This presentation will outline our recent findings on the molecular composition of the serological repertoire and on the role of Fc receptors on effector functions.

In this presentation, I will give a short introduction into the technology that enables to perform these measures, "DropMap," and show some of its applications within our research projects. In particular, the talk focuses on how single-antibody resolution is used to quantitatively study immunizations in my group; and how we use multidimensional assays and functional readouts to characterize the secreted antibody repertoire.

Utilizing its proprietary DNA technology to write synthetic libraries, Twist Biopharma provides end-to-end antibody discovery libraries including both highly diverse synthetic naïve antibody phage display libraries and target class specific antibody phage display libraries against difficult-to-drug targets.  In this talk, Aaron, will present several POC data on each member of their Library of Libraries.  For some of the targets, the power of selecting multiple libraries against each target will be highlighted.

In this talk we will highlight Icosagen’s antibody developments against SARS-CoV-2 and demonstrate the efficacy of alternative antibody isotypes to viral neutralization, including potential viral variants. We demonstrate in vivo efficacy of these approaches that have implications for more effective delivery of neutralizing antibodies to the primary sites of infection. 

To improve the safety profile of an immunotherapy, an on/off switch, along with the ability to locally activate T cells, can provide the much-needed control. Here, we leverage the unique T cell activating capabilities of superantigens and use computational protein design methods to build an AND gate logic via self-assembly. A two-component self-assembling protein is designed to reconstitute superantigen function, enabling a new modality for controlled T cell activation with de novo designed proteins.

Despite much progress in computational protein design, significant challenges remain in the complexity of protein geometries and functions that can be designed at present. I will discuss our recent progress with (i) reshaping of protein conformations for reprogrammed functions, (ii) engineering small molecule binding sites de novo to detect and respond to new small molecule signals, and (iii) controlling protein shapes to create fold families for new functions.

Next-generation sequencing of antibody repertoires has provided new insights into natural immune response.  The correlation between the B-cell receptor repertoire and the serological antibody repertoire, however, has only been analyzed in a small number of studies.  In this talk we will discuss the use of serum antibodies to guide antibody discovery in an immunized llama.  Further, we use next-generation sequencing to mine the clonal lineage of serum-identified antibodies.

Sorting cells based on secreted products enables the discovery of antibodies, the development of cell lines producing recombinant products, and the selection of functional cells for cell therapies. However, approaches to rapidly analyze and sort viable cells based on secretions are not easily accessible. I discuss nanovial technology that enables the isolation of individual cells in uniform drops with simple mixing massively in parallel, the accumulation of secreted products at high concentrations, and the downstream sorting of cells based on their secretions using standard FACS. This approach promises to democratize the ability to discover and manufacture drugs and cell therapies.

A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition can be complicated by the poor correlation that exists between antigen binding and T cell activation and the risk of introducing cross-reactivity to off-targets. To overcome this, we implement genome editing and computational methods to profile TCR activity and specificity at high-throughput on the surface of human T cells. This reveals a substantial discordance between antigen binding and antigen-induced TCR activity, and allows for accurate prediction of antigen off-targets. We engineer synthetic TCRs with enhanced activity and high specificity for the MAGE-A3 tumor antigen with no detectable cross-reactivity. Thus, high- throughput engineering of synthetic TCRs on the basis of their activity enables the development of more potent and safe therapeutic candidates.

Clinical successes for engineered T cell therapies has led to efforts to expand these treatments to new applications. Many attempts to develop these treatments rely upon inherently low-throughput methods. We have developed a selection-based approach to identify novel CAR intracellular domain combinations based upon their induced cell phenotypes. Initial applications of this approach to CD19-targeting CARs show novel signaling compositions and biological functions that were previously not observed.

The SARS-CoV-2 pandemic has resulted in an extraordinary worldwide unplanned experiment, in which numerous scientific groups have generated antibodies against a single target: the CoV-2 spike antigen, allowing the comparison of different methods and derived antibodies. The most potent neutralizing antibodies have been generated from convalescent patients and immunized animals, with non-immune phage libraries usually yielding significantly less potent antibodies. Here we show it is possible to generate ultra-potent (IC50 <2ng/ml) human neutralizing antibodies directly from a novel naïve antibody library format with affinities, developability properties and neutralization activities comparable to the best from hyperimmune sources.

Epidemics and pandemics with RNA viruses are occurring at an accelerating pace. We have embarked on a long term project to discover best-in-class human monoclonal antibodies for the 100 most likely epidemic viruses, a project called AHEAD100. We will describe rapid technologies for the discovery of antibodies, principles underlying common mechanisms of action, and rational approaches to the selection of synergistic combinations of antibodies.

Antibodies have become important in treating infectious diseases. We recently developed a triple antibody cocktail against Ebola virus, the first FDA approved therapy for this indication. Now, we describe the generation and characterization of an antibody cocktail against SARS-CoV-2. Early clinical data confirmed its antiviral activity and demonstrated clinical benefit by significantly reducing medical visits of symptomatic ambulatory patients. Our cocktail received Emergency Use Authorization, while clinical testing is continuing.

We developed recombinant antibodies against SARS-CoV-2 using our fast-track TrailBlazer Antibody service. The process combined antibody phage display and our new modular antibody assembly platform based on SpyTag-SpyCatcher technology, which allows the rapid construction of antibodies in various formats from pre-produced protein modules. Here we explain how the combination of these powerful technologies reduced the time from antigen receipt to shipment of synthetic IgGs to just 4 weeks.

Currently in development, OptiMAL® is Fusion’s new mammalian antibody library – a discovery platform yielding fully human antibodies.

OptiMAL® is for clients looking to streamline the discovery and preclinical optimization of novel antibodies. Incorporating Fusion Antibodies’ proprietary protein engineering technologies, the library eliminates the need for platform switching and reformatting common with other approaches. The output from OptiMAL® is a fully-human antibody with no need for further humanisation.