Selecting Agonists from Single Cells Infected with Combinatorial Antibody Libraries

Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana I.; Wilson, Ian A.; Lerner, Richard A.

doi:10.1016/j.chembiol.2013.04.012

Cited by 47 publications

(55 citation statements)

References 11 publications

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“…There is much evidence that the TPOR is the identified target of the antibody as opposed to some offtarget interaction. First, there is no induction of signaling pathways in the indicator cells when TPOR is knocked out (12).…”

Section: Discussionmentioning

confidence: 99%

“…The antibody that induces killer cells was developed originally as a TPOR agonist (12). To confirm again the activity of the antibody in TPOR stimulation, the antibody or TPO was incubated with normal BM CD34 + cells.…”

Section: Nk Cell Induction Is Context Dependentmentioning

confidence: 99%

“…Here, we report on a rare antibody against the thrombopoietin receptor (TPOR), again obtained by autocrine-based selection, that efficiently transforms malignant acute myeloblastic leukemia (AML) cells into highly activated NK cells. This highly specific antibody has an EC 50 of 5 pM (that of TPO is 70 pM) and shows no activity in cells in which the TPOR is knocked out (12). The induced AML cells have extensive filopodia at their surface and express the CD11c dendritic cell marker.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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Agonist antibody that induces human malignant cells to kill one another

Yea

Zhang

Xie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Nk Cell Induction Is Context Dependentmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Agonist antibody that induces human malignant cells to kill one another

Yea

Zhang

Xie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…As such, the method should be limited only by the creativity one can bring to the screening process. To date, we have isolated antibodies that are agonists for cytokine receptors as well as those that induce transdifferentiation of stem cells (2,3).…”

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confidence: 99%

Converting stem cells to dendritic cells by agonist antibodies from unbiased morphogenic selections

Yea

Zhang

Xie

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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When combinatorial antibody libraries are rendered infectious for eukaryotic cells, the integrated antibody genotype and cellular phenotype become permanently linked and each cell becomes a selection system unto itself. These systems should be ideal for the identification of proteins and pathways that regulate differentiation so long as selection systems can be devised. Here we use a selection system based on the ability of secreted antibodies to alter the morphology of colonies expressing them when grown in soft agar. Importantly, this approach is different from all previous studies in that it used a pure discovery format where unbiased libraries that were not preselected against any known protein were used as probes. As such, the strategy is analogous to classical forward genetic approaches except that it operates directly at the protein level. This approach led to the identification of integrinbinding agonist antibodies that efficiently converted human stem cells to dendritic cells. intracellular combinatorial antibodies | phenotypic selections

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Selection of a Full Agonist Combinatorial Antibody that Rescues Leptin Deficiency In Vivo

et al. 2020

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Growth factor deficiency in adulthood constitutes a distinct clinical syndrome with significant morbidities including abnormal body composition, reduced energy, affective disturbances, dyslipidemia, and increased cardiovascular risk. Protein replacement therapies using recombinant proteins or enzymes represent the only approved treatment. Combinatorial antibodies have shown great promise as a new class of therapeutic molecules because they act as “mechanism‐based antibodies” with both agonist and antagonist activities. Using leptin, a key hormone in energy metabolism, as an example, a function‐guided approach is developed to select combinatorial antibodies with high potency and full agonist activity that substitute natural growth factors in vivo. The identified antibody shows identical biochemical properties and cellular profiles as leptin, and rescues leptin‐deficiency in ob/ob mice. Remarkably, the antibody activates leptin receptors that are otherwise nonfunctional because of mutations (L372A and A409E). Combinatorial antibodies have significant advantages over recombinant proteins for chronical usage in terms of immunological tolerance and biological stability.

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Selecting Agonists from Single Cells Infected with Combinatorial Antibody Libraries

Cited by 47 publications

References 11 publications

Agonist antibody that induces human malignant cells to kill one another

Agonist antibody that induces human malignant cells to kill one another

Converting stem cells to dendritic cells by agonist antibodies from unbiased morphogenic selections

Selection of a Full Agonist Combinatorial Antibody that Rescues Leptin Deficiency In Vivo

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