To exploit highly conserved and difficult drug targets, including GPCRs and ion channels, monoclonal antibody discovery efforts are increasingly relying on the advantages offered by divergent species such as rabbits, camelids, and chickens. Divergent host species enable robust immune responses against highly conserved binding sites and yield antibodies capable of penetrating functional pockets via long HCDR3 regions. Pan-reactive molecules are often produced by divergent hosts, and these antibodies can be tested in accessible animal models, offering a faster path to clinical development. In this webinar, Dr. Ross Chambers will analyze gaps in therapeutic antibodies that stem from the historic use of mice and examine opportunities to exploit previously inaccessible targets through discovery in alternate species. Examples of preclinical and clinical-stage antibodies raised in divergent species will be highlighted, providing an overview of their success

What does it take to develop a portfolio of immune-oncology candidates? In this fireside chat, Dr. Tom Burt, Sofinnova Partners SAS, will discuss the strategies needed and the path to building a world-class immuno-oncology biotech, along with Dr. Martin Welschof and experts Drs. Christine Power and Björn Cochlovius. During the session, Dr. Welschof, CEO of BioInvent, a clinical-stage company based in Sweden that is developing immuno-modulatory antibodies for the treatment of cancer, and the panel will detail their experiences of the many facets that contribute to building an innovative clinical stage antibody enterprise, including antibody discovery, clinical development, partnership, manufacturing and finance.

The commercialization of innovative antibody therapeutics needs significant capital investments to fund pre-clinical and clinical studies. Many small biotech that are focused on development lack these resources and the infrastructure needed to launch new biologics. Forming partnerships with larger pharmaceutical companies is one strategy that provides access to the resources needed for later stage development but partnering companies will want to scrutinize the data behind the candidate molecule. For this reason, it is crucial for a biotech company to understand the data packages that need to be generated. These will need to show that the biotech company can meet the necessary regulatory requirements but also answer other key questions that potential development and/or exit partners will have. In this webinar, we will provide a general overview of both areas.

It has been reported that approximately 80% of the FDA-approved medicines over the last 10 years were not registered by the originator or patent assignee. Many novel therapeutic molecules and technologies are initially conceived and developed by small biotechnology (startup) companies or universities, but it is usually big pharma and biotech companies that will bring the resulting therapeutics to the market and commercialize the product. In recent years there has been a trend in large pharma companies to reduce in-house research and development activities and increase in-licensing or acquisition of products to fill their pipelines. New technologies are also being developed so rapidly that it is more feasible for pharma companies to rely on startups for the initial drug development in order to acquire de-risked programs at a later stage in development. However, once a potential asset has been identified it is necessary to perform an in-depth scientific evaluation and due diligence in order to increase the probability of a success or dodge a damp squib. In this presentation, I will describe what this process entails with case studies and some of the pitfalls that may be encountered.

The Specifica Generation 3 platform is able to generate 500-5000 different antibody clonotypes against targets of interest, with over 80% of selected antibodies having no measurable biophysical liabilities and 20% having subnanomolar affinities. The most common approach to selecting antibodies from display technologies involves low-throughput random colony screening. However, this misses many potential therapeutic leads, particularly when diversity is high. Specifica uses next generation sequencing (NGS) to build its libraries as well as characterize selection outputs. In order to fully exploit the universe of selectable antibodies, Specifica has developed a cloud-based software platform, designed exclusively for antibody engineers and bioinformaticians, to enable a streamlined identification of leads with broad epitope coverage. Application of this to selection outputs has increased the number of clonotype leads by five to ten fold over random colony screening, significantly expanding the explorable paratope space.

The SARS-CoV-2 pandemic has spread all over the world in the past year and there is still no efficient treatment available for COVID-19, particularly for patients undergoing severe courses, which often lead to fatal consequences. Antiviral drugs such as virus-neutralizing antibody therapeutics are still urgently needed to save millions of lives. Corat Therapeutics developed a novel SARS-CoV-2 neutralizing, fully human antibody derived from convalescent patients. Ultra-fast development strategies shortened timelines from discovery to GMP manufactured material to less than 8 months. This was possible by parallelizing discovery and development steps, as well as performing crucial steps on risk. First-in-human studies were recently initiated. This webinar gives an overview of the challenges faced during discovery and development of the lead antibody, COR-101.

In this webinar, Dr. John McCafferty presents results from the deep-mining of the antibody repertoires of hospitalized COVID-19 patients using a combination of phage display technology and B cell receptor repertoire sequencing to isolate neutralizing antibodies and gain insights into the early antibody response. This comprehensive discovery approach yielded potent neutralizing antibodies with distinct mechanisms of action. In particular, a novel non-ACE2 receptor blocking antibody that is not expected to be affected by any of the major viral variants reported was identified. Potent neutralizing antibodies with near germline sequences within both the IgG and IgM pools at early stages of infection were also found. The study results highlight a highly convergent antibody response with the same sequences occurring both within this patient group and within the responses described in previously published anti-SARS-CoV-2 antibody studies.

Accelerating the timeline from biopharmaceutical discovery to clinical evaluation has long been a focus for industry. For potentially life-saving therapies, the earliest clinical testing enables accelerated pivotal trials and maximum patient benefit. In 2020, novel discovery and development strategies have rapidly evaluated antibodies for passive immunization or treatment of COVID-19, employing CMC timelines from lead identification to clinic cut in half. These strategies combine the latest advances in established platforms with acceptance of higher business risk or costs, while ensuring no increased patient risk. But speed to clinic for COVID-19 antibody therapies must be matched by speed to launch and immediate ramp-up in supply to realize a meaningful impact on the global pandemic. Parallel workflows must be initiated at the onset for process and product development as well as cGMP manufacturing. The initial focus on speed to clinic complements a slower approach to development of the most productive commercial cell line, efficient manufacturing process and optimal drug product configuration. Rapid production of initial clinical material followed by pivotal and commercial production arising from cell line, process and formulation optimization emphasizes the importance of product comparability, structure/function knowledge and appropriate control strategies. Meanwhile, scale-up and technology transfer to large manufacturing facilities starts before the first patient is dosed. These strategies impact the program’s technical and regulatory risk profiles, staff and capital resourcing, and set up trade-offs in multiple areas. This case study describes the development history of a COVID-19 antibody, reviewing CMC milestones from lead identification to preparation of the commercial license application as well as plans for post-licensure opportunities, all in one year.

Whereas vaccines significantly contribute to halting transmission of SARS-CoV-2, they are not universally effective. Therapeutic antibodies can fill this gap to efficiently combat SARS-CoV-2. Obviously, long-lasting efficacy of anti-viral approaches heavily depends on the ability to protect against virus variants. As a multi-targeting strategy reduces the risk of mutagenic escape, we have isolated a diversified pool of anti-spike protein antibodies by leveraging our expertise to generate antibody libraries across multiple discovery platforms in different species, to eventually formulate a sensible therapeutic cocktail. A broad range of in vitro characterizations was applied to gain early insight into the epitope landscape and functional characteristics as well as developability profiles. This comprehensive, high-throughput characterization of the obtained lead candidate pool guided the rational combination of high value antibodies into multi-membered cocktails that unlock synergistic effects, significantly boosting neutralization potency in vitro. To accelerate further clinical development of our prioritized antibody cocktails, 2 individual components were subjected to in silico modeling-guided light molecular optimization to minimize liabilities, while in parallel, in vivo efficacy evaluation in a hamster challenge model validated efficient prevention and treatment of SARS-CoV-2 infection following administration of our prioritized antibody cocktails. Although we anticipate that a multi-targeting strategy is the best solution to reduce mutagenic risk escape, we continuously analyze binding of the antibodies of our lead pool for reactivity towards emerging SARS-CoV-2 variants empirically. To date, we screened our prioritized antibody cocktails towards spike protein of the S. African (B.1.351 lineage), Brazilian (P.1 lineage), UK (B.1.1.7 lineage), New York (B.1.526 lineage) and Californian (B.1.429 lineage) strains and confirmed retained binding. Our pandemic preparedness is further strengthened by the readily accessible, diverse pool of antibodies that we generated, which provides enormous possibilities for plug-and-play cocktails to address future SARS-CoV-2 variants.

Monoclonal antibodies have become one of the most clinically successful therapeutic agents against a range of diseases, including cancer, autoimmune diseases, and most recently SARS-CoV-2. Although engagement of the antigen via the variable Fab portion of the antibody is essential, the function of many therapeutic antibodies also depends, to varying degrees, on the hinge and Fc portion of the antibody and the interaction with receptors on effector cells. Antibody subclass choice is crucial for optimal function and safety of therapeutic antibodies because the functional profile of each subclass differs greatly. Targeted modification of the Fc region and its associated glycan is also a potent and effective approach to tailor the therapeutic function of antibodies for the disease of choice, by improving or reducing the immune cell-associated effector functions and altering the circulating half-life of the antibody. One advantage of these Fc modifications is that they can be easily transferred to antibodies of any target, and so development of novel antibodies against a wide range of diseases have benefited from the modifications previously developed and characterized for different indications. 

Landmark advances in the engineering and development of bispecific antibodies bsAbs are enabling unprecedented innovation and versatility in therapeutic antibody concepts. A defining bsAb feature is their potential for novel functionalities — that is, activities that do not exist in mixtures of the parental or reference antibodies. These so-called obligate bsAb are having a tremendous impact and potential in current and future drug development.

Bispecific engagers that target and activate effector cells, most commonly T cells, represent about 50% of bispecific antibodies in development. Here, next generation bispecific T cell engagers (bsTCEs) with a widened therapeutic window characterized by high potency and high tumor selectivity have strong potential for the treatment of both hematological as well as solid cancers. Lava Therapeutics is developing products building on a platform to conditionally and selectively recruit Vγ9Vδ2 T cells for eradicating tumor cells. This γδ T cell subset has been shown to display powerful anti-tumor immune effector activity, to preferentially kill tumor cells relative to normal cells and has a demonstrated ability to infiltrate human tumors. LAVA’s γδ bsTCEs designed to target and engage Vγ9Vδ2-T cells for the development of novel cancer immunotherapies will be discussed.

Modelling in Chemistry obviously depends on a strong link to reality. Even though the mathematical description of chemistry has been possible for almost 100 years, realistic modelling has only recently become available due to the massive increase of computing power following Moore’s law. Still, appropriate statistics, initial conditions and boundaries pose considerable challenges. Nowadays, methodological advances and progress in hardware allows the observation of biological systems for relevant time periods. Hence, dynamic processes like reorientations, folding and binding can be seen in atomistic resolution leading to completely new insights.

Describing an antibody’s binding site using only one single static structure limits the understanding and characterization of the antibody’s function and properties, whereas various biophysical properties are governed by its dynamics, e.g., antibody-antigen binding. This limitation is even more pronounced when no experimentally determined structure is available or the crystal structure is distorted by packing effects, which can result in misleading antibody paratope structures. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities. These kinetically characterized paratope ensembles with their respective state probabilities allow the identification of the dominant conformation in solution, which frequently has been shown to coincide with the binding competent conformation. Therefore, the definition of kinetically and functionally relevant states, so-called paratope states, can be successfully used to improve the accuracy and enhance the predictivity of antibody-antigen docking.

Novel therapeutic modalities such as bispecific antibodies are increasingly being explored as more effective alternatives to monoclonal antibodies for a range of diseases. Therapeutics such as bispecifics, can have a combinatorial effect by targeting two antigens,  resulting in treatments with enhanced utility, higher efficacy, fewer side effects and less resistance compared to mAbs.

Generating a bispecific antibody, which is correctly and stably paired, is a major production concern. Many solutions require significant changes to native antibody structure, which increases antibody complexity and forces adaptation of downstream processes. While a various platforms have been developed to mitigate Heavy-Light chain (HC-LC) mispairing, there are many other rate limiting steps for efficiently expressing these molecules in a CHO system. bYlok® technology is a design engineering approach that stabilise the interaction between the HC and LC, essentially removing the mispairing problem whilst retaining a more natural antibody structure.

This presentation will introduce you to a mechanistic review of the bispecific pipeline to demonstrate how a various tools and technologies can enable you execute bispecifics.  Case studies will be presented to show how the bYlok® technology can be used to stabilise and select for novel bispecifics from a panel of parental immunotherapeutic mAbs. Our data demonstrates that correct heterodimerisation can be achieved consistently and how standard downstream purification processes can be used during production.

Antibodies are nature’s pro-drugs, wonderfully evolved to target pathogens and activate immune systems. For certain indications where ADCC or CDC are required this is ideal, but for many other applications activation of inflammatory responses is unnecessary and potentially highly undesirable. In these situations silenced antibodies with either naturally low effector function or engineered Fc domains are the preferred option. However, many of the commonly used options in the clinic, such as IgG4, LALA or aglycosylation, are widely reported to still have residual Fc receptor binding and cytokine activation in patients.

This presentation will describe the first thorough comparison of most of the generic and proprietary Fc silencing mutations, demonstrating that all previously reported variants show residual binding to Fc receptors. It will also describe the discovery of a novel set of mutations, known as STR, that show no detectable binding to Fcγ receptors and do not elicit inflammatory cytokine responses. Meanwhile, immunogenicity, stability and PK are unaffected. This totally silenced variant has the potential to improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.

Understanding immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Towards this end, Dr. Walker and her colleagues profiled spike (S)-specific B cell responses following Omicron/BA.1 infection in mRNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit toward the receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 variants of concern. Dr. Walker will discuss these findings, which provide insights into the role of pre-existing immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.  

Biolayer interferometry (BLI) is gaining popularity for protein and small molecule quantitation and kinetics research. The new advancements in biosensors, ease of use, reproducibility and low cost is driving its adoption. Even though BLI is one of the easiest of the tools, as with many other techniques, getting the best data depends on optimization of some key experimental factors. This webinar will discuss the best practices in BLI and result of such implementation by way of an example of screening of a broadly neutralizing antibody of snake venoms.

Snake envenomation results in over 100,000 deaths and 300,000 permanent disabilities in humans annually. Contemporary antivenoms are produced from the polyclonal serum of venom-immunized livestock and are specific to a single or narrow genetic range of related snakes. Could a broadly neutralizing monoclonal antibody, or a cocktail of a few broad components, provide protection from diverse snake venoms? Centi-3FTX-D09, originating from the B-cell memory of a human subject with an extensive history of diverse snake venom exposure, recognized a conserved neutralizing epitope of 3-finger toxins (3FTXs), a dominant snake neurotoxin. Four crystal structures of Centi-3FTX-D09 in complex with 3FTXs from mamba, taipan, krait, and cobra revealed the mechanism of broad neutralization to be epitope mimicry of the interface between these neurotoxins and their native host target, the nicotinic acetylcholine receptor. Centi-3FTX-D09 provided in-vivo protection against diverse 3FTXs and, in combination with the phospholipase inhibitor varespladib, protection against whole venom challenge for diverse, genetically distinct, elapid species.

The large size and complexity of biologic molecules creates unique sets of safety, efficacy, and developability hurdles that have to be overcome in order to bring biotherapeutics to market.  This webinar will provide an overview of computational modeling strategies for antibody design. The presentation will describe how calculated properties derived from physics-based 3D structural analyses and simulation are applied to not only predict binding affinity, but also identify and mitigate potential liabilities in the development of antibody-based biotherapeutics. Such computational modeling efforts can contribute to significant reductions in project costs and timelines by directing experimental focus toward the most promising candidates.

Mapping the molecular features of antibody immune responses has remained a challenge for many years, partly due to the high genetic diversity that is encoded by millions of single immune cells. This presentation summarizes the past several years of progress we have made in large-scale sequencing and functional screening of antibody immune libraries. We will also share unpublished data and recent advances for antibody discovery in complex cell populations and against difficult disease targets.

Not every antibody can be combined to produce well-behaved multi-specifics. The valency and geometry of each design can determine the production, target engagement and ultimately the requisite biological functions. In this case study, we selected two established antibody therapeutics, trastuzumab and a humanized OKT3 to produce 17 different bispecific formats to compare the feasibility of each format.

The development of antibody drugs has greatly depended on the establishment of new technologies and platforms, which are also the key factors that have led to the great success in the development of antibody drugs in the last three decades. Antibodies have become a pivotal role in the biopharmaceutical field, but antibody discovery has been constrained by a series of bottlenecks, such as time-consuming and inefficient screening process, poor tissue permeability, difficulties in modular application, and immunogenicity. This talk presents new solutions to these challenges through complete case studies, from antibody discovery to functional assays, antibody optimization, and up to application, using VHH antibody as an example. More case studies will show how new technologies and platforms can be applied to solve common problems in antibody discovery.

The SpyTag/SpyCatcher protein ligation technology is a versatile method to covalently link two proteins. Addition of the SpyTag protein ligation technology to antibodies creates a modular platform that offers a wide range of new opportunities. In this webinar Dr. Ylera will demonstrate the use of Spytagged antibodies in combination with prefabricated SpyCatcher modules for rapid site-specific labeling, as well as changing antibody valency, species and isotype. Furthermore, Dr. Ylera will present the use of SpyTag for antibody phage display selection (SpyDisplay) and for the generation of prototype bispecific antibodies. The work presented illustrates how these technologies work hand in hand for the generation of new therapeutic lead candidates.

Optimization of Fc function can lead to the development of safer and more efficacious therapeutic antibody products, but analyses of Fc function may be underexploited in the antibody design process. We introduce a high-throughput platform for antigen-specific testing of Fc effector activities, empowering enhanced hit-to-lead screening in early stages of antibody development for the treatment of cancer, autoimmunity, neurodegeneration, and infectious diseases.

Monoclonal IgE antibodies targeting tumor-associated antigens may mediate potent immune-activating functions in tissues, resulting in anti-tumor activity. Dr. Bax will present in vitro and in vivo functions of two anti-cancer IgEs, associations with monocyte/macrophage polarisation, macrophage infiltration, and enriched pro-inflammatory signatures within tumors, the absence of preliminary evidence of type 1 hypersensitivity, and key outcomes of the first-in-class Phase 1 clinical trial; together supporting the potential of IgE-based cancer immunotherapies.

OpenEye’s suite of antibody modeling tools, accessed via the cloud platform Orion®, includes Specifica’s state-of-the-art antibody sequence analysis tool AbXtract and open-source tools such as ImmuneBuilder for antibody structure prediction. In this webinar, Dr. Jesper Sørensen will guide viewers through the process of modeling antibody structure on Orion, which begins with taking sequences from a selection campaign analyzed using AbXtract, or other methods such as internal or public databases. 3D structures are then generated with the AI-driven structure predictor ImmuneBuilder (requiring only around 100 ms per structure when predicting at the multi-thousand scale). From these structures a wide variety of physico-chemical properties are calculated to enable selection of those antibodies/sequences most likely to be successfully developed into human therapies. Structural diversity in the complementarity-determining region (CDR) can be further explored using knowledge-based loop modeling, while molecular dynamics and enhanced sampling molecular dynamics is used to explore global conformational diversity. Structural families within computed ensembles can be identified by clustering using similarity based on a physically rigorous shape and chemical feature distribution of the CDRs. Individual sequences can be further optimized by single or multi-point mutations and/or loop replacement and these new hypotheses submitted to physico-chemical property profiling and conformational exploration.

Antibody-drug conjugates (ADCs) have emerged as an important class of targeted therapeutics, combining the targeting specificity of antibodies with the potency of cytotoxic drugs. Recent advances in ADC research have led to improved stability, efficacy, and safety. There is a clear trend within Antibody therapeutics towards ADCs with the improvement of novel technologies to address a growing cancer population worldwide. However, developing effective ADCs is expensive and poses unique informatics challenges. Researchers must integrate data across multiple modalities - from antibody discovery and engineering to small molecule payload development and optimization. Seamless collaboration between immunologists, protein engineers, chemists, and pharmacologists are essential. The Signals™ Research Suite is the first integrated informatics platform purpose-built to accelerate multi-modal drug development like ADCs and is composed of a trio of scientific software applications: 

• Signals™ Notebook: The premier cloud-based electronic lab notebook that facilitates creation and communication about molecules of interest via hierarchical editing language for macromolecules (HELM), powered Chemdraw®.    
• Signals™ VitroVivo: For data analysis, visualization, and curve fitting bioassay results for standardized and consistent results, powered by Spotfire®.  
• Signals™ Inventa: Enabling multi-assay or multi-study comparison, powered by Spotfire, with the ability to find the best candidate to move forward, accelerating decision making. Researchers gain better visibility into ADC candidate profiling and can quickly determine structure-activity and structure-property relationships across modalities to select optimal conjugation sites and pairings. 

Attendees will gain insights into the latest trends and challenges in ADC development, informed by recent research and advancements in the field. The presentation will also emphasize the importance of integrating various data types and sources in the ADC development process, showcasing how the Signals Research Suite facilitates this integration, thereby driving more efficient, safer drug development. 

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B and T cell receptors play a critical role in responding to pathogens and vaccination, and in the pathology of several diseases of the immune system. Gene segments at the T cell receptor and immunoglobulin loci serve as templates for the generation and expression of T and B cell receptors and antibodies. Defining genetic variation within these highly polymorphic loci is critical to furthering our understanding of immunological diseases, and informing the design of vaccines and therapeutics. However, at the genomic level, these loci have been difficult to analyze due to their repetitive nature, rich in segmental duplications, simple repeats and retrotransposon elements. To overcome this complexity, several sequencing technologies and algorithms have been developed to more fully define the spectrum of genetic variation in these immune loci in human populations and other species. This webinar includes demonstrations of three orthogonal and complementary methods. First, Dr. Corcoran will present IgDiscover, an IG and TR adaptive immune repertoire sequencing (AIRR-seq) germline inference tool that has been in use for several years and applied to multiple species. The IgDiscover output is highly reproducible and can facilitate the comparison of multiple individuals in disease cohorts to identify disease associated allelic or structural variants. Ayelet Peres will present on VDJbase and RAbHIT, two bioinformatics tools for germline variation detection from AIRR-seq using population analysis and chromosomal phasing. These tools have been used to discover germline variations affecting the expressed repertoires. Finally, Dr. Rodriguez will demonstrate an approach using long-read sequencing and a bioinformatics tool, IGenotyper, to fully characterize both coding and non-coding single-nucleotide variants, small insertions and deletions, and structural variants across IG and TCR loci in a haplotype-specific manner. This will also include discussion on how IGenotyper is being applied to survey immune loci in non-human species.

In this webinar, Vadim I. Nazarov will demonstrate the applications of AIRR data analysis to immunotherapy development and how R package Immunarch simplifies this type of work. The webinar's goal is to enable listeners to apply AIRR bioinformatics to real-world problems and identify biomarkers that inform decision-making in pre-clinical and clinical studies. AIRR analysis has been a particularly challenging area of research since it is highly interdisciplinary. Immunarch R package helps standardize the analysis and provides quick access to advanced methods, letting you focus more on research rather than coding. Key topics covered on the webinar: TCR or BCR clonality and diversity as biomarkers of clinical activity in cellular immunotherapy studies, clonotype convergence and public clonotype analysis, annotation of clonotype associations with disease, V(D)J gene usage analysis, clonotype tracking to characterize CAR-T or TCR-T persistence and expansion, which inform the choice of optimal design for TCR-based immunotherapy.

T cells are at the heart of the immune system's ability to distinguish between self and non-self, playing a critical role in both health and disease. The specificity of the T-cell response is mediated by the T-cell receptor (TCR), a product of the unique V(D)J recombination process, which enables interaction with a wide variety of antigens. Given the sheer scale of potential TCR-epitope interactions – stemming from both the enormous epitope and TCR repertoire diversity -- experimental validation of each TCR interaction is not feasible. This has spurred the development of TCR-epitope prediction models that aim to narrow down the search for immunogenic epitopes, thereby streamlining research and reducing costs. Our webinar will delve into these predictive strategies, highlighting their importance in advancing immunological research and applications. During the webinar we will discuss a range of prediction strategies, including databases, machine learning, and structure-based methods. To improve accessibility and understanding on when to implement a tool, we will use real-life examples to illustrate their practical benefits. Additionally, we will address the challenges and pitfalls associated with these tools, including the complexities of handling negative data in TCR-epitope analysis. Join us as we unlock the potential of TCR-epitope prediction tools and provide you with the knowledge and skills to effectively integrate them into your own research.

In this 2-part workshop on the fundamentals of the immune system, Dr. Jamie Scott will first provide an overview of humoral and cellular immunity, and the basic structure of the immune system, including its cells, tissues and compartments, along with the “superhighway” of the immune system: the circulatory and lymphatic systems. In that context, innate and adaptive immune systems and their interaction, and the general timing and dynamics of immune responses will be presented.

The processes of lymphocyte development, including the various B- and T-cell subsets, positive and negative selection, and the genetic basis of B-cell and T-cell receptor diversification, will be presented to provide a clear idea of what adaptive-immune receptor repertoires (AIRRs) are, and in general terms, how they are currently assessed via high-throughput sequencing.

Dr. Scott will then cover the signaling, activation, proliferation and differentiation of T-cell and B-cell clones in the context of lymphoid compartments where antigen is concentrated and presented to naïve and memory B and T cells. The role of co-stimulation in determining the type immune response generated will be emphasized.

In Part II, Dr. Scott will review the orchestration of systemic and mucosal immune responses, including the roles of tolerance and inflammation in these processes. Examples of immune responses to vaccines, chronic viral infection, and/or cancer, as well as autoimmunity, will be presented as variations on a common theme, reiterating the dynamics of the immune response. Some engineered immunotherapies, such as therapeutic antibodies, CAR-T cells and dendritic-cell vaccines, will be introduced as well.

The importance of AIRR-sequencing data to our understanding of immune responses will be emphasized throughout the latter half of this workshop.

In this 2-part workshop on the fundamentals of the immune system, Dr. Jamie Scott will first provide an overview of humoral and cellular immunity, and the basic structure of the immune system, including its cells, tissues and compartments, along with the “superhighway” of the immune system: the circulatory and lymphatic systems. In that context, innate and adaptive immune systems and their interaction, and the general timing and dynamics of immune responses will be presented. The processes of lymphocyte development, including the various B- and T-cell subsets, positive and negative selection, and the genetic basis of B-cell and T-cell receptor diversification, will be presented to provide a clear idea of what adaptive-immune receptor repertoires (AIRRs) are, and in general terms, how they are currently assessed via high-throughput sequencing.

Dr. Scott will then cover the signaling, activation, proliferation and differentiation of T-cell and B-cell clones in the context of lymphoid compartments where antigen is concentrated and presented to naïve and memory B and T cells. The role of co-stimulation in determining the type immune response generated will be emphasized.

In Part II, Dr. Scott will review the orchestration of systemic and mucosal immune responses, including the roles of tolerance and inflammation in these processes. Examples of immune responses to vaccines, chronic viral infection, and/or cancer, as well as autoimmunity, will be presented as variations on a common theme, reiterating the dynamics of the immune response. Some engineered immunotherapies, such as therapeutic antibodies, CAR-T cells and dendritic-cell vaccines, will be introduced as well. The importance of AIRR-sequencing data to our understanding of immune responses will be emphasized throughout the latter half of this workshop.

In this webinar, Drs. Charlotte Deane, Matthew Raybould and Fergus Boyles (Oxford Protein Informatics Group, Department of Statistics, University of Oxford) will share examples of how structure prediction enriches antibody sequence data and provide practical guidance for getting started using Oxford Protein Informatics Group (OPIG) tools to structurally featurise your antibody sequences. In particular, they will demonstrate the added value to tasks such as antibody functional clustering, repertoire disease-response diagnosis, and virtual screening.

Adaptive immune receptor repertoires (AIRRs) capture past and present immune responses and therefore represent a powerful resource for developing diagnostics and therapeutics. Machine learning (ML) has the ability to discover complex sequence patterns and help further these diagnostic and therapeutic aims. However, to exploit these opportunities, it is necessary to overcome the intrinsic challenges of AIRR data: unknown rules determining antigen binding, high diversity and specificity of receptors with low overlap between AIRRs, and low signal-to-noise ratio. Further, different ML approaches need to be validated and compared before they could be deployed in practice. In this webinar, we will focus on standardized and reproducible ML workflows, benchmarking, and comparison of AIRR ML approaches. We will argue for the use of simulation for validation and benchmarking of ML methods before moving to experimental datasets.

Drs. Encarnita Mariotti-Ferrandiz and Nina Luning Prak, members of the Adaptive Immune Receptor Repertoire (AIRR) Community Biological Resources Working Group, will describe quality control (QC) procedures for immune repertoire profiling. Dr. Mariotti-Ferrandiz will describe QC pipelines for sequencing of T cell receptor gene rearrangements that are in use in her laboratory in the Department of Immunology, Immunopathology and Immunotherapy at the Sorbonne. Next, Dr. Luning Prak will describe QC pipelines for sequencing of B cell receptor gene rearrangements that are in use in her laboratory and in the Human Immunology Core facility at the University of Pennsylvania. They will then focus on frequently asked questions and respond to other questions posed by attendees during a Q&A period.

Human B cells play a fundamental role in the adaptive immune response to infection and vaccination, as well as the pathology of allergies and many autoimmune diseases. Central to all of these processes is the fact that B cells are an evolutionary system, and undergo rapid somatic hypermutation and antigen-driven selection as part of the adaptive immune response. The similarities between this B cell response and evolution by natural selection have made phylogenetic methods a powerful means of characterizing important processes, such as immunological memory formation. Recent methodological work has led to the development of phylogenetic methods that adjust for the unique features of B cell evolution. Further, advances in single cell sequencing can now provide an unprecedented resolution of information, including linked heavy and light chain data, as well as the associated transcriptional states of individual B cells. In this webinar, we show how single cell information can be integrated into B cell phylogenetic analysis using the Immcantation suite (Immcantation.org). Beginning with processed single cell RNA-seq (scRNA-seq) + BCR data from 10X Genomics, we will show how cell type annotations can be associated with BCR sequences, how clonal clusters can be identified, and how B cell phylogenetic trees can be built and visualized using these data sources.

Adaptive immune repertoire sequencing ('Rep-Seq') is increasingly being used to evaluate the immune system, interventions targeting the immune system (such as vaccination) [1], and immune-derived therapeutics (e.g., immunotherapy and antibodies) [2]. For antibody discovery, repertoire sequencing has become an indispensable technology capable of generating vast pools of data from which to identify and characterize the best candidates using tools such as IGX Platform [3]. In this webinar, we describe our journey of setting up a validated Rep-Seq assay for BCR/Antibodies. Given the biological characteristics of the adaptive immune repertoire, important conditions for developing a high-quality Rep-Seq assay include: well-curated germline databases, high-quality sample prep and sequencing, and rock-solid processing software. To validate sequence processing and analysis software, we make use of a simulation framework that takes in an AIRR-compatible repertoire and outputs highly realistic HTS validation data. Furthermore, ENPICOM teamed up with Viroclinics/DDL (a Cerba company) to set up a reliable and robust high-quality Rep-Seq method. By designing and including spike-ins in pilot sequencing runs, we are able to better assess the characteristics of our Rep-Seq assay. By integrating both wet- and dry-lab development and testing, we provide a robust Rep-Seq quantification solution that makes use of the latest developments in genomics, bioinformatics, and drug development.

References:

[1] Arnaout et al, The Future of Blood Testing Is the Immunome; Front Imm, 2021, doi: https://doi.org/10.3389/fimmu.2021.626793

[2] Oude Lohuis et al, High-throughput Sequencing Technologies are Revolutionising Antibody Discovery; IBI, 2021. https://tinyurl.com/yrx637kp

[3] Technologies, challenges, and applications of immune repertoire sequencing; ENPICOM 2020, https://enpicom.com/download-white-paper-applications/

High-throughput sequencing has enabled the capture of adaptive immune receptor repertoire (AIRR) data at unprecedented depth and precision. This webinar will give an in-depth walk-through of best practices to conceive, analyze and perform AIRR studies for answering fundamental immunological questions as well as discovering novel immunodiagnostic biomarkers and design (therapeutic) immune receptors. Specifically, Dr. Greiff will address current approaches to perform AIRR-compliant AIRR data processing encompassing bulk and single-cell approaches and experimental and bioinformatics quality control. Furthermore, he will summarize the computational methods that have been recently developed to deconstruct the high-dimensional complexity of immune receptor repertoires, e.g., 1) diversity-, 2) phylogenetic-, 3) networks- and 4) machine learning-based methods that have been applied to dissect and understand the diversity, architecture, evolution and antigen specificity of immune repertoires. Finally, Dr. Greiff will discuss experimental and computational methods in light of their underlying assumptions, limitations and pitfalls and highlight promising avenues of future research in basic and applied AIRR systems immunology.

The adaptive immune system has evolved a unique molecular diversification mechanism designed to produce a highly diverse set of antigen receptors, necessary to recognize and remove the ever-changing array of pathogens an individual will encounter during their lifetime (e.g., novel coronaviruses). The sheer immensity of each individuals Adaptive Immune Receptor Repertoires (antibody/B-cell and T-cell sequences, or AIRR-seq data) present challenges for producing, storing, sharing, and analyzing these data. The AIRR Community is a group of immunogeneticists, bioinformaticians, and experts in ethics and legal issues of data sharing who joined together to develop standards and protocols for sharing and analyzing these data. Two products of the AIRR-C are the miAIRR standards for storing AIRR-seq data in a common format, and the AIRR Data Commons (ADC), a set of geographically distributed repositories of AIRR-seq data, all adopting these community standards. We are dedicated to the belief that sharing these AIRR-seq data through the AIRR Data Commons will greatly increase their utility for biomedical research and patient care.

The ADC Webinar will discuss the benefits to openly sharing and analyzing these data in an interoperable manner, including access to the >4 billion receptor rearrangements presently queryable through the ADC. We will present demos of how to add your data to the ADC, how to query data through VDJServer and the iReceptor Gateway and preview upcoming analysis tools and repositories being added to the ADC. We will include plenty of time for questions and answers from the audience, and look forward to explaining this ever-expanding resource to our community.

The COVID-19 pandemic has presented many challenges to the biopharmaceutical industry. Initiating programs to discover and develop new antibodies that targeted SARS-CoV-2 was critical, but at the same time, programs bringing existing investigational therapies through late-stage clinical studies and regulatory review also needed to be maintained.

Dr. Janice Reichert (The Antibody Society) provides an update on antibody therapeutics approved in the US and European Union during 2020, those that may be approved by the end of 2021, and those that might enter regulatory review in the US or EU soon. She will also discuss current and potential emergency use authorizations for anti-SARS-CoV-2 antibodies.

Dr. Nick Hutchinson (FUJIFILM Diosynth Biotechnologies) discusses how the pandemic has driven scientists and engineers to find new ways to leverage antibody production capacity most effectively in order to meet the need for rapid early phase development, as well as high-demand commercial manufacturing and what this may mean for antibody manufacturing strategies in the future.

Drs. Janice Reichert (The Antibody Society), Alicia Chenoweth (King'sCollege London) and Silvia Crescioli (King'sCollege London) will discuss key events in antibody therapeutics development that occurred in 2021 and forecast events that might occur in 2022. They will provide an update on antibody therapeutics first approved in the US and European Union, as well as the rest of the world, during 2021, and those in regulatory review. Current and potential emergency use authorizations and approvals for anti-SARS-CoV-2 antibodies will also be discussed.

“Antibodies to Watch in 2023” highlights key events in commercial monoclonal antibody therapeutics development that occurred in 2022 and forecasts events that might occur in 2023. In this presentation, we will discuss the antibody therapeutics granted first approvals in either the United States or European Union in 2022, which include 4 bispecific antibodies ((tebentafusp, faricimab, mosunetuzumab and teclistamab) and 1 ADC (mirvetuximab soravtansine). We will also discuss approvals for antibody therapeutics that were first granted in China or Japan in 2022, which include 2 bispecific antibodies (cadonilimab and ozoralizumab). Globally, at least 24 investigational antibody therapeutics are undergoing review by regulatory agencies. Our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline grew by ~20% in the past year to include nearly 140 investigational antibody therapeutics that were designed using a wide variety of formats and engineering techniques. Of those in late-stage development, marketing application submissions for at least 23 may occur by the end of 2023, of which 5 are bispecific (odronextamab, erfonrilimab, linvoseltamab, zanidatamab, and talquetamab) and 2 are ADCs (datopotamab deruxtecan, and tusamitamab ravtansine).

The ‘Antibodies to Watch’ series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this webinar, we discuss key details for antibody therapeutics granted a first approval in 2023. We briefly review 27 product candidates for which marketing applications are under consideration in at least one country or region, and 22 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies and antibody-drug conjugates. We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutics development efforts by the biopharmaceutical industry are robust and increasingly successful.

The extraordinary scope and scale of the COVID-19 pandemic has elicited extraordinary responses world-wide. Organizations located across the globe have mobilized teams to research the SARS-CoV-2 virus and COVID-19, conduct clinical studies of repurposed biologics, and research and develop anti-SARS-CoV-2 biologics. Disruptions at companies and regulatory agencies, however, have raised concerns about the effects of the pandemic on possible approvals of non-COVID-19 antibody therapeutics. In a series of webinars, The Antibody Society will report on important developments in the commercial pipeline of antibody therapeutics for COVID-19, as well as other indications.

In “Antibodies to Watch in a Pandemic”, Dr. Janice Reichert (The Antibody Society) provides an update on non-COVID-19 antibody therapeutics approved in the first half of 2020, and those that might be approved by the end of the year. She also discusses the ~ 130 biologics currently in development for COVID-19, which includes over 50 repurposed biologics and over 80 anti-SARS-CoV-2 biologics. Additionally, Dr. Thomas Schirrmann (Yumab) presents a case study of how to develop anti-SARS-CoV-2 antibodies in both academic and industrial settings.

Since 2014, the number of antibody therapeutics entering clinical development annually has increased steadily, from 71 in 2014 to 286 in 2022. This has resulted in a clinical pipeline currently composed of ~1250 molecules, of which ~1100 and ~150 molecules are in early- and late-stage development, respectively. Despite the great interest in trends in early-stage clinical development, due to the difference in scale and difficulty in tracking molecules newly entered in clinical studies, analyses of trends in the global commercial development of antibody therapeutics are often limited to the late-stage clinical pipeline only. Luckily, The Antibody Society meticulously collects data for antibody therapeutics at all stages of clinical development. This webinar will provide an exhaustive analysis of the early-stage pipeline stratified by cancer and non-cancer indications, revealing trends in the molecular formats, targets, and mechanism of action.

In this introduction to the topic, Professor Andreas Plückthun, University of Zürich, discusses the biology of the 3 principal types of commercial antibodies: polyclonal, monoclonal, and recombinant.  Surprisingly, only recombinants offer a reasonable hope of reproducibility in the long term – yet they remain very much the minority.

Professor Glenn Begley, Biocurate Pty Ltd, and Professor Cecilia Williams, KTH  Royal Institute of Technology, describe arduous, alarming and very costly experiences in failing to confirm “well established” critical data in oncology –a failure often driven by ineptly characterized antibodies.

Dr. Jan Voskuil, Aeonian Biotech, and Professor Andy Chalmers, University of Bath and CiteAb, delve into the mysterious world of original equipment manufacturers (OEMs), which can veil the identity of antibodies, and data-base repositories that help unveil which antibody has produced reliable results.

Professor Anita Bandrowski, University California San Diego and SciCrunch, and Dr. Jan Voskuil, Aeonian Biotech, probe how antibody reagents are identified.  If we can’t identify which antibody has been used, we can never reproduce experiments.  The Research Reagent Identifier systematically tags antibodies so they can be tracked, but the small-print on the data-sheets still hides many things.

Dr. Giovanna Roncador, Centro Nacional de Investigaciones Oncológicas and EuroMabNet, examinesthe criticality ofusing appropriate fit-for-purpose controls, both positive and negative, to validate antibodies in every experimental context.

Professors Aldrin Gomes and James Trimmer, both from University of California, Davis, dissect two “basic” validation technologies, Western blot and immunohistochemistry, to expose the very many things that can distort validation data.

Dr. Travis Hardcastle, Horizon, and Dr. Alejandra Solache, Abcam, describe the character of different gene-knockout technologies, one of the strongest validation technologies, and their value in large-scale antibody screening. 

Dr. Mike Taussig, Cambridge Protein Arrays, and Dr. Fridtjof Lund-Johansen, Oslo University Hospital, look at array and immunoprecipitation-mass spectrometry technologies, which offer a broader and deeper image of antibody specificity and selectivity for validation, than classical validation technologies.

Dr. Andrew Bradbury, Specifica, suggests ways out of the validation maze by rigorous molecular identification of recombinant tool antibodies. This achievable goal could eliminate many of the shadowy issues described in this series of webinars.

Future recombinant binding tools may avoid antibodies, and use diversified libraries based on small and versatile protein scaffolds, for example the DARPins (Designed Ankyrin Repeat Proteins).  DARPins are single-chain, monodisperse, and non-immunogenic, and can be made rapidly and cheaply in bacteria in many formats.  They can also be expressed in and on cells as non-aggregating fusion proteins with tunable valencies, which opens a wide range of previously inaccessible approaches in cell biology and biochemistry.