A collaborative scientific team led by researchers at the Applied Biomedical Science Institute (ABS), Scripps Research, Kansas State University (K-State), University of Louisville, OmniAb, Inc., and Ligand Pharmaceuticals has discovered and validated a potential new class of therapeutic agent based on the unique antigen binding regions of cow antibodies. In their paper published in the Proceedings of the National Academy of Sciences, "The smallest functional antibody fragment: ultralong CDR H3 antibody knob regions potently neutralize SARS-CoV-2", the team of researchers discovered cow antibodies with broad reactivity and high potency against several SARS-CoV-2 virus variants. They then developed the technology to produce only the coronavirus binding portion of the antibody, termed a 'knob' region, which is a tiny fragment of the large parent antibody.

"At about 3% the size of the original antibody, cow knob regions represent the smallest known functional antibody fragment. They approach the size of some small molecule drugs and are three times smaller than camel antibody-derived 'nanobodies'. Knobs potentially have many biomedical uses, including as therapeutics and diagnostics," said Dr. Vaughn Smider, the senior author of the study and President of ABS.

Potential advantages of such small antibody fragments include improved tissue penetration, clearance, and stability. While the current study reveals the utility of knobs in targeting coronavirus, their potential as a therapeutic class spans many therapeutic areas, including oncology and immunology. Future research applications of knobs include using them as targeting regions for nanoparticles, antibody drug conjugates or multispecific therapeutics.

The antibodies and derivative knob regions were induced in cows by Dr. Waithaka Mwangi's laboratory at K-State, and discovered and evaluated at ABS by first author Ruiqi Huang and a team of scientists at ABS, then characterized for anti-viral properties by the laboratories of Drs. Kyeong-Ok Chang (K-State), Donghoon Chung (Louisville), John Teijaro (Scripps Research), and Dennis Burton (Scripps Research), and detailed structural characterization was accomplished at Scripps Research in the laboratories of Drs. Ian Wilson, Robyn Stanfield, Andrew Ward, Jane Dyson and Peter Wright.

Industry collaborators led by Dr. William Harriman at OmniAb, Inc., and Dr. Jeff Allen at Pelican, a subsidiary of Ligand Pharmaceuticals collaborated in the analytical characterization and the manufacturing of the knobs. Minotaur Therapeutics (an ABS spin-out company) is developing commercial technologies related to knob region (picobody) discovery and development under a sublicense from OmniAb, Inc.