Agonist antibody that induces human malignant cells to kill one another.
An attractive, but as yet generally unrealized, approach to cancer therapy concerns discovering agents that change the state of differentiation of the cancer cells. Recently, we discovered a phenomenon that we call "receptor pleiotropism" in which agonist antibodies against known receptors induce cell fates that are very different from those induced by the natural agonist to the same receptor. Here, we show that one can take advantage of this phenomenon to convert acute myeloblastic leukemic cells into natural killer cells. Upon induction with the antibody, these leukemic cells enter into a differentiation cascade in which as many as 80% of the starting leukemic cells can be differentiated. The antibody-induced killer cells make large amounts of perforin, IFN-γ, and granzyme B and attack and kill other members of the leukemic cell population. Importantly, induction of killer cells is confined to transformed cells, in that normal bone marrow cells are not induced to form killer cells. Thus, it seems possible to use agonist antibodies to change the differentiation state of cancer cells into those that attack and kill other members of the malignant clone from which they originate.
Shanghai Institute for Advanced Immunological Studies, ShanghaiTech University, Shanghai 200031, China;
Kyungmoo
K
Yea
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Hongkai
H
Zhang
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Jia
J
Xie
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Teresa M
TM
Jones
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Chih-Wei
CW
Lin
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037;
Walter
W
Francesconi
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
Fulvia
F
Berton
BioInformatics Core, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458;
Mohammad
M
Fallahi
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
Karsten
K
Sauer
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; rlerner@scripps.edu.
Richard A
RA
Lerner
D000906:Antibodies / Q000276:immunology* / Q000627:therapeutic use; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods* / Q000639:trends; D019295:Computational Biology; D005434:Flow Cytometry; D053804:Granzymes; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D008855:Microscopy, Electron, Scanning; D054353:Perforin / Q000378:metabolism
D000906:Antibodies; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes
agonist antibody; combinatorial antibody libraries; differentiation; natural killer cell