingly complex molecules and diversity of modalities require continuous process improvements to the protein production platform. In this regard, two process optimization examples are reported: Enhance productivity by media development and increase platform robustness by designing a high throughput downstream platform for challenging modalities.
In this work we will present how capillary electrophoresis (CE) is being used to profile and analytical test new Gene Therapy products. The methods take advantage of the traditional approaches of CE and adapts them to analysing the building blocks of the gene therapy products and their delivery vehicles. CE is normally used to look at intact RNA or viral proteins but to dig deeper into small structural changes that effect this class of biopharmaceutical drugs scientists often employ mass spectrometry methods (LC-MS/MS). In this talk we will also look at how LC-MS/MS can be used to detect small changes in viral proteins in viral vectors, ionizable lipids impurity analysis and RNA analysis (after restricted digestion).
- Discussion of the role of glycans and glycan-binding immune receptors in cancer
- New approach to modify the tumor microenvironment
- Synergistic combination therapies of glycan-targeting therapeutics a T cell-based immunotherapies
To help decision-making in scientifical and pharmaceutical organizations, it is of major importance to monitor the development of products and technologies. Therefore, the aim of this study is analyze the landscape of nAbs for COVID-19.We identified 227 nAbs and performed an extensive literature review of 16 nAbs in late clinical development, including development technologies, responses to variants of concern (VOCs), manufacturing, and clinical aspects. Even though the emergence of new VOCs is a threat to the effectiveness of this treatment, demanding constant genomic surveillance, the use of nAbs to treat and prevent COVID-19 will probably continue to be relevant due to excellent safety profiles and the possibility of immediate immunity transfer, especially in patients showing inadequate immunological response to vaccination. Therefore, we suggest that organizations should keep investing in improvements in this technology.
Senior Representative, Twist Bioscience
Bispecific antibodies are an important and quickly growing treatment modality that can enable powerful mechanisms of action, such as redirecting the immune system to treat cancer and inflammation. However, limitations with conventional discovery and engineering approaches typically add time, cost, and risk to development programs. These challenges can be overcome with technologies that improve the identification and engineering of diverse, developable, and easy-to-manufacture bispecifics. AbCellera’s antibody discovery and development engine streamlines bispecific development by systematically integrating proprietary technologies to find optimal candidates from the start. Here, we present a case study demonstrating the discovery of hundreds of diverse parental antibodies with specific target-binding and cross-reactivity profiles. These were used to generate a large panel of precisely assembled heavy and light chain pairs using our OrthoMab™ multispecific engineering platform. We characterized the resulting bispecifics using our high-throughput antibody assessment and computational technologies, and rapidly identified high-quality bispecific development candidates.
Twist Biopharma, a division of twist Bioscience, combines HT DNA synthesis technology with expertise in antibody engineering to provide end-to-end antibody discovery solutions — from gene synthesis to antibody optimization. The result is a make-test cycle that yields better antibodies against challenging targets from immunization, libraries, and machine learning. Twist Biopharma will continue to optimize and expand its discovery, library synthesis and screening capabilities in partnership with others to further utilize their make-test cycle.
The Novartis BioFuture program has “redefined” how we develop and manufacture biologically derived protein therapies to our patients. A key innovation of the BioFuture Vision is the concept of an integrated end-to-end production process, integrating high-density perfused batch (HDPB), continuous product capture, and connected-downstream purification. The Novartis team carried out the process characterization of the first ever BioFuture processes
The conventional linear triage funnel approach has long dominated the landscape of antibody discovery and optimization. However, IPA’s recent advancements in highly scalable, computational biology and high-throughput, early-stage screening capabilities have revolutionized the lead selection process. The presented integrated workflow of function-first single B cell discovery with in silico antibody de-risking assessment – including immunogenicity and developability screening – and lead optimization underpins the power of combining experimental and computational insights to significantly expedite the development of the most suitable candidate for clinical application.
AATec Medical develops ATL-105, a novel product platform based on recombinant alpha-1 antitrypsin (AAT) for inhalation for the treatment of virus infections and inflammatory diseases. AAT provides combined broadband antiviral and anti-inflammatory therapeutic effects through targeted protease inhibition and cytokine modulation. Proof-of-principle was demonstrated for ATL-105 in several indications. During the presentation, updates will be provided on efficacy studies, inhalation technology and product development.
Although there is significant interest in unveiling the principles of antibody pharmacokinetics, our understanding of multi-specific antibodies remains limited. By estimating the surface patch landscape of the cross-over dual variable Ig-like (CODV-Ig) format, we were able to correlate such in silico findings with in vivo clearance, establishing the principles of pharmacokinetic predictions for multi-specific antibodies.
Discussion topics include:
At LifeArc we carry out high-throughput antibody screening to discover, characterise and deliver therapeutic monoclonal antibodies. We perform detailed kinetic profiling, epitope specificity, cross reactivity, functional binding and a suite of developability assessment assays to ensure successful downstream development of our lead molecule. We are always looking at ways to innovate our screening platform to ensure we remain at the cutting edge of technology, enabling us to characterise more molecules in a more efficient process. Recently we have purchased the Carterra LSA and here we will share the evolution of our screening platform and how the LSA will enhance our discovery workflow.
Senior Representative, Biotechne
Novel modalities of Cell and Gene Therapy have huge potential in treating diseases but bringing them to patients remains a big challenge. While patient-centric, on-demand and on-time manufacturing represents the future in the field, understanding the specific needs of personalized treatment requires a holistic vision of the whole process, from the hard-core scientific and medical background of each patient to operational and manufacturing. Our approach through collaboration with a multidisciplinary team of experts in all parts of this equation and state-of-the-art technology, enables us to follow and characterize the product in time, as it is being developed. As each treatment is unique, we use technology to steer and control the process, aiming the best quality for the final product.
CD270 has three known ligands, of which both CD160 and BTLA are co-inhibitory, whereas LIGHT is co-stimulatory to T cells. High expression of the CD270 on tumors strongly correlates with poor survival and an immunosuppressive TME. Anti-CD270 antibodies were selected that specifically inhibit the interaction with immune suppressive ligands CD160 and BTLA but do not inhibit the immune stimulating CD270-LIGHT interaction.
Bi- and multispecific antibodies are important molecules for new therapeutics not only for cancer immunotherapy but have also a high potential for other indications ranging from infectious diseases to bleeding disorders. Single domain antibodies are the smallest robust antibody units. The talk will present a comprehensive comparison of formats for the generation of robust bispecific antibodies through fusion of single-domain antibodies on IgG scaffolds in combination with Fab. It comprises a toolbox of complementary methods for in-depth analysis of key features, such as in-solution dual antigen binding, thermal stability, and aggregation propensity, to ensure high bsAb quality. Furthermore, a set of novel in-silico designed humanized single-domain antibody phage display libraries with maximal functional diversity and CDR3 lengths from 10 to 25 aminoacids for generating fusion partners will be presented.
Steering cellular processes with the same type of molecules that normally govern cells would be a powerful approach for new therapies. The challenge to deliver macromolecules like proteins, RNA or DNA to the inside of cells has so far limited the use of these molecules as drugs. However, the approval of RNA-based vaccines during the pandemic has just recently demonstrated how previously perceived limits can be shifted. Exploring further approaches for intracellular delivery of biologicals may allow the development of promising, entirely new types of therapeutics. Strategies for targeting the inside of cells with biologicals with their opportunities and limitations are discussed.
Discuss antibody therapeutics development and immune-mediated targeting strategies in various inflammatory pathways including asthma, psoriasis, inflammatory bowel disease and autoimmune disorders
Therapeutic modalities used for B-cell lymphoma include chemotherapy, radiation therapy, inhibition of signal transduction and immunotherapy. Chemotherapy together with anti-CD20 monoclonal antibodies forms the cornerstone of therapy and has a curative, as well as a palliative role in these diseases. As B cell lymphomas get resistant to repeated therapies, new modalities targeting specific molecules on the lymphoma cells are intensively investigated. One such target on cells that became therapy resistant for treatment is JAM-C, a molecule implicated in B cell adhesion, migration and killing by ADCC (antibody dependent cellular cytotoxicity). Occupancy of JAM-C by a humanized antibody blocks B cell lymphomas from reaching their supportive microenvironments in organs and reduces the number of tumor cells in animal models. This strategy will help to improve survival of B cell lymphoma patients.
Therapeutic antibody producing Chinese Hamster Ovary (CHO) cell lines have been pushed to their limit, leaving developability and formulation groups to stabilise biologics that were not designed with aggregation in mind. Aura+ is the first instrument designed to characterise antibody stability as early as cell line development (CLD). Aura enables low volume, high throughput subvisible particle imaging, counting, sizing, and identification. It easily handles and analyses the biologically complex cellular and protein samples present in CLD to characterize protein stability at the point of production, following release from CHO cell lines. In this talk, we will show how Aura+ quickly and accurately characterizes secreted antibody stability during CHO CLD in unfiltered cell line samples and using the same antibody labeling protocols established by the innovators to characterise protein titre to rank cell lines according to the physical stability of secreted antibodies using volumes as low as 40 µL per sample. In addition, the Aura+ brings with it the capability to rapidly assess different formulation strategies and, for the first time, distinguish polysorbate degradants from other protein aggregates through the application of a novel fluorescent workflow.
Alligator’s Neo-X-Prime platform comprises bispecific tumor-associated antigen-conditional CD40 agonistic antibodies capable of delivering tumor-derived material to antigen presenting cells and enhancing priming of tumor neoantigen-specific T cells. The Neo-X-Prime compound ATOR-4066, targeting CD40 and CEACAM5, is designed for optimal activity in the tumor area and activates tumor-infiltrating immune cells in human primary tumor samples. ATOR-4066 has strong in vivo anti-tumor activity and shows promise for clinical development in CEACAM5-expressing indications.
Process development and manufacturing of cysteine linked Antibody-Drug Conjugates – Control of product heterogeneity
- Overview of different ADC platforms used at Byondis
- Challenges and strategies for ADC manufacturing
- Control of product heterogeneity
- Improvement for future processes
Guy de Roo, Principal Scientist, Byondis (CONFIRMED)
- There is a current over-reliance on preclinical efficacy read outs at the expense of mechanism
- Biomarker directed therapy is the biggest predictor of phase 1 success
- Multi-parameter data from publicly available datasets can be leveraged to drive success
·ON104 is a human antibody directed against oxMIF with optimal physicochemical properties.
·ON104 ameliorates inflammation in preclinical models of Rheumatoid Arthritis, Inflammatory Bowel Disease, and Nephritis.
·Neutralization of oxMIF represents a new treatment option in chronic inflammatory diseases - including patients with limited response to steroids or anti-TNF treatment.
Opto™ Plasma B Discovery Workflows on the Beacon® Optofluidic systems offer customers an attractive alternative in rapid function-first screening that allows antibody discovery in multiple species and physiologically relevant repertoires without significant investment or limitations that exist in hybridoma or phage display. In this presentation, we review how we and our customers have used existing Opto™ PlasmaB Discovery products and protocols to accelerate antibody discovery for their clients, and how these were adapted to different species to achieve a broader sequence diversity to meet client objectives.
Physics-based free energy perturbation (FEP) calculations provide accurate energetics while allowing conformational flexibility by using explicit solvent molecular dynamics (MD) simulations with a state-of-the-art force field. The accuracy and efficiency of these calculations can be improved through enhanced sampling protocols for mutating residue and nearby waters, effective handling of proline and charged amino acids, and automated parameterization of non-canonical amino acids. FEP+ and our new constant-pH molecular dynamics (CpHMD) implementation can account for protonation and tautomeric state changes, both upon binding/folding and at different pH values. Our approach was recently demonstrated in a real-world collaboration, where it was able to reduce cost and accelerate the development process significantly.
This approach will addvalue to the team in delivering high-quality, life-changing drugs
Knob architectures obtained from bovine ultralong CDR-H3 antibodies were inserted into the AB loop or EF loop of the CH3 domain, enabling the introduction of an artificial binding specificity into an IgG molecule. We demonstrate that inserted knob domains largely retain their binding affinities, resulting into bispecific antibody derivatives versatile for effector cell redirection. Essentially, generated bispecifics demonstrated adequate biophysical properties and were not significantly compromised in their Fc mediated functionalities
In a time-bound situation, a second generation mAb process was developed with new media, feeds, resins and membrane usage with a reliable supply chain. The productivity was improved approximately 3-fold with a robust upstream and purification process. An extensive comparability testing and reference standard bridging was accomplished. The process, which was scaled up from lab to GMP manufacturing scale through a lean development approach.
After several decades of protein analytics in the focus, now the biopharma world is facing the challenge to use the established analytical technologies for new, more complex, therapeutic molecules. With the extensive experiences gained in the last 20 years to evaluate the significant chemical and physicochemical properties of proteins, we can now apply this knowledge for analytics of upcoming nucleic acid therapeutics. A special challenge arises from the packaging for delivery of the nucleic acids. Both LNP systems but also viral systems are ready, but many questions still arise regarding meaningful and relevant characterization approaches. The inventive spirit of analytical chemists is now needed to provide reliable and safe analytical test methods and sound analytical strategies for comprehensive quality attribute monitoring.
We make a foray from small to large nucleic acids and show insights how viral and lipid based nano particles can be physicochemically analyzed, providing useful characteristics of these complex systems relevant for the use as therapeutics.
Small molecule pharmaceuticals represent a multibillion-dollar slice of the healthcare market, and more than 90% of all the small molecule pharmaceutical API’s are crystalline solids. We see a demand for the development of technologies that will produce uniform small molecule and biomolecule crystals, not only for pharma, but for agriculture, food (flavors and fragrances), and cosmetics. Suitable hardware and protocols need to be developed and the hypothesis needs to be further explored. Herein we describe our program for producing crystals for industry and explain how interested parties can work with us to develop crystals produced in the microgravity environment of Low Earth Orbit for their own applications.
Affibody molecules are small engineered alternative scaffold affinity proteins that can be site-specifically loaded with cytotoxic drugs to create homogenous conjugates with a desired drug-to-carrier ratio. The presentation will explore the targeting of HER2 and HER3 with affibody-based drug conjugates. It will also describe the impact on biodistribution and in vivo cytotoxic efficacy of drug conjugates loaded with auristatin and maytansine-derived payloads.
A continuous manufacturing process for bio-pharmaceuticals offers multiple benefits, such as improved product consistency, increased productivity, and lower production costs. A key need for process development and characterization is to develop a qualified small-scale model for the manufacturing process.
Miniaturized process models reduce complexity, shorten experiments, and utilize fewer amount of process intermediates. Therefore, we developed a set of small-scale and micro-scale models for fast and accurate process development and characterization of continuous manufacturing processes.
The talk will summarize the Novartis Advanced Integrated Biologics Manufacturing Platform concept along with an overview of the developed small-scale and micro-scale models used for process development and characterization. In a case study, we will show how we used these technologies to optimize a cleaning in place (CIP) for a continuous capture step.
A monoclonal antibody (mAb) developability platform relies on a panel of physicochemistry tools as well as biological assays to challenge the biological activity and to screen potential leads. Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide tools for the early selection mAb candidates. In such a context, a case study of mAb optimization to enhance pK is presented.
Stan De Kleijn, Manager Fill and Finish Process, Janssen
Developability assessment of monoclonal antibody (mAb) candidates is a critical early process to improve the likelihood of selecting a biologic therapeutic that reaches the clinic. Many biophysical and biochemical attributes are of interest in the assessment process, and with advances in machine learning, it is possible to predict how alterations made to the primary sequence of a mAb impact these traits, in particular stability. Here, the Protein Sciences Department within Biologics Discovery at Merck & Co. Inc used NanoTemper’s Prometheus Panta to collect and rank parameters related to the conformational and colloidal stability of their mAb candidates to enhance their developability profiling.
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Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti–PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of “costimulatory bispecifics” that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. These TSAxCD28 bispecifics (e.g. PSMAxCD28, REGN5678) can also synergize with the broader anti–PD-1 approach and endow responsiveness against tumors that otherwise do not respond to anti–PD-1 alone, such as metastatic castration resistant prostate cancer (mCRPC). By combining these costimulatory bispecifics as “off-the-shelf” drugs, with Libtayo (aPD-1), we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers.
If you’d like to be involved, please contact Derek Cavanagh (email@example.com or +44 (0)207 092 1297)
Immunogenicity risk assessment has become an essential component of developability appraisal for biologic drug candidates including monoclonal (mAb), bispecific (bsAb) and multispecific (msAb) antibody constructs. The incidence of anti-drug antibody (ADA) formation is correlated with CD4+ T cell epitope content, which can be assessed in advance of development using in silico tools. We describe the adaptation of an approach validated by mAb clinical data to the immunogenicity analysis of bsAbs, msAbs, and non-antibody scaffolds. Tools available on the Interactive Screening and Protein Re-engineering Interface (ISPRI) are applied, integrating CD4 T cell epitope assessment and with regard to tolerizing T cell epitopes, for a comprehensive estimation of immunogenicity risk. The contribution of individual, regional, and global HLA prevalence is also addressed. Immunogenicity risk assessments of multi-domain molecules are generally consistent with clinical observations.As biologic formats become more complex, it is necessary to consider immunogenic potential of novel constructs and their individual components’ distinct T cell epitope characteristics in concert with the domain composition, mechanism of action, target population HLA prevalence, delivery route and indication.
The complexity in designing potent multispecific immune engagers to treat cancer is multi-factorial requiring empirical and rational approaches. The Ichnos discovery engine will be presented: common light chain (cLC) Fab discovery by phage and mammalian display; screening for optimal affinity, specificity and developability and automated architecture exploration based on functional screening. Case studies will include the discovery and optimisation of the Ichnos clinical assets ISB 1442 and ISB 2001 to treat multiple myeloma
Antibodies specific to oxidative post-translationally modified proteins (oxPTM) are present in individuals with autoimmune diseases. In type 1 diabetes antibodies to oxPTM insulin (oxPTM-INS) are present even before the clinical onset. We investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in T1D. We combined size-exclusion chromatography, LC-MS/MS, ELISA, and T cells proliferation assays to identify the oxPTM-INSPs that are involved in the immunopathogenesis of T1D.
Recombinase-activating gene (RAG) deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T-cell receptor genes. The two RAG genes are acting as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients, who lack a suitable stem cell donor, but developing such therapy for RAG1/2 has proven challenging, given the high expression levels needed, especially for RAG1.
We tested clinically relevant lentiviral SIN vectors with 8 different internal promoters driving codon optimized versions of the RAG1 or RAG2 genes to ensure optimal expression. We used Rag1-/- or Rag2-/-mice as a preclinical model for RAG-SCID to assess the efficacy of the various vectors at low vector copy number. In parallel, the-conditioning regimen in these mice was optimized using busulfan instead of commonly used total body irradiation. To minimize the risks of insertional mutagenesis, we have chosen to aim for VCN around one, to avoid multiple integrations in the same stem cell clone. This preclinical program resulted, surprisingly, in different promoter choice in the LV vectors for RAG1 and RAG2.
A clinical trial for RAG1-SCID (RECOMB) has been initiated, while for RAG2 a clinical batch vector has been generated in preparation for a Phase/II trail in 2024. Two patients have thus far been included in the RAG1-SCID trial with a favourable clinical and immunological outcome, and polyclonal haematopoiesis. The RECOMB trial has a unique multinational design with clinical sites in Europe, Asia and Australia. Patients’ mobilized stem cells will be sent to Leiden (Netherlands) with, genetically modified and after QC returned to these centres as cryopreserved IMP. Thus, the paradigm of this consortium (cells travel, while patients stay home) has become realistic and may serve as a prototype for other gene therapy trials for rare diseases.
HIV viremia may be controlled by chronic antiretroviral therapy. However, medication compliance remains an issue particularly as individuals age and face polypharmacy induced side-effects. To address these challenges, we explore an innovative single-shot alternative: transplantation of ex-vivo engineered B cells. We also highlight that B cells can be engineered in-vivo. Finally, beyond viral infections, we demonstrate strategies to exploit B cell engineering for the treatment of cancer.
Identification and further characterization of antibody charge variants is a crucial step during biopharmaceutical drug development, particularly with regard to the increasing complexity of novel antibody formats. As a standard analytical approach, manual offline fractionation of charge variants by cation-exchange chromatography followed by comprehensive analytical testing is applied. These conventional workflows are time-consuming and labor-intensive and overall reach their limits in terms of chromatographic separation of enhanced structural heterogeneities raised from new antibody formats. For these reasons, we aimed to develop an alternative online characterization strategy for charge variant characterization of a therapeutic bispecific antibody by online mD-LC-MS at middle-up (2D-LC-MS) and bottom-up (4D-LC-MS) level. Using the implemented online mD-LC-MS approach, all medium- and even low-abundant product variants previously identified by offline fraction experiments and liquid chromatography mass spectrometry could be monitored. The herein reported automated online mD-LC-MS methodology therefore represents a complementary and in part alternative approach for analytical method validation including multiattribute monitoring (MAM) strategies by mass spectrometry, offering various benefits including increased throughput and reduced sample handling and combined protein information at intact protein and peptide level.
The goal of biologics drug discovery is to maximize clone diversity to increase the chances of finding and selecting a manufacturable and potent Development Candidate fast. Depending on the method used to capture clones (e.g., hybridoma libraries, single B cell screen, immunized libraries, in vitro translation), different biases and losses of diversity will be evident. Traditional and newer technologies will be discussed. Case studies from biologics drug development, where library design and sources of V regions affect the success of identified leads, will be presented
At Alchemab we harness the power of the human immune system to counter complex diseases, with a focus on oncology and neurodegeneration. We identify antibodies from patients who are resilient to disease using antibody repertoire deep sequencing, serum proteomics, computational biology and machine learning. Target deconvolution of these antibodies has uncovered both novel disease-relevant antigens and existing therapeutic targets with distinct modes of engagement. This talk will outline our approach to target-agnostic antibody discovery and highlight an example of one of our key programmes that is progressing towards the clinic.
Chemical modifications such as iso aspartic acid or succinimide in the antibody complementarity determining region (CDR) can impair binding activity in Biologics, and are therefore considered as a risk in the developability assessment. Sequence degradation motifs identified experimentally are therefore used to predict in silico chemical modification liabilities.
This talk will focus on the cases of predicted and unpredicted isomerization events at aspartic acid residues in the CDR of biologics as a major degradation pathway, but resulting in different outcomes.
The characterization of the iso-aspartic acid and succinimide variants, the specificity and sensitivity offered by modern mass spectrometry, and the opportunity to monitor critical quality attributes in biological matrices will be discussed.
Learnings from these predicted and unpredicted isomerization events will be shared.
Bispecific anti-CD3 T cell engagers (TCEs) show promise in cancer immunotherapy through the engagement of T cells and tumor cells. TCE discovery is challenged by the need to balance tumor-killing potency, toxicity, developability, and cynomolgus monkey (cyno) cross-reactivity. This presentation demonstrates how to overcome these challenges with machine learning (ML)-driven epitope steering and mammalian-display antibody libraries to efficiently discover diverse TCE arms tuned for potency, toxicity, developability and cyno cross-reactivity.
Bispecific antibodies dominate the TCE (T-cell engager) field but their efficacy is largely limited to liquid tumours. Soluble T cell receptors (TCRs) are ideal for targeting intracellular antigens and have been recently validated as an effective modality to treat solid tumours. Despite their therapeutic potential, challenges remain, including poor protein stability, a limited understanding of favourable molecular architectures and the risk of introducing unwanted cross-reactivity during the affinity maturation process.
Here, we present an unbiased pooled approach to screening 40 TCE molecular soluble TCR format families containing thousands of individual formats, and identify favourable configurations for efficient redirection of T cell activation and killing.
Therapeutic antibodies have revolutionized the treatment of many diseases; however, their safety and efficacy are often altered by their immunogenicity, as many patients frequently develop anti-drug antibodies. Aggregation is a contributing factor to antibodies’ immunogenicity. We aim to better understand the role of antibody aggregates in the initiation of a specific T-cell response. Thus, we developed a model of small-sized, well-characterized infliximab (IFX) aggregates by exposing the native antibody to ultraviolet light. Using an autologous co-culture model with monocyte-derived dendritic cells (moDC) and CD4 T cells, we identified a higher frequency of CD4 T cells recognizing IFX aggregates compared to the native antibody. Even though IFX aggregates did not induce moDC maturation, they tend to be more internalized by healthy donors’ moDC compared to native IFX, with endocytosis being the main pathway. The implicated receptors and mechanisms are currently under investigation. Our results indicate that small-sized aggregates have a significant role in immune system activation, emphasizing the importance of assessing the implicated cellular mechanisms.
Overall, the presented approach offers a powerful tool for researchers and analysts in the biopharmaceutical industry to gain deeper insights into potential critical quality attributes of therapeutic antibodies and further novel formats. Witnessing the increased implementation of mD-LC-MS methods over the last couple of years, this technology is well on the way towards becoming a standard tool for biopharmaceutical development.
Anti-drug antibodies (ADAs) against therapeutic proteins frequently cause attrition owing to their potential impact on pharmacokinetics, pharmacodynamics, efficacy, and safety. Predicting clinical ADAs is complex due to their multifactorial drivers, including compound properties, subject characteristics, and treatment parameters. The Immunogenicity (IG) Quantitative Systems Pharmacology (QSP) Simulator, a mechanistic in silico model of the IG cascade, was developed to integrate these. We ultimately envisage combining it with non-clinical IG data to predict clinical ADA prevalence over time and the impact on pharmacokinetics. To assess its current credibility for application during the drug development process, we single-blindly evaluated the IG QSP Simulator with subject-level clinical data from 10 Roche monoclonals.
- Cimeio’s technology platform is based on the design and expression of precision-engineered variants of cell surface receptors of the hematopoietic system
- We will show that such receptor variants can be introduced efficiently into human HSCs and are fully functional, but are resistant to depletion by a paired immunotherapy
- In vivo data in humanized mice confirm that the administration of bio-active IgGs or antibody-drug conjugates eliminates wildtype hematopoietic cells, while allowing edited cells to engraft, proliferate and differentiate
- These pairs of potent immunotherapy and matching shielded cells are used to develop curative treatments for patients with genetic diseases, heme malignancies and autoimmune diseases