Agonist antibody that induces human malignant cells to kill one another

Abstract

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.

Combinatorial antibody libraries: new advances, new immunological insights

“…Also, the broadly neutralizing haemagglutinin-specific antibodies discussed above have indicated a way forward for the generation of a universal influenza virus vaccine. However, today one often wants more and many experimenters would like to directly select for functional antibodies such as those that activate signal transduction cascades or those that change cell fates [46][47][48][49][50][51][52][53][54] . So far, we have discussed the engineering of antibodies and below we discuss engineering with antibodies.…”

“…In the selection of antibodies that regulate cell fates the two most interesting selections are those based on activation of signal transduction systems or those based on cellular morphology [46][47][48][49][50][51][52][53][54] The phenomenon of receptor pleitropism. These intracellular libraries coupled to autocrine selections have yielded many antibody agonists that regulate cell fate by inducing differentiation and transdifferentiation [46][47][48][49][50][51][52][53][54] .…”

“…These intracellular libraries coupled to autocrine selections have yielded many antibody agonists that regulate cell fate by inducing differentiation and transdifferentiation [46][47][48][49][50][51][52][53][54] . The central idea is that cell differentiation and development are regulated, at least partly, by events at the cell surface.…”

“…Part c is adapted with permission from REF. 46, Copyright (2008) National Academy of Sciences, USA. granulocyte colony-stimulating factor (G-CSF) signals through the G-CSF receptor (GCSFR) on human CD34 + bone marrow stem cells to promote their differentiation into granulocytes.…”

Activating pleiotropic receptors to kill cancer cells

“…1 The overall process involves selection of an antibody that transforms AML cells into NK cells that then kill their erstwhile brothers or sisters in a fratricidal process (Fig. 1).…”