Sevion is overcoming the constraints of conventional antibody discovery approaches by applying an integrated suite of technologies that unlocks previously inaccessible targets, enabling entirely new therapeutic classes to be discovered. Sevion is applying this technology to develop both a proprietary product pipeline, and to assist drug development partners in discovering new and novel therapeutic candidates.
Antibody Discovery
Target Opportunity: Multispanning membrane proteins, particularly GPCRs and ion channels, represent major classes of cell surface therapeutic targets involved in nearly every therapeutic area, and are the targets of >50% of all therapeutics.
Despite this importance, only a minor subset of these targets has been successfully drugged by small molecules due to difficulty in specificity and overcoming inherent pharmacological challenges.
Sevion overcomes this challenge in two ways. First, our ultralong CDR3 scaffold provides a unique protruding structure (unprecedented in typical human antibodies) that allows binding to unique epitopes, including the pores of ion channels. Second, our addressed libraries allow screening to high-value cell-surface targets directly on the cell surface. Intact live cells maintain the pharmacologically relevant conformations of the target in the context of the plasma membrane and its associated proteins, carbohydrates and lipids. Target expressing cells are screened by high throughput flow cytometry for binding to each of the library’s antibody constituents. This format allows for multiplexed screening of several cell and target types in a single discovery campaign, and additionally allows engineering optimization directly on the cell for enhanced affinity or activity.
Cow Antibody Scaffold Accesses Difficult Therapeutic Targets: Despite the enormous diversity of the antibody repertoire, human antibodies all have a similar geometry, shape and binding mode. Sevion scientists have discovered and humanized a novel class of therapeutic antibodies derived from cows that have a highly unusual structure for binding targets.
This unique ultralong CDR3 structural domain found in cow antibodies is comprised of a knob on a stalk that protrudes far from the antibody surface, creating the potential for entirely new types of therapeutic functionality. Using both our humanized spatially addressed library and direct engineering of the knob, we are exploring the ability of utilizing the knob and stalk structure to functionally interact with important therapeutic targets, including GPCRs, ion channels and other multispanning membrane therapeutic targets on the cell surface. Our lead antibody SVN-001 was derived from these efforts.
Spatially Addressed Antibody Libraries: Traditional antibody drug discovery methods (phage/yeast display or immunization) rely on competitive selection from a pool of antibodies to identify a lead therapeutic candidate. While this approach has led to many successful antibody therapeutics, targets have been limited to proteins which can be easily purified.
Additionally, when discovery is driven by selection based on competitive binding, the result is a narrow range of antibody functionalities driven by high affinity antagonism. The highest affinity antibody, however, isn’t always the best therapeutic, and modulating a pathway more subtly to treat disease is often preferable to affecting it in a binary fashion through high-affinity binding.
Sevion has developed the world’s first “spatially addressed” antibody library with an expansive combinatorial collection of recombinant antibodies in microtiter plates in which each well contains a single species of antibody of known concentration, composition and sequence. Our spatially addressed library allows us to evaluate the therapeutic potential of each antibody individually in a non-competitive way and allows direct discovery on the cell surface. This approach is more analogous to traditional small molecule drug discovery and allows us to screen antibodies for functional drug activity as opposed to simple binding properties. This next generation discovery system unlocks epitopes, targets, and functions that are only identifiable in the context of a living cell.
Sevion’s Chimerasome technology is based on a single protein that can be assembled to form a spherical protein nanocage encapsulating drugs or nucleic acid therapeutics.
The Chimerasome can be coupled to antibodies or peptides externally, enabling highly-specific cellular targeting of the payload. For small molecule drugs, Chimerasome technology has the potential to deliver thousands of active drug molecules per antibody-decorated nanocage. The Chimerasome biologics approach allows for specific optimization of regions of the building block responsible for the key functions required for a successful delivery system, including serum stability, triggered opening and payload release, tunable PK and biodistribution, as well as safety.
Combining the Chimerasome nanocage with Sevion’s proprietary antibody technology has the potential to deliver massive payloads of either small molecule drugs or unique biologics like siRNA to very targeted locations in the body, broadening the therapeutic utility of our antibodies.