Antibody Drug Advantages
Antibodies offer several favorable characteristics such as high specificity, minimal off-target effects and good safety profiles. By triggering several immune effector mechanisms, antibodies can effectively neutralize pathogens, inactivate target antigens or destroy malignant cells. In addition, because antibody manufacturing follows a similar process regardless of the intended drug target, costs and risks of development are lower than with new small molecule drugs. Given these advantages, it is perhaps not surprising that antibodies have proven enormously successful both medically and commercially, transforming treatment and producing more than 50% of all drug sales, reaching a total of $80B globally in revenue in 2015. With over 500 new antibodies in the pipeline, the trend is expected to continue and antibody drug sales are projected to nearly double by 2020, reaching $150B globally.
OmniAb®, an Outstanding Antibody Discovery Platform
Although a few therapeutic antibodies on the market were identified using in vitro techniques, the vast majority of approved monoclonal antibodies were generated using mice. Immunization of rodents leverages complex immune processes, notably antibody affinity maturation and repertoire selection, that cannot be recreated completely in vitro. However, to avoid triggering a harmful immune reaction in human patients, non-human immunoglobulin (Ig) sequences must be eliminated from rodent antibodies. This can be accomplished through humanization of antibodies produced from endogenous rodent Ig genes. However, it is less time consuming and risky to simply immunize transgenic animals bearing human immunoglobulin sequences. As part of its mission to provide innovative technologies to enhance drug discovery, Ligand Pharmaceuticals offers an antibody platform called OmniAb. Since its introduction five years ago, the OmniAb platform has proven to be a highly successful antibody discovery engine, with over 300 successfully completed antibody discovery projects to date, including four IND submissions and testing in human patients.
The OmniAb platform encompasses three animal species, OmniRat®, OmniMouse®, and OmniChicken and a model for bispecific antibody generation, OmniFlic®. All produce diverse, high titer antigen-specific antibodies and offer several important advantages over competing humanized rodent platforms:
- Freedom to operate worldwide and all indications
- Complementary humanized rat and mouse models for broader epitope coverage and greater antibody diversity
- Development of bi-specific antibodies with a common light chain
- Potential outsourcing of animal care and antibody generation to Ligand-approved animal service providers and contract research organizations (CROs)
A Unique Patented Technology
Various transgenic mice expressing human antibodies have been developed using embryonic stem (ES) cell technology. The ES methods developed in mice proved unworkable in rat, initially limiting commercial antibody discovery to a few transgenic mouse models. The OmniAb platform is based on groundbreaking work in gene editing to overcome this problem. As reported in Science in 2009, a sequence-specific Zn-finger exonuclease was used to inactivate the endogenous Ig loci in rat embryos, enabling creation of OmniRat, the first rat model for human antibody discovery.1–4 For many target indications and antigens, murine models are encumbered by existing intellectual property (IP) and on-going litigation presents a considerable risk. In contrast, the OmniAb platform is protected by numerous patents and offers partners freedom to operate across all potential targets and indications worldwide. With the OmniAb platform, it is possible to generate diverse therapeutic human antibodies in both rat and mouse, without concern of infringement.
Similarly, the chicken platform is also well protected by numerous patents. In OmniChicken endogenous V genes are precisely replaced by human V’s, and these are diversified through the natural chicken mechanisms of gene conversion and somatic hypermutaton to generate a diverse and novel repertoire of antibodies with human idiotypes. The greater phylogenetic distance of chickens can be exploited for raising antibodies to targets that are highly conserved and thereby poorly immunogenic in mammals. Additionally, OmniChicken will routinely produce antibodies to are cross-reactive to the target antigen across different mammalian species, facilitating the use of common animal models of disease.
OmniAb Models Maximize Probability of Success
The OmniAb platform encompasses four different transgenic animal models for human antibody discovery:
- OmniRat 2.0, launched in 2017, harbors a complete set of human VH genes and both light chains for replicating a full range of human mono-specific antibodies
- OmniMouse, developed as a complement to the OmniRat, expands the universe of possible antibodies that can be elicited by a given antigen
- OmniChicken, generated by replacing the endogenous chicken immunoglobulin genes with corresponding human genes, provides more robust immune response against human proteins and access to novel epitopes
- OmniFlic, like OmniRat, bears a complete human VH locus, but has a fixed light chain type (kappa) to facilitate engineering and production of bi-specific antibodies
All four OmniAb animal models are patent protected and enable generation of fully human antibodies with high affinity, specificity, expression, solubility and stability. Because each individual animal mounts a different antibody response following immunization with a target antigen, the availability of all three species, rat, mouse, and chicken, OmniAb models is a key platform advantage that ensures drug discoverers more ‘shots on goal’ and the greatest probability of success.
The OmniAb platform has been extensively characterized and validated.1–4 Rodent antibody expression is inactivated and antibody generation includes all transgenic human VH and VK and VL genes. B-cell development, antibody production, and affinity maturation occur normally. Immunization produces a diverse antibody repertoire of human Ig’s, including high-titer, high-affinity (subnanomolar) antibodies with broad epitope coverage, and complementarity-determining regions (CDR) diversity and length similar to that seen in a human immune response.
The OmniChicken model, generated by Crystal Bioscience (acquired by Ligand in October 2017), has been available since 2016 and enables the isolation of antibodies against highly conserved proteins, with a documented ability to recognize novel epitopes, including multi-species cross-reactive epitopes.5–9
Partnering for Success
Ligand provides access to all OmniAb animal platforms under flexible licensing terms suitable for small biotech as well as large pharmaceutical companies. The focus of every deal is on maximizing the probability of program success. Options include unlimited or single-target licenses with annual access fee, clinical milestone payments and royalties or unlimited access without milestones or royalties. So far about 30 companies have licensed the OmniAb platform, including Genentech, Roche, Pfizer, Merck KGaA, Amgen, Celgene and Janssen. The latter recently filed an IND for an antibody discovered using the OmniAb technology, which represents the fourth OmniAb antibody entering clinical development.
Recognizing that smaller biotechs and start-ups may prefer to outsource animal care and antibody generation, Ligand has also partnered with Charles River Laboratories and Taconic and several CROs to ensure the widest possible access to the OmniAb platform, and ultimately to maximize advances in drug development. For the OmniChicken campaigns, Ligand typically conducts the initial antibody discovery process by leveraging its proprietary Gel-Encapsulated Microenvironment (GEM) technology that enables rapid recovery of single antigen-specific B cells from immunized OmniChickens.
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1. Geurts AM, Cost GJ, Freyvert Y, et al 2009. Science 325(5939):433
2. Menoret S, Iscache A-L, Tesson, L, et al 2010. Eur J Immunol 40:2932
3. Osborn MJ, Ma B, Avis S, et al 2013. J Immunol 190:1481
4. Bruggemann M, Osborn, MJ, Ma B, et al. 2015. Arch Immunol Ther Exp 63:101
5. Schusser B, Collarini EJ, Yi H, et al 2013. PNAS 110:20170
6. Schusser B, Yi H, Collarini EJ, et al 2013. PLOS ONE 8:e80108
7. Leighton PA, Pedersen D, Ching K, et al 2016. Transgenic Res 25:609
8. Mettler Izquierdo S, Varela S, Park M, et al 2016. Microscopy 65:341
9. Konitzer JD, Pramanick S, Pan Q, et al 2017. MABS 0-1