We have developed a plasma-stable antibody drug conjugate (ADC) that has glucocorticoid receptor modulator (GRM) molecules linked to an anti-TNF-α mAb. This ADC is targeted to TNF-α expressing inflammatory cells and internalized into lysosomes where GRM payload is released. This significantly reduces the efficacious GRM dose to below levels that induce undesired side effects. Activity of a surrogate anti-TNF GRM conjugate in inflammatory disease models will be described.

The majority of immune agonist antibodies currently in clinical development rely on extrinsic crosslinking by Fc receptors to enable in vivo pharmacologic activity. We have explored multiple technology platforms to enable antibodies to promote receptor signaling without relying on Fc receptor engagement. This talk will describe engineering approaches and considerations, present data demonstrating in vitro and in vivo proof of concept, and discuss biological and clinical context for immunotherapy.

The driving role of complement in a single disease, paroxysmal nocturnal hemoglobinuria, provoked the development and FDA approval in 2007 of eculizumab (Soliris™), an anti-C5 antibody. No other drug has since been approved for any other indication. A high attrition rate in complement drug development means that the unmet need for therapy in many complement-driven diseases remains. I will discuss the challenges associated with therapeutic inhibition of complement, highlighting lessons learnt and hurdles cleared by various different therapeutic approaches.

Several active vaccines and monoclonal antibodies have been tested in human clinical trials and despite removing amyloid deposits, only Aducanumab has been reported to slow cognitive decline. Those that failed in clinical trials target plaques that may represent tombstone markers of antecedent amyloid pathology. Antibodies that target oligomers, but do not bind plaques, have not been fully evaluated yet. Anti-amyloid antibodies with these and other novel properties remain to be tested in human clinical trials.

Genovac Antibody Discovery became the first company to successfully combine three powerful antibody discovery platforms while developing humanized antibodies against SARS-CoV-2 targets. Genovac AbD utilized its proprietary genetic immunization technology, Ligand’s OmniRat platform, and Berkeley Lights’ Beacon platform to develop high-affinity antibodies that recognize viral proteins and are potentially capable of neutralizing SARS-CoV-2.

Adipose tissue dysfunction is at the heart of diabetes, fatty liver disease, organ fibrosis and enhanced growth for invading tumor lesions in a variety of cancers. We have targeted two key players in that area, leptin and endotrophin. Neutralizing antibodies against these factors whose production is enriched in metabolically challenged adipose tissue are highly effective in preclinical settings as anti-obesity, anti-diabetic, anti-fibrotic, and chemosensitizing agents in the breast cancer area.

Developing functional antibodies targeting G-protein-coupled receptors remains challenging. Here we report structure-based and function-based approaches for generating functional single domain antibodies (sdAbs) against human apelin receptor (huAPJ). We co-crystallized an orthosteric sdAb antagonist complexed with huAPJ and converted it into an agonist by structure-guided design. We further developed an HTS method for directly isolating functional antibodies against GPCRs and identified a panel of sdAb antagonists and an agonist to huAPJ.

The human antibody repertoire is a valuable source of therapeutic grade antibodies. However, identifying the rare B cells expressing these antibodies can be challenging. We have built a platform that uses microfluidics to encapsulate millions of primary B cells into droplets, capturing a paired repertoire that can be screened by phage-display. This presentation will describe the technology and its use in rapidly identifying natively-paired and functional antibodies across multiple campaigns.

CMV and EBV are pervasive, typically asymptomatic viral infections that can be deadly for immunocompromised individuals. Patients suffering from these infections have been successfully treated with transfer of ex vivo expanded virus-specific T cells in clinical trials. This treatment is labor-intensive and highly individualized, limiting broader use. Combining an immunostimulatory IL-2/antibody fusion protein with viral antigens, we are developing an injectable alternative for robust virus-specific T cell activation.

Antimicrobial proteins (AMPs) present the opportunity for efficient discovery of potent, selective therapeutics for antibiotic-resistant infection. This presentation will discuss platforms to engineer AMP stability, selectivity, and potency via bioinformatics-guided library design and high-throughput discovery assays. Co-evolutionary models enhanced library strategies to engineer endolysin stability and activity against Clostridium perfringens and Enterococcus. A sequence depletion assay mapped oncocin’s sequence-function relationship. These methods are broadly applicable to protein engineering.

The serine protease β-tryptase is an important mediator of the allergic inflammatory responses in asthma. Protease inhibitory antibodies employ a mechanism of action (MOA) in which Fab binding directly or allosterically inhibits the protease. I will discuss a novel inhibitory anti-tryptase antibody with a unique bivalent IgG-driven MOA that reveals a new way in which IgGs can inhibit a target and may provide a new strategy for engineering novel antibodies.

Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs stimulated innate and adaptive immunity and acted as a type-2 adjuvant. Antibodies directed against key epitopes of the CLC crystallization interface dissolved CLCs from patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E synthesis, and bronchial hyperreactivity in a humanized mouse model of asthma.

The blood-brain barrier presents a major obstacle to brain drug delivery. We have developed several different enabling platforms for the identification of antibodies against blood-brain barrier resident receptors that could ultimately be used to ferry drug cargo into the brain. Here we will describe our recent efforts to identify such blood-brain barrier-targeting antibodies.

WNT molecules have the potential to induce tissue regeneration and repair. However, their poor biophysical characteristics and lack of selectivity have hindered their application as therapeutics. We have developed a novel antibody based platform for potent, selective WNT surrogate generation, and identified key requirements for maximal signaling.