Antibody Engineering: Driving Therapeutic Discovery and Diagnostics Forward

We recently spoke to GenScript’s VP of Marketing, Eric Wang, to learn more about the company’s mission to “make people and nature healthier through biotechnology”. Eric discusses the key phases of antibody therapeutic discovery and development, GenScript’s role in advancing drug discovery research, and tells us more about MonoRab^TM – the company’s recently launched custom rabbit monoclonal antibody service.

Laura Mason (LM): Could you tell us more about GenScript, the company mission and goals?

Eric Wang (EW): In 2002, our current CEO, Frank Zang, Ph.D. came to realization that biologists spend a large amount of time generating and trouble-shooting laboratory reagents, rather than focusing on scientific discovery. Therefore, he founded GenScript with the mission of making research easy by generating reliable, high quality gene synthesis reagents for scientists in every discipline. Over the past 16 years, GenScript has matured to a leading biology contract research organization, providing completely custom reagent generation services including gene, peptide, protein, CRISPR, antibody, and therapeutic discovery/development research to scientists in over 100 different countries worldwide. Our products are characterized by fast delivery and consistent quality which greatly increase success and reproducibility of biology experiments. GenScript prides ourselves in our “from the lab-for the lab” mantra through our deep understanding of researchers and laboratories, as we have over 600 employees with higher level degrees in the life sciences available for in depth scientific planning and execution of our customer’s projects. We believe that we are playing an important role within this amazing time period for biology, in which revolutionary breakthroughs will finally solve fundamental issues of humanity: from cleaning our environment, to providing us safe and sustainable sources of food, and curing disease from cancer, to HIV, and everything in-between.

LM: The overall discovery and development process for antibody therapeutics can be broadly divided into five stages. What are these stages?

EW: Other companies may use different terminology to segregate the phases of therapeutic antibody discovery and development, however the services included in each milestone are grouped similarly according to end deliverables. The terminology that we use to describe these phases are target identification and validation, antibody lead generation, antibody lead optimization, antibody lead functionality analysis (characterization), and antibody production and preclinical development. Target identification and validation involves narrowing down molecular targets through combinations of approaches including biochemical methods, genetic interactions, and computational inference in order to fully characterize & validate the antibody-antigen binding mechanism. Antibody lead generation is part of the discovery stage of therapeutic antibody discovery and development. In this phase, validated molecular targets are used as antigens to initiate an immune response in a host animal to generate therapeutic antibody candidates. Antibody lead optimization is the final stage of therapeutic antibody discovery where a drug candidate is modified to increase its effectiveness, affinity, and to diminish immunogenicity. It’s also the stage where rodent monoclonal antibodies are converted to their humanized forms.  Antibody lead functionality analysis (characterization) involves in vitro and in vivo testing to further evaluate potential drug candidates in order to check their feasibility and efficiency. Antibody production and preclinical development is the final stage of preclinical development, where final antibody drug candidate selection and recombinant expression takes place. After these milestones, our customer will have a fully function therapeutic antibody candidate which can be used for preclinical animal testing and optimized for subsequent clinical trials.

LM: Could you touch on the different services you offer within the drug discovery and development field?

EW: GenScript offers a wide range of custom services to accelerate therapeutic discovery and development. We are truly a one stop provider which helps researchers from idea all the way to commercialization. Specifically, in therapeutic antibody, we offer multiple immunization strategies, including protein, peptide, DNA, and cell line, as well as immunogen optimization services in order to generate a large amount of high specificity antibodies against any type of antigen. We combine this, with our award winning hybridoma or phage display based antibody generation platforms for rodents, rabbits, and even humans. Once antibody leads have been generated, we provide our customers with a fully comprehensive antibody optimization platform, including antibody sequencing, humanization, and affinity maturation. As opposed to other CRO’s, GenScript also provides therapeutic antibody lead development services. These range from a wide array of in vitro and in vivo functional and cell-based assays, drug metabolism and pharmacokinetic analysis, immune checkpoint assays, and our proprietary fast screening of expression biophysical properties and affinity (FASEBA) platform. GenScript also offers reagent antibodies which are required for thorough analysis of therapeutic candidates, including anti-idiotype antibody generation, analytical kit development, and IHC tailored rabbit antibody development. Through our fully integrated therapeutic antibody discovery and development platform, our clients will be able to greatly accelerate their process to translate innovation from laboratories into commercial products.

LM: You recently announced the launch of a custom rabbit monoclonal antibody service, MonoRab^TM. What are the benefits of using rabbit monoclonal antibodies (mAbs)? What applications is MonoRab^TM well suited to?

EW: The benefits of generating antibodies in rabbits, as opposed to more traditional species like mice or rats are truly endless. First and foremost, rabbits are able to generate highly specific antibodies due to their enhanced means of B cell maturation. Rather than relying on common mechanisms of gene conversion and somatic hyper mutation, immature rabbit B-cells also go through a complex gene conversion-like mechanism for sequence development. This enhanced maturation process allows for the development of longer and more heterogeneous complementarity-determining regions (CDRs) than those commonly produced in mice or humans. Secondly, the rabbits immune system is capable of eliciting a strong immune response against small, non-amino acid antigens, which are either non-immunogenic in mice or mount a weaker response in mice than in rabbits. As a result, rabbit mAbs can easily recognize phospho-peptides, carbohydrates, haptens, and small molecules. Third, the evolutionary distance between human and rabbit is farther than the one between human and mouse. As a result, rabbits can recognize a larger number of targetable epitopes compared with mice and, therefore, can generate antibodies capable of cross-reacting with mouse orthologs of human antigens. This in turn avoids the issue of self-antigen recognition occurring in the application of an antibody. Fourth, compared to human and mouse, rabbit immunoglobulins have a simpler and more stable structure. In addition, rabbit IgGs contain fewer amino acids at their N terminal and D-E loop as well as extra disulfide bonds in the variable region of their heavy chain. These characteristics are suggested to render rabbit Abs more stable and, therefore, easier to work with.

Rabbit antibodies make great reagents for everything from basic research through to therapeutic antibody discovery. Some applications which require the high specificity, affinity, and sensitivity of rabbit antibodies are diagnostics, pharmacokinetics, and therapeutics. In terms of diagnostics, rabbit mAbs enable the development of a wide range of in vitro and in vivo diagnostics. A variety of IVD assays, such as IHC, ELISA, and radio immunoassays (RI) are based on the principles of antigen-antibody binding. Given the critical role of these assays in patient or animal care, it is extremely important that IVD assays are carried out using the highest sensitivity and affinity mAbs available. In drug development, pharmacokinetic (PK) assays are used to measure the absorption and excretion rates, distribution, and half-life of candidate small molecules or mAb therapeutics. High sensitivity and specificity rabbit mAbs are, hence, useful reagents in PK studies for obtaining accurate quantitative measurements of a drug’s concentration with no worries about false positive or negative results. For therapeutics, specificity and sensitivity of an antibody towards its target antigen ensure both safety and toxicity concerns: highly specific antibodies avoid off-target binding and hence, offer safety; highly sensitive antibodies require low dosage administration and hence, cause a minimum level of toxicity. Given that rabbit mAbs have both of these sought-after characteristics, they are considered as excellent therapeutic candidates in order to directly target disease-specific cell surface antigens or used as cytotoxic drug delivery agents. Rabbit antibodies are also highly effective in generating single chain variable fragment (ScFv) antibodies for Chimeric Antigen Receptor Antigen T-Cell therapy (CAR-T).

LM: Could you tell us more about your partnership with iGEM?

EW: GenScript has been proudly partnering and sponsoring the iGEM Giant Jamboree competition since 2009. As an iGEM partner, GenScript is responsible for distributing iGEM DNA Distribution Kits worldwide. Each kit has a curated selection of the best parts teams have previously built and tools to help iGEMers test their competent cells and re-submit samples at the end of the season. For the 2018 Giant Jamboree, GenScript is extending sponsorship for 5 iGEM teams, providing $4,000 of total support for each group. In addition, GenScript is extending special discounts on its DNA synthesis services to all iGEM Teams.

Eric Wang was speaking to Laura Elizabeth Mason, Science Writer for Technology Networks.