期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 434, 期 5, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167402
关键词
antibody engineering; tumor marker; multivalency; apoptosis; cytotoxic antibody
资金
- NIH [R21 CA246457, R01 CA245502, R01 CA194864, R01 CA212608, R21 AI158997]
- Leukemia & Lymphoma Society
- Hyundai Hope Scholar Grant
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that requires intensive chemotherapy. CD99, which is overexpressed on T-ALL cells, has been identified as a promising therapeutic target. Research has successfully developed human antibodies that selectively target and kill T-ALL cells.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that currently requires intensive chemotherapy. While childhood T-ALL is associated with high cure rates, adult T-ALL is not, and both are associated with significant short-and long-term morbidities. Thus, less toxic and effective strategies to treat T-ALL are needed. CD99 is overexpressed on T-ALL blasts at diagnosis and at relapse. Although targeting CD99 with cytotoxic antibodies has been proposed, the molecular features required for their activity are undefined. We identified human antibodies that selectively bound to the extracellular domain of human CD99, and the most potent clone, 10A1, shared an epitope with a previously described cytotoxic IgM antibody. We engineered clone 10A1 in bivalent, trivalent, tetravalent, and dodecavalent for-mats. Increasing the antibody valency beyond two had no effects on binding to T-ALL cells. In contrast, a valency of > 3 was required for cytotoxicity, suggesting a mechanism of action in which an antibody clusters > 3 CD99 molecules to induce cytotoxicity. We developed a human IgG-based tetravalent version of 10A1 that exhibited cytotoxic activity to T-ALL cells but not to healthy peripheral blood cells. The crystal structure of the 10A1 Fab in complex with a CD99 fragment revealed that the antibody primarily recognizes a proline-rich motif (PRM) of CD99 in a manner reminiscent of SH3-PRM interactions. This work further validates CD99 as a promising therapeutic target in T-ALL and defines a pathway toward the development of a selective therapy against T-ALL. (C) 2021 The Author(s). Published by Elsevier Ltd.
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