While in vivo immunization remains the main source of antibody identification, progress in gene synthesis opened up the development of fully synthetic libraries. We designed several humanized single-domain scaffolds and generated high-diversity libraries that can be screened by phage display. We will show here that such libraries enable the fast identification of highly specific antibodies that can be used to identify novel tumor antigen, stain or destroy cancer cells.

In contrast to the prevalent static view of the binding interface, we demonstrate a dynamic perspective not only of the paratope, but of whole Fvs and Fabs. We show that antibodies exist as ensembles of paratope states. These paratope states are defined by a characteristic combination of CDR loop conformations and interdomain orientations. They interconvert into each other in the micro-to-millisecond timescale by correlated loop and interdomain rearrangements. We demonstrate that crystal packing effects can distort the paratope state and thus, result in misleading X-ray structures. By advancing the repertoire of cutting-edge simulation techniques, for the first time we achieve a complete description of conformations, thermodynamics, and kinetics of the whole binding paratope in solution. These findings have broad implications in the field of antibody design and in the development of biotherapeutics, as they provide a new paradigm in the understanding of CDR-binding loop states, antibody-antigen recognition, relative VH and VL interface angles, and elbow-angle distributions and their respective dynamics. Preliminary findings are already published in six manuscripts, but a considerable number of further publications is upcoming. These upcoming publications will also address issues like inter-loop correlation and the relationship of Fv-interface dynamics with loop rearrangements.

The discovery of antibodies against difficult targets, the high-hanging fruit, will require technology that can functionally screen the B cell repertoire.  This presentation will demonstrate how users of the Beacon^® optofluidic system can generate diverse hit panels and down-select lead candidates in less than 1 week.

Cellular therapies show high promise for the treatment of cancer and are part of the standard of care in some lymphoma and leukemia types. There, cell therapies come with two major limitations which are toxicities due to uncontrolled T cell activation and disease escape driven by antigen loss or down regulation. We have recently developed a novel modular cell therapy platform constituted of fully synthetic inert proteins introduced into T cells that can only be triggered through antibodies specific for said fusion proteins and bound to the tumor cell. This platform is actionable, controllable, and modular, as targeting can be altered by changing the bispecific antibody to be used. I will present data describing the properties of the platform and supporting its use for cancer treatment, warranting its further clinical translation.

Numab’s MATCH platform was exploited for the generation of a monovalent trispecific 4-1BB/PD-L1/HSA MATCH3 molecule (NM21-1480) that agonizes 4-1BB on anti-cancer T cells, conditionally upon binding to and blockade of PD-L1 on tumor cells. NM21-1480 shows superior efficacy over conventional CPI therapies and avoid dose limiting toxicities of systemic 4-1BB agonism. Further, tetra-specific MATCH4 molecules are exploited to improve on safety and efficacy of conventional bispecific strategies.

High-throughput single-cell screening is enabling the rapid generation of large, diverse antibody sequence datasets. By combining immune repertoire sequencing with functionally validated single-cell data, we further expand antibody diversity accessible for lead identification. Celium™, AbCellera's interactive software, interprets these complex datasets to guide the selection of valuable antibodies.

Agonists for G-protein-coupled receptors (GPCRs) in treating diseases are needed, whereas it remains a big challenge in developing antibody agonist as a novel modality targeting GPCR. Here, we report a full agonist, JN241-9, for human apelin receptor (APJ), realized by structure-guided conversion of single-domain antibody antagonist, JN241. 

Erenumab is the only US FDA-approved mAb therapy against the CGRP receptor (CGRPR) for the prevention of migraine, and also against a G-protein-coupled receptor (GPCR). Here, we report the architecture and functional attributes of erenumab critical for its potent antagonism against CGRPR. The crystal structure of erenumab, in complex with CGRPR, reveals a direct ligand-blocking mechanism, enabled by a remarkable 21-residue-long CDR-H3 loop that projects deep into CGRPR. Such structural insights reveal the drug action mechanism of erenumab and shed light on developing antibody therapeutics targeting GPCRs.

Engineering of de novo proteins has the revolutionary potential to transform the field of therapeutic development, from traditional molecule discovery to a purposeful, ad hoc, molecule engineering. Although still in its early phase, the first examples of this new approach are already showing tangible results that hint at its enormous potential to deliver the next generation of therapeutics, tailored on demand to treat disease. I will illustrate the concept with a few of our recent research developments.

Utilizing its proprietary DNA technology to write synthetic libraries, Twist Biopharma provides antibody discovery and optimization solutions for the biotechnology industry, based on a strategy of combining highly diverse synthetic naïve antibody phage display libraries with an end-to-end digitalization workflow that allows us to identify leads against difficult-to-drug targets in high-throughput. Here, we present a panel of high affinity anti-SARS-CoV-2 S1 and anti-ACE2 antibodies we have identified that may have both therapeutic and/or diagnostic applications.

The blood-brain barrier (BBB) severely limits the number of antibodies that reaches the brain, impeding the development of immunotherapy. We have developed a transporter for antibodies, which increases the brain uptake 80 times and enables novel treatment strategies. Here I illustrate this by showing data from a treatment study where we have managed to decrease amyloid amounts in the brain of mice with Alzheimer's disease. 

Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We have developed a transport vehicle (TV) by engineering the Fc fragment to exploit receptor-mediated transcytosis by binding to a highly expressed BBB cell target. The TV platform significantly improves CNS uptake of peripherally administered protein therapeutics and results in sustained pharmacodynamic responses in both mice and non-human primates.

The structure of N-glycans is important in QC of antibody drugs. In 2018, we launched TSKgel FcR-IIIA-NPR with a modified FcgRIIIa ligand as HPLC column for rapid analysis of antibodies. A preparative column for more detailed analysis will be launched soon. Characteristics and applications of these products will be introduced.