Abstract
Most of the approved monoclonal antibodies used in the clinic were initially discovered in mice. However, many targets of therapeutic interest are highly conserved proteins that do not elicit a robust immune response in mice. There is a need for non-mammalian antibody discovery platforms which would allow researchers to access epitopes that are not recognized in mammalian hosts. Recently, we introduced the OmniChicken®, a transgenic animal carrying human VH3-23 and VK3-15 at its immunoglobulin loci. Here, we describe a new version of the OmniChicken which carries VH3-23 and either VL1-44 or VL3-19 at its heavy and light chain loci, respectively. The Vλ-expressing birds showed normal B and T populations in the periphery. A panel of monoclonal antibodies demonstrated comparable epitope coverage of a model antigen compared to both wild-type and Vκ-expressing OmniChickens. Kinetic analysis identified binders in the picomolar range. The Vλ-expressing bird increases the antibody diversity available in the OmniChicken platform, further enabling discovery of therapeutic leads.
Highlights
Since the first monoclonal antibody therapies were approved over 30 years ago, the antibody therapeutics space has continued to expand to an increasing number of indications in oncology, autoimmunity and infectious disease [1]
We demonstrated that the OmniChicken could generate antibodies to brain-derived neurotrophic factor (BDNF), which is 97% conserved between humans and mice, and 91.5% conserved between humans and chickens
We investigated whether the improved levels of Vλ-containing IgY in OmniChickens as compared to Vκ could be explained at least in part by a possible improvement in protein stability in the chimeric human V/chicken CL or fully human light chain
Summary
Since the first monoclonal antibody (mAb) therapies were approved over 30 years ago, the antibody therapeutics space has continued to expand to an increasing number of indications in oncology, autoimmunity and infectious disease [1]. According to the most recent report by the Antibody Society, 864 unique antibody-based therapies, either in development or already approved, addressed 884 different clinical indications, demonstrating the vast landscape targeted by antibody technologies [2]. As the antibody therapeutics space expands, tools to develop and identify potential antibody candidates have grown increasingly sophisticated. From early efforts to engineer chimeric antibodies or introduce humanizing mutations, to transgenic animals carrying human V, D and J genes, the platforms and engineering tools available to generate therapeutic candidates with greater human content continue to evolve.
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