Antibody Screening in the Fast Lane
Regina Kelder

Antibody Screening in the Fast Lane

A next-generation tool that is changing the way therapeutic antibodies are discovered.

Thor, the protector of mankind, is a hammer-wielding god who swoops in to save the world.  You could argue that monoclonal antibodies (mAbs) sort of serve the same purpose. Monoclonal antibodies (mAbs), which are manufactured in the laboratory and then cloned, produce custom-designed and uniform antibodies that can attach to specific disease cells — bacteria, viruses or cancer cells—without injuring healthy tissue.

Since 1986, when the US Food and Drug Administration approved the first mAb (in this case to limit organ transplant rejection) more than 70 therapeutic or diagnostic mAbs have been approved. Today, mAbs comprise more than 50 percent of the overall biotherapeutic market, a market that is continuing to grow.  

Most large pharmaceutical biopharmaceutical companies are generating candidate antibodies for 10-20 targets per year. As small to mid-sized biotechs and academic drug discovery centers likely add 50-100% to this volume, the estimated global industrial needs for therapeutic antibody generation is in the neighborhood of 300-800 projects per year.

[High-throughput monoclonal antibody library screening has never been faster]

Despite this progression, the fact remains that determining which mAbs do the best job of slinging that hammer is still a rather tedious process. Production of high-quality, functional antibodies remains a major challenge. Over the past 25 years, Phage Display has been the favored way of amassing large amounts of antibodies. The technology is based on the fact that phage phenotype and genotype are physically linked. The phage display technique allows the creation of human libraries which contain up to 1010 different variants. (A variety of immunoglobulin gene sources including blood lymphocytes, bone marrow, and spleen are used for library construction).

The libraries need to be diverse enough in order to achieve a successful outcome and identify the best antibodies for targeted therapies. Historically, libraries were designed to maximize diversity but this came at the expense of non-specific binding and significantly increased pressure on chemistry, manufacturing and control (CMC) activities necessary to successfully advance new monoclonal antibody products from discovery to first-in-human trials and the market as quickly and economically as possible.

As a next-generation approach, Distributed Bio (DBio), a California company whose self-described mission is to “define a new paradigm in revolutionary bioengineered medicines for the entire biotechnology industry” has developed antibody discovery and engineering platforms that maximize structural diversity within the boundaries of naturally occurring antibody sequence landscapes. By joining an advanced computationally optimized human antibody library for antibody discovery (called SuperHuman) with a separate library that provides years of camelid repertoire analysis to inform a computationally optimized synthetic single domain library (called Tungsten) the technologies are able to offer pharmaceutical/biotech companies a differentiated and potentially robust solution that addresses  maximum diversity (billions of antibodies) while avoiding known liabilities such as immunogenicity, thermostability and aggregation potential.

[Check it Out: Changing the Way Therapeutic Antibodies are Discovered.]

The efficiency of this system can’t be underscored enough. The library contains roughly 76 billion unique antibodies, many orders of magnitude larger than the human naïve antibody repertoire, which should contain enough diversity to yield useful, high affinity hits across a broad range of target classes. At the same time, through a range of design strategies, DBio engineers have avoided inclusion of sequences that could promote CMC liabilities. The single-pass multi-parameter optimization, easy affinity maturation and cross-species optimization means a speedier process all-around. Importantly, are also capable of producing scFv for use in cell therapy and bispecific modalities alongside standard IgG paradigms.

Just think what the power of those hammers would be.

Charles River recently announced an exclusive partnership with Distributed Bio that provides clients access to Distributed Bio’s antibody libraries and integrated antibody optimization technologies. The partnership integrates a next-generation antibody library platform in Charles River's biology, PK, pharmacology, biologics and safety services.