The Fc region of antibodies is vital for most of their physiological effects. However, these effects are not always helpful or wanted for many therapeutic antibodies, and can sometimes cause catastrophic adverse reactions. Over the past 40 years, there have been intensive efforts to “silence” unwanted binding to C1q and Fc-gamma receptors, resulting in at least 45 different variants which have entered clinical trials. One of the best known is “LALA” (L234A/L235A). However, neither this, nor most of the other variants in clinical use are completely silenced. We have made a comprehensive comparison of a large number of Fc-silenced variants and find that most of them still have residual activity and the biophysical stability of many has been compromised. With the rise of powerful uses of antibody therapy such as bispecific T-cell engagers, antibody-drug conjugates, and checkpoint inhibitors, it is important to optimize the Fc region as well as the antibody binding site in order to achieve the best combination of safety and efficacy.

Monoclonal antibodies (mAbs) have revolutionized the pharmaceutical landscape offering safe and effective therapeutic options for life-threatening diseases including cancer and autoimmune diseases. Well beyond 100 antibody-derived products have been approved by regulatory agencies for therapeutic use.

The vast therapeutic promise brings forth significant structural intricacies. mAbs are large (150 kDa) and heterogeneous because of the biosynthetic process and subsequent manufacturing and storage. Hundreds of mAb species, differing in amino acid sequence, post-translational modifications (PTMs) and higher order structure co-exist, making up the safety and efficacy profile of the product.

These heterogeneous molecular giants exert different functions, facilitated by the Fab or Fc part, including antigen, FcRn, FcγR and C1q binding. The latter, mediated through the Fc domain, are crucial in, respectively, regulating half-life of mAbs in circulation and triggering the immune system through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). mAb binding is highly sensitive to amino acid substitutions and PTMs such as glycosylation, oxidation, deamidation and isomerization and it is primordial to understand the impact of these structural attributes on functionality. This knowledge resulted, amongst others, in the development of next generation mAb variants engineered to boost or silence specific functionalities.

Advances in liquid chromatography (LC) and mass spectrometry (MS) have made it possible to study these structure/function relationships in great detail. The current presentation will reflect on several of these advancements based on affinity chromatography, size exclusion chromatography (SEC), multidimensional LC, multi-angle light scattering (MALS) detection, native MS and hydrogen-deuterium exchange MS (HDX-MS) for the assessment of the latter relation.

In-vitro Diagnostics Regulation (IVDR) involves a set of directives that govern production and distribution of medical devices performing an in vitro function (IVDs). They aim to guarantee quality, safety and reliability of IVDs by encompassing their concept, design, manufacturing, performance evaluation, safety, and traceability. The main issue relies on a lack of alignment between IVDRs and clinical trial regulations. Furthermore, these directives are region-specific, and are inconsistent across regulatory agencies, leading to redundant applications and severe delays in approvals. This presentation will be discussing how the intricacies of regulatory frameworks for early drug development are currently navigated, balancing current challenges and the need for fast paced – but high quality – developments in oncology.

Twist Biopharma Solutions offers a comprehensive antibody discovery and optimization platform, leveraging its high-throughput DNA synthesis to create the « Library of Libraries »—a vast collection of precisely engineered synthetic antibody libraries. This enables rapid identification of high-affinity antibodies against diverse targets. Integrating in vitro phage display with in vivo capabilities and in silico approaches, Twist Biopharma provides a unique « discovery trifecta. » This platform accelerates the identification of developable therapeutic candidates through advanced screening and characterization.

Twist’s services span the preclinical continuum, including custom library generation, antibody discovery, optimization (humanization, affinity maturation), and supporting development capabilities like IgG conversion and functional characterization. By partnering with pharmaceutical and biotech companies, Twist Biopharma aims to advance the development of innovative biologic therapeutics. Their technology has already contributed to antibodies in clinical trials and established collaborations with major industry players.

In the last two decades, the number of therapeutic options to manage Inflammatory Bowel Disease (IBD) has increased thanks to the development of biologics. Yet, no treatment was able to demonstrate stable control of the disease, and prescription is based on clinician’s expertise or reimbursement guidelines. On the clinical development side, the inclusion of patients with similar therapeutic history remains a challenge.
We used routine care data collected at “Institut des MICI”, a private IBD dedicated care center, respectively in 387 Crohn’s disease (CD) and 183 ulcerative colitis (UC) patients, with comprehensive information of treatment history and disease activity score, to fuel the KEM® explainable Artificial Intelligence platform. Using Logical Reasoning, KEM® is designed to systematically identify the most relevant hypotheses, complementary to standard statistics.
Here, we identified subgroups of patient showing the efficacy of biologics in the last line of treatment in CD and UC. These subgroups, characterized by specific treatment sequences, supports hypotheses for therapeutic recommendation and drug development.
This preliminary work shows that KEM® helps identify the best therapeutic sequences and could thus contribute to the sequencing of treatments for IBD. Additionally, it could support and accelerate drug development by providing valuable insights into treatment effectiveness and optimization.

 “AI-based technologies are transforming antibody therapeutics by predicting properties like stability and solubility early in development. Utilizing algorithms and machine learning, these tools enhance lead candidate selection and antibody engineering, reducing time and cost in drug development and advancing personalized medicine.”

~95% of anti-cancer drugs successful in preclinical studies fail in late-stage human clinical trials. A major reason for this attrition is that existing preclinical models (mouse models as well as in-vitro models) do not contextually preserve the architecture of human tumours and thus efficacy and mechanistic data is not often predictive of patient outcome. To address this issue, we have invested pioneered the Patient-Derived Explant (PDE) platform that represents the ex-vivo culture of intact fragments of freshly resected human tumours and their direct use for anti-cancer drug testing. PDEs contextually preserve the patient-specific tumour microenvironment, 3D structure, and histo-architecture of the original tumours. We have previously demonstrated the clinical predictivity of this approach in Non-Small Cell Lung Cancer and Breast Cancer PDEs, as well as patient-specific responses of PDEs to antibody therapies including immunotherapies. We have developed multi-modal assays for endpoint analysis including « omic » technologies and invested in the application of multiplexed imaging and digital pathology to generate spatial information. Crucially, the PDEs allow co-registration of drug responses with the histo-architecture of the tumours and correlation with clinico-pathological features of the patients/tumours. This talk will provide examples of the power of PDEs for informing Go/No-Go decisions in the drug discovery pipeline.

The transition to 3D cell cultures, such as spheroids and organoids, has revolutionized drug development and testing, driving the need for novel cultivation methods and materials. These 3D models often require extracellular matrix (ECM)-mimicking, mainly rely on animal-derived components like gelatin, collagen, and Matrigel. However, their use is increasingly limited by ethical concerns, variability, and regulatory challenges. Furthermore, it is complicated to produce a large quantity of these spheroids or organoids (> 1000). 

To address these two main issues, we developed a new synthetic ECM alternative based on a droplet microfluidic pipeline. Thanks to this pipeline, we successfully produced hundreds of thousands of spheroids in a single experiment. Additionally, these spheroids encapsulated in a hydrogel shell demonstrated superior robustness and compatibility with manual and automated handling, including pipetting, centrifugation, and advanced analyses. We also observed significant differences in IC50 values between these spheroids and 2D cell models.

Inovotion is a groundbreaking NAM in vivo platform that reduces animal experimentation, adhering to the 3Rs principles, with multiple high-value applications in Drug Discovery, Biomaterials, and Personalized Medicine.

Inovotion’s Drug Discovery solution for anticancer drugs, including Immuno-Oncology, delivers faster results, higher sensitivity, strong reliability, and significant cost savings. By evaluating drug efficacy (tumor growth, metastatic invasion, toxicity, immune cell infiltration, inflammation, angiogenesis, fibrosis, target validation, mechanisms of action), Inovotion accelerates the drug discovery process, significantly reduces costs, and minimizes animal use. Inovotion has conducted over 650 in vivo studies for more than 180 clients in the Pharma and Biotech sectors across Europe, the USA, and Asia.

Inovotion is also developing new applications for Personalized Medicine, based on a unique assay to grow tumor avatars derived from patients’ Organoids, Biopsies, or Circulating Tumor Cells (CTCs).

Inovotion’s biomaterial services assess the in vivo behavior of biomaterials (e.g., biocompatibility, angiogenesis, fibrosis, immune cell infiltration, inflammation) and evaluate all types of materials, such as drug delivery scaffolds, nanostructure, encapsulation material and others.

We assist biologists and chemists in developing new compounds or validating new targets through affordable in vivo evaluation. These accessible efficacy and toxicity assays open new screening perspectives for a wide variety of research projects.

T cell-engaging antibodies (TCEs) are bispecific adaptor proteins that connect any kind of cytotoxic T cells with target cells for redirected lysis. One arm of a TCE typically binds a surface antigen on the target cell, the other arm binds to the invariant CD3 epsilon subunit of the T cell receptor complex. Over the last three years, TCEs have seen an unparalleled surge in approvals as a standalone cancer therapy. A total of eleven TCEs are now approved by the FDA or EMA that very effectively treat as a monotherapy B cell-derived leukemia, lymphomas and multiple myeloma, but also solid tumors derived from uveal melanoma and small cell lung and ovarian cancer. I will review the learnings from eleven approved TCEs in terms of target selection, design, biochemical characteristics, mitigation of cytokine release syndrome (CRS), dose and schedule, potential for combination with standard of care (SoC), and clinical outcome. Future trends such as the combination of TCEs with SoC, dual targeting, tumor-selective activation, and the addition of costimulatory signals will be discussed. CLN-978 will be highlighted as TCE that is being developed for the treatment of various immune diseases.