Rapid, site-specific labeling of “off-the-shelf” and native serum autoantibodies with T cell–redirecting domains

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Abstract

Extensive antibody engineering and cloning is typically required to generate new bispecific antibodies. Made-to-order genes, advanced expression systems, and high-efficiency cloning can simplify and accelerate this process, but it still can take months before a functional product is realized. We developed a simple method to site-specifically and covalently attach a T cell–redirecting domain to any off-the-shelf, human immunoglobulin G (IgG) or native IgG isolated from serum. No antibody engineering, cloning, or knowledge of the antibody sequence is required. Bispecific antibodies are generated in just hours. By labeling antibodies isolated from tumor-bearing mice, including two syngeneic models, we generated T cell–redirecting autoantibodies (TRAAbs) that act as an effective therapeutic. TRAAbs preferentially bind tumor tissue over healthy tissue, indicating a previously unexplored therapeutic window. The use of autoantibodies to direct the tumor targeting of bispecific antibodies represents a new paradigm in personalized medicine that eliminates the need to identify tumor biomarkers.

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Zappala, F., Higbee-Dempsey, E., Jang, B., Miller, J., Yan, L., Minutolo, N. G., … Ozdemir, B. A. (2022). Rapid, site-specific labeling of “off-the-shelf” and native serum autoantibodies with T cell–redirecting domains. Science Advances, 8(18). https://doi.org/10.1126/sciadv.abn4613

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