Antibodies from combinatorial libraries use functional receptor pleiotropism to regulate cell fates

Abstract

Abstract. To date, most antibodies from combinatorial libraries have been selected purely on the basis of binding. However, new methods now allow selection on the basis of function in animal cells. These selected agonist antibodies have given new insights into the important problem of signal transduction. Remarkably, when some antibodies bind to a given receptor they induce a cell fate that is different than that induced by the natural agonist to the same receptor. The fact that receptors can be functionally pleiotropic may yield new insights into the important problem of signal transduction.

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.…”

Agonist antibody that induces human malignant cells to kill one another

“…The recent discovery of many agonist antibodies that govern cell fates has opened the way to induce selectively a large variety of specific cells of the immune system from normal or malignant bone marrow (BM) or blood (7)(8)(9)(10)(11)(12)(13). Sometimes these agonist antibodies induce cell differentiation along lineages expected from the known function of the receptor to which they bind.…”

“…However, when some rare antibodies, which were found by autocrine selection from antibody libraries, bind to this same receptor, neural cells, instead of granulocytes, are formed efficiently (7). We call this phenomenon "receptor pleiotropism," and we have identified several examples (13). Receptor pleiotropism may relate to the plasticity of fate conversion of hematopoietic cells (14,15).…”