Strategies for Generating Diverse Antibody Repertoires Using Transgenic Animals Expressing Human Antibodies

Abstract

Therapeutic molecules derived from antibodies have become a dominant class of drugs used to treat human disease. Increasingly, therapeutic antibodies are discovered using transgenic animal systems that have been engineered to express human antibodies. While the engineering details differ, these platforms share the ability to raise an immune response that is comprised of antibodies with fully human idiotypes. Although the predominant transgenic host species has been mouse, the genomes of rats, rabbits, chickens, and cows have also been modified to express human antibodies. The creation of transgenic animal platforms expressing human antibody repertoires has revolutionized therapeutic antibody drug discovery. The observation that the immune systems of these animals are able to recognize and respond to a wide range of therapeutically relevant human targets has led to a surge in antibody-derived drugs in current development. While the clinical success of fully human monoclonal antibodies derived from transgenic animals is well established, recent trends have seen increasingly stringent functional design goals and a shift in difficulty as the industry attempts to tackle the next generation of disease-associated targets. These challenges have been met with a number of novel approaches focused on the generation of large, high-quality, and diverse antibody repertoires. In this perspective, we describe some of the strategies and considerations we use for manipulating the immune systems of transgenic animal platforms (such as XenoMouse®) with a focus on maximizing the diversity of the primary response and steering the ensuing antibody repertoire toward a desired outcome.

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

“…A cocktail of two antibodies, REGN10933 and REGN10987, is currently in clinical trials for treating hospitalized ( NCT04426695 ) or ambulatory ( NCT04425629 ) adult patients. Other humanized mouse technologies for isolation of monoclonal exist, and a review of different monoclonal antibodies isolated with these platforms can be found elsewhere [ 121 ].…”

Innovative Immunization Strategies for Antivenom Development

“…However, despite the numerous accounts of the successful use of novel immunization strategies reported by different antivenom research laboratories, very few of these strategies have found their way to the industrial setting. In the future, the possibility also exists that a combination of innovative immunization strategies with transgenic animals expressing the human antibody repertoire [ 228 , 229 , 230 , 231 ] could be employed in antivenom manufacture. This may not improve efficacy or affordability, however, it may indeed provide safer antivenoms, as the therapeutic antibodies would be of human, rather than animal origin.…”

Hybridoma technology a versatile method for isolation of monoclonal antibodies, its applicability across species, limitations, advancement and future perspectives

“…Humanization of these antibodies can have great potential for biopharmaceutical development [86,87]. The recent development of transgenic chicken with human immunoglobulin loci has expedited the use of transgenic chicken derived mAbs directly for human therapeutic use [88,89]. These engineered transgenic chickens express antibodies from immunoglobulin heavy and light chain loci containing human variable regions and exhibit normal B cell development raising immune responses to conserved human targets that are non-immunogenic in mice [90].…”