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

Yea, Kyungmoo; Zhang, Hongkai; Xie, Jia; Jones, Teresa M.; Yang, Guang; Song, Byeong Doo; Lerner, Richard A.

doi:10.1073/pnas.1313671110

Cited by 34 publications

(28 citation statements)

References 33 publications

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“…184 The ability to transduce mammalian cells with antibody libraries, providing a direct link between antibody genotype and cell phenotype, can facilitate direct phenotypic selections and screening. 173,175 …”

Section: Making It More Relevantmentioning

confidence: 99%

New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

Smith¹

2015

SLAS Discovery

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Antibody drugs have become an increasingly significant component of the therapeutic landscape. Their success has been driven by some of their unique properties, in particular their very high specificity and selectivity, in contrast to the offtarget liabilities of small molecules (SMs). Antibodies can bring additional functionality to the table with their ability to interact with the immune system, and this can be further manipulated with advances in antibody engineering. This review summarizes what antibody therapeutics have achieved to date and what opportunities and challenges lie ahead. The target landscape for large molecules (LMs) versus SMs and some of the challenges for antibody drug development are discussed. Effective penetration of membrane barriers and intracellular targeting is one challenge, particularly across the highly resistant blood-brain barrier. The expanding pipeline of antibody-drug conjugates offers the potential to combine SM and LM modalities in a variety of creative ways, and antibodies also offer exciting potential to build bi-and multispecific molecules. The ability to pursue more challenging targets can also be further exploited but highlights the need for earlier screening in functional cell-based assays. I discuss how this might be addressed given the practical constraints imposed by high-throughput screening sample type and process differences in antibody primary screening.

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Section: Making It More Relevantmentioning

confidence: 99%

New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

Smith¹

2015

SLAS Discovery

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“…Two recent advances in our laboratory have put us in position to test these ideas. The first is the advent of large intracellular combinatorial libraries in which as many as 1.0 Â 10 8 different antibodies or peptides encoded by lentivirus are expressed in cells that also express the receptor of interest [3][4][5][6][7][8]. Since each cell has both the receptor and a different potential agonist, each cell becomes a reaction compartment unto itself.…”

Section: Introductionmentioning

confidence: 99%

“…To achieve this, we employed an enzyme-substrate system that is similar to one used in the Arrestin-GPCR reporter system [9]. However, we constructed it in a way that would be generalizable to any molecular interaction in the plasma membrane [5][6][7][8][9]. In our system the ligand and receptor are anchored and co-localized in the plasma membrane, and because of this we could engineer them so that each carries only one component of the enzyme-substrate reporter system.…”

Section: Introductionmentioning

confidence: 99%

A proximity based general method for identification of ligand and receptor interactions in living cells

Zhang

Xie

Lerner

2014

Biochemical and Biophysical Research Communications

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“…To study this, we took a combinatorial approach to the problem similar to that used for antibody libraries (5,6). We prepared a library in lentiviruses of the genes encoding 209 cytokines.…”

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confidence: 99%

Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation

Zha

Bucher

Nejatfard

et al. 2017

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

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Cytokines are protein mediators that are known to be involved in many biological processes, including cell growth, survival, inflammation, and development. To study their regulation, we generated a library of 209 different cytokines. This was used in a combinatorial format to study the effects of cytokines on each other, with particular reference to the control of differentiation. This study showed that IFN-γ is a master checkpoint regulator for many cytokines. It operates via an autocrine mechanism to elevate STAT1 and induce internalization of gp130, a common component of many heterodimeric cytokine receptors. This targeting of a receptor subunit that is common to all members of an otherwise diverse family solves the problem of how a master regulator can control so many diverse receptors. When one adds an autocrine mechanism, fine control at the level of individual cells is achieved.A s our understanding of physiology grows, we are increasingly aware of its Newtonian aspects in that for every action there is another reaction with opposite consequences (1). Irrespective of whether one thinks in terms of homeostasis, feedback loops, or checkpoints, we increasingly uncover molecular systems that, in terms of function, induce cells to move in opposite ways. For example, although immune T-cell activation is critical in controlling disease, one needs a checkpoint to guard against overactivity that could result in autoimmunity (2, 3).In addition to adding to our general knowledge of cellular physiology, detailed understanding of the molecular mechanisms of activation and checkpoint processes has important therapeutic implications. Such an understanding allows two separate entry points into the regulation of cellular events. Thus, if one wants to promote a cellular function, the same outcome can be achieved by either enhancing the effector or inhibiting the checkpoint pathways, usually by perturbing the molecules that initiate them.One of the most important physiological systems is the cytokine cascade (4). However, here, because the cascade contains large numbers of separate molecules, each operating through different receptors, simple models of regulation break down. While one can imagine that each cytokine is paired with a separate checkpoint system operating in an opposite direction, it seemed to us to be unlikely, if for no other reason than the economical use of genetic information. Given that one had large sets of related molecules with overlapping signal transduction mechanisms and pathways, it seemed more reasonable to assume that, depending on the circumstance, some members of the cytokine repertoire regulate other members of the repertoire. This differs from situations such as PD-1, where the checkpoint mechanistic cascade differs completely from the activation mechanism. By contrast, we propose that cytokine members of a family regulate each other by perturbing common molecular mechanisms. Thus, if gene action economy is proposed for a family, its hallmark should be that some of the same molecules used for...

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

Cited by 34 publications

References 33 publications

New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

A proximity based general method for identification of ligand and receptor interactions in living cells

Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation

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