Bispecific antibodies (bsAbs) are rapidly emerging as a transformative class in biotherapeutics, offering unique mechanisms of action by simultaneously engaging two different targets. Their potential spans oncology, immunotherapy, and beyond, making their efficient and precise development a cornerstone of modern biologics research.
This webinar will delve into the innovative SpyLock technology, a groundbreaking advancement in the site-specific assembly and screening of bispecific antibodies. Leveraging the SpyCatcher-SpyTag system, SpyLock introduces a reversible locking mechanism to the SpyCatcher that can be applied to rapidly generate hundreds of bispecific antibodies for high-throughput screening of antibody pairs with optimal epitope recognition and affinity matching. Interesting candidates can then be further assessed in their final bispecific format, streamlining the identification of bispecific antibodies.

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.

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.