Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to the lysosome for degradation. Here, we describe the potential of different lysosomal targeting receptors such as asialoglycoprotein receptor (ASGPR), which is specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins by a new class of antibody conjugates.

The cell surface proteome (surfaceome) is the major biohub for cells to engage their extracellular world and represents the primary target for small molecules and virtually all biologics. We have developed a new technology called AbTAC, that is fashioned after intracellular PROTACs, but utilize genetically encoded bi-specific antibodies that recruit transmembrane E3 ligases to membrane targets of interest inducing their degradation. We will discuss their properties and structure activity relationships.

Nanobodies (sdAbs) are antibody fragments derived from heavy-chain-only antibodies. Owing to their small size (~15 kDa) and unique biochemical properties, nanobodies emerged as promising protein based reagents. In this presentation, a high-throughput nanobody discovery platform using yeast surface display libraries will be introduced. Approaches to characterize nanobody stability and specificity along with the live cell imaging and targeted protein degradation applications will be discussed.

One of the most advantageous features of antibody-based therapeutics is their diverse and multi-layered mechanisms of action, including activities such as neutralization, signal modulation, and immune recruitment. For each of these various mechanisms, the format of the employed antibody plays a critical role in determining its efficacy. This talk will highlight the effects of antibody geometry on functional performance for several representative multi-specific antibodies that act through distinct therapeutic mechanisms.

TCR mimetic (TCRm) antibodies represent a powerful new therapeutic/diagnostic modality in immuno-oncology. By recognizing specific peptide:major histocompatibility complexes (pMHCs), they offer a vector to target cancerous cells with pinpoint accuracy through intracellular biomarkers and an ability to sidestep immunosuppressive microenvironments that downregulate T cell signaling. In this talk, I will share a computational analysis of immunoglobulin:general antigen and immunoglobulin:pMHC complexes which yields guiding principles for future pMHC-specific TCRm design.

Rabbit mAb 4A11 (rbt4A11) disrupts both TGFß2 and TGFß3 signaling. During the humanization of rbt4A11 where, two variants of humanized 4A11, v2 and v7 had identical CDRs, maintained high-affinity binding to TGFß2/3, yet exhibited distinct differences in activity. The complex structure of v2 or v7 with TGFß2 identified a novel interaction between two heavy chain molecules. Further characterization revealed heavy chain framework residue variations at either position 19, 79, or 81 strikingly interconvert antibody function. Our work suggests that in addition to CDRs, framework residues between Fabs in an antibody could be engineered to further modulate antibody activity.

Advances in biologics discovery have rendered essentially all cell surface and extracellular proteins druggable. In contrast, there remain many intracellular targets that are undruggable using conventional therapeutic modalities. Intracellular biologics, such as genetically encoded monobodies and monobody-VHL fusions (“bio-degraders”), are invaluable tools to advance mechanistic understanding of target biology and inform drug discovery strategies. This talk will illustrate opportunities and challenges of such approaches with focus on RAS oncoproteins.

Multi-spanner receptors, including GPCRs, constitute a therapeutically interesting yet technically challenging target class for therapeutic antibodies. Factors contributing to the difficulty of targeting these receptors include high homology across species resulting in immune silencing during immunization, relatively low or transient cell-surface expression levels, and difficulty in formulation as a soluble protein applicable to immunogen and screening reagent applications. This talk will cover some examples of approaches to overcome these challenges.

Discovery and selection of biotherapeutics, as antibodies, is traditionally driven by affinity, PK profiles and potency. Optimization of such properties does not necessarily translate in candidates with favourable biophysical properties. This can lead to longer timelines in CMC and downstream process development. It is, therefore, imperative to include biophysical characterization early in discovery workflows and insure a fit for purpose design of screening cascades for every stage of the discovery process.

In this presentation, Tracey Mullen, VP/GM of Abveris, a division of Twist Bioscience will discuss:
•Challenges in the therapeutic mAb discovery against cell surface receptors and transmembrane proteins such as GPCR & ion channels

•Overview of key technologies to access development-ready lead candidates for conventionally challenging targets

•A case study of a discovery campaign against a cell surface receptor using both humanized & hyperimmune mice for risk-mitigation & expanded diversity

Launched only a few years ago, the Leap-In Transposase platform has rapidly become an industry standard technology for the generation of CHO cells for the manufacturing of antibodies and other biologics.  This presentation will highlight achievements and case studies of the platform including high titer mAb manufacturing, rapid anti-COVID responses, and some novel, next generation, applications.  

Monoclonal antibody (mAb) products have broad applications in infectious and autoimmune diseases as well as oncology. Alternative approaches to mAb delivery could expand both the applications and use of this impactful technology. We are developing replicating RNA for the delivery of gene-encoded mAbs in order to enable 1) enhanced antibody expression following peripheral administration, including intramuscular injection routes, 2) rapid response to pandemics, and 3) sequence-independent manufacturing processes.

Therapeutic administration of IL-15 to enhance the number and effector status of tumor-reactive lymphocytes is desired for cancer immunotherapy. To accomplish this goal, we designed a recombinant IL-15 that selectively agonizes lymphocytes that express PD1, a marker of T cell activation. In this talk, we will demonstrate how protein engineering enables long half-life, PD1+ selectivity in vitro, and efficacy in a range of tumor models in vivo.

During this talk I will highlight the potential of Icosagen's proprietary technology platforms in developing highly potent SARS-CoV-2 neutralizing antibodies. Although neutralizing antibodies against SARS-CoV-2 demonstrate efficacy in reducing the development of severe COVID-19, the cumbersome intravenous administration of antibodies limits the effective use of such therapies. Here we demonstrate the potential use of inhalation based delivery of SARS-CoV-2 neutralizing antibodies for generating rapid passive immunity.

A compilation of COVID-19 lessons and their application to human immunology, future vaccines, and how we might continue to address the enduring threat of emerging infectious diseases and novel pandemic pathogens shall be discussed.

Brain uptake of therapeutic antibodies has been reported using different experimental systems and diverse methodologies, but the precise measurement of drug levels in all relevant brain compartments is often hampered by technical difficulties. We present the comprehensive characterization of a Brain Shuttle anti-amyloid antibody in Cynomolgus monkeys, including modeling-supported plasma and brain pharmacokinetics, and provide first evidence for brain uptake in humans.

While it has become increasingly appreciated that regulatory T cells (Tregs) act in a tissue-specific manner to control inflammatory circuits and tissue repair, the unique biology of human tissue Tregs was poorly understood. To this end, we developed a high-resolution map of human immune-regulatory pathways by single-cell RNA sequencing of healthy, inflammatory, or cancer tissues. Modern computational tools paired with rapid functional validation in disease-relevant human Treg assays allow us to prioritize pathways and targets for modulation in disease. This approach identified novel regulatory nodes and forms the foundation of our growing pipeline of tissue-Treg-focused therapeutics.