Open Assay Calls

PDi calls for proposals

This is an open call for phenotypic assay proposals funded by the Phenomics Discovery Initiative (PDi). PDi is a public-private partnership between industrial pharmaceutical companies and NPSC. PDi seeks to identify, develop, screen and validate innovative phenotypic assays that are relevant to human disease.

Selected proposals are screened free of charge.
Calls are currently open and accepting assay proposals.
The deadline for the next round of selections is 31st October 2018.
This deadline has now been extended to 11th November 2018.

Find out more about PDi. *We use the EU commission definition of SME that can be found here.


How to apply?

Phenotypic assays are recruited from academic, clinical and SME communities thorugh an online applications portal.

Assays can be at various stages of development: from an early concept to a screening format (96-well / 384-well). Assays are assessed and selected by the PDi scientific committee, which is made up of a panel of industry and academic experts. Important characteristics for selection are scientific quality, novelty, relevance to human health, feasibility for medium to high-throughput and high-content screening, and value in drug discovery or chemical biology.

  • Selected assays are screened free of charge.
  • All assay results are delivered to the applicant.

PDi covers the following costs

  • Assay development from concept to high throughput format.
  • Reagents including generation of cell lines and cell/tissue culture.
  • Access to a high quality industry standard compound collection (including annotated reference compounds and approved drugs targeting known pathways), world class high content screening facilities and state of the art chemoinformatics and bioinformatics.

Cell assays/disease models currently being considered (call details in adjacent tabs)

  • Solid tumour model showing immune exclusion - Immune Exclusion
  • Expanding the Immuno-Oncology Toolbox with Next-generation Small Molecule Therapeutics - Immuno-oncology
  • Tissue Regeneration and Repair Assays - Tissue Regeneration & Repair
  • Neurodegeneration
  • Regulatory T cell (Treg) assays - T reg assays
  • Cellular stress assaysCell stress
  • Human bronchoepithelial cell air-liquid assaysHuman Broncoepithelial cells
  • Innovative phenotypic assays - Blue Sky

If your assay is screened, you can exploit the data generated and the developed assay as you wish

  • You can patent or commercialise the data and/or license it to other parties.
  • You can seek consent from the PDi scientific committee to publish the data immediately, which takes up to 30 days to be granted. The scientific committee can impose a maximum of 90 day delay in publication, should they decide that IP from the project requires protecting.
  • You can use the developed assay on your own compound sets (private screens).
  • If your assay is validated you automatically grant the PDi industry members a licence to use this assay.
  • If the validated assay results are used by PDi industry members in private screens, and you agree to delay publication by 18 months – you will receive a one-off milestone payment of £75,000 from each of the companies using the assay.
  • You can develop collaborations with PDi industry members.
  • Above is a summary of your rights and obligations: Full T&Cs for the consortium can be found here.

How to put your assay proposal forward for consideration?

You qualify to put an assay forward if you are a member of staff in a university, research institution, hospital or SME.

If you think you have a phenotypic assay that meets PDi requirements, please go to the NPSC online application portal and apply to the call category you are interested in. The site requires registration.

  • The application form is very short and straightforward.
  • We are looking for non-confidential information only at this stage.

If we are interested in accessing more details, we will contact you directly.

Oncology - Solid tumour model showing immune exclusion

High-level brief for the call

Clinical studies on solid tumours have defined three main phenotypes: immune-desert tumour, immune-excluded tumour, and inflamed tumour.
Immune-excluded tumours display the following high-level characteristics:
  • The presence of abundant immune cells that are retained in the tumour stroma: CD4- and CD8-expressing T cells, myeloid cells, and monocytic cells
  • Treatment of the immune excluded tumour with anti-PD-L1/PD-1 agents can activate stroma-associated T cells and cause them to proliferate - but no tumour infiltration is observed or these cells.
  • T-cell migration through the tumour stroma is thought to be the bottle-neck for an effective anti-tumour response.

Assay description, desired readouts, and end points

In this call we are looking for solid-tumour cancer models that demonstrate an immune-exclusion phenotype that are suitable for small molecule high content screening. The assay should demonstrate as many of the following characteristics as possible:
  • The model should demonstrate immune exclusion, so the choice of tumour cells to be used in the assay is critical. The following options can be considered:
  • Human solid cancer cell models: Human cancer cell lines could be selected based on immune exclusion phenotype from the literature or, more likely, experimentally. We could consider testing conditioned culture medium from various cell lines in a migration assay to identify candidates.
  • Mouse solid cancer cell models: Mouse cancer cell lines would be selected from the more limited set of syngeneic models. Although not the clinical species, the advantage of the syngeneic mouse cell lines is that hits identified in the screen could be more readily validated in immune competent mice.
  • The model should be able to demonstrate a reversal of the immune-excluded phenotype, and could include the following end points:
  • The ability to locate and track immune cells in the tumour micro-environment
  • The ability to measure activity and proliferation of immune cells in the tumour micro-environment
  • The ability to measure functional changes tumour cell growth and viability
  • Assays should be capable of measuring relevant immune effector cell migration or a robust marker for migration. An obvious choice for measuring cell migration is by using a trans-well migration system, but seeing as this is not easy to carry out in high throughput screens, we are particularly interested in alternative cell migration formats.
  • Although WNT signalling in tumour cells was shown to be associated with immune exclusion, evidence for other mechanisms are of interest. We would like to expand the focus of the screen to include WNT unrelated mechanisms for immune exclusion. The screen would therefore not rely on detection of WNT signalling inhibition, but on reversal of the immune exclusion phenotype.
  • We would like the model to represent the patient tumour micro-environment as closely as possible. Inclusion of cancer associated fibroblasts, or other important tumour associated cells is also of interest.

Current knowledge, background, existing comparable assays

Chen, D.S., and Mellman, I. (2017). Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330.

Yaguchi et al. (2012) Immune Suppression and Resistance Mediated by Constitutive Activation of Wnt/ β-Catenin Signaling in Human Melanoma Cells J Immunol; 189:2110-2117

Zhao et al. (2018) Paracrine Wnt5a-b-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization. Immunity 48, 147–160

Sprenger et al. (2015) Melanoma-intrinsic b-catenin signalling prevents anti-tumour immunity. Nature, 523, 231-238.

Immuno-Oncology - Expanding the Immuno-Oncology Toolbox with Next-generation Small Molecule Therapeutics

High-level brief

Since 2011 immuno-oncology (IO) has become the fastest-growing area in oncology, generating unprecedented interest from patients, clinicians and almost the entire pharmaceutical industry due to its potential for significant and sustained clinical benefits.
Historically, advances in oncology drug development have been largely incremental, however immune-oncology advances such as the first two generations of immune checkpoint inhibitors have clearly delivered substantial benefit over the previous standards of care. Despite this success, the field is still young and there are many unknowns and many opportunities for translational and clinical improvements, supported by the increased investment in the field. Some patients may achieve long-term disease control with current IO treatments, but the reality is that in most cancer types, over 80% of patients do not respond to checkpoint inhibition and even if they do, further relapse often occurs.
There is a widely recognised opportunity to improve on this by identifying new “third generation” IO therapeutics by mobilising and manipulating the adaptive and innate immune systems, separately or in combination. This large pool of potential new technologies further diversifies the immuno-oncology space to fully utilize the potential of the immune system across multiple mechanisms and modalities against cancer.

Assay description, desired readouts, and end points

In this call we are looking for novel phenotypic cellular assays that can deliver game-changing strategies to discover new therapeutics in this field. Assay ideas could include, but are not limited to:

  • Phenotypic assays that accurately model the complexity of the tumour microenvironment. These should allow screening to be carried out in more relevant immune contexts, and be more representative of the pathophysiology of the disease.
  • Novel assays for intracellular (or even extracellular) immune-regulatory mechanisms that cannot be targeted by current monoclonal antibody-based approaches. These assays should help broaden the potential mechanisms that can be targeted by new therapies.
  • Assays that allow the discovery of small molecules that synergise with known therapeutics (biologics or CAR-T) to extend their scope and efficacy.
  • Models for immunologically “warming” up “cold” tumours, including ones involving infiltration of 3D tumour spheroids by T cells. It is expected that these models will be complex in order to accurately represent the disease model.
  • Models that can explore novel ways of activating exhausted intra-tumoral T cells.
  • Models involving the manipulation of immunosuppressive Treg cells and/or key cytokines.
  • Assays that involve other immunosuppressive cell types (for example, MDSCs, dendritic cells and TAMs).
  • Models that could uncover new targets in innate immune system cell types (eg. NK cells, dendritic cells and macrophages).

Current knowledge and background

Adams JL et. al. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. Sep;14(9):603-22.

Allard B et. al. (2018) Immuno-oncology-101: overview of major concepts and translational perspectives.
Semin Cancer Biol. 2018 Feb 8.

Cavnar, S. et. al. (2017). The immuno-oncology race: myths and emerging realities. Nature Reviews Drug Discovery, 16, 83. Retrieved from

Hoos, A. (2016). Development of immuno-oncology drugs — from CTLA4 to PD1 to the next generations. Nature Reviews Drug Discovery, 15, 235.

Sheng J et. Al. (2017) Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors. J Clin Pharmacol. Oct;57 Suppl 10:S26-S42

Tissue Regeneration and Repair Assays


We are seeking proposals for novel induced pluripotent stem cell (iPSC) derived models of tissue regeneration or tissue repair applicable to multiple disease areas.

The assays should be translationally relevant with direct line of sight to a specific human disease.
The assays should be able to identify phenotypic changes associated with tissue regeneration and repair responses in a therapeutic target agnostic manner by leveraging high content image-based techniques or genetically encoded reporters of key pathway endpoints e.g. to track and characterize, morphological, subcellular, metabolic and pathway endpoints in an automated manner suitable for medium- to high-throughput screening.

In partnership with the assay proposer the National Phenotypic Screening Centre will support the adaptation of tissue regeneration and repair models into robust 96-well or 384-well phenotypic screening formats and subsequent screening across high quality compound libraries.

Neurodegeneration

The NPSC/PDi is seeking proposals for novel induced pluripotent stem cell (iPSC) or primary cell derived models of neurodegeneration across multiple neurodegeneration pathologies.

The assays should be translationally relevant with direct line of sight to a specific human disease.

The assays should be able to identify specific disease associated phenotypes suspected of being strongly linked to disease modifying outcomes in a therapeutic target agnostic manner by leveraging high throughput assays including high content image-based techniques or genetically encoded reporters of key pathway endpoints e.g. to track and characterize, morphological, subcellular, metabolic and pathway endpoints in an automated manner suitable for medium- to high-throughput screening.

In partnership with the assay proposer, the National Phenotypic Screening Centre will support the adaptation of phenotypic assay into robust 96-well or 384-well phenotypic screening formats and subsequent screening across high quality compound libraries.

Regulatory T cell (Treg) assays

Assay description, desired readouts, and end points

High-level brief for the call: The main objectives are to identify a potential surrogate human Treg population, and unique identifying markers/signatures that could serve as readouts for Treg cell differentiation and suppressive capacity.

We are seeking a system capable of testing the effect of small molecules on Treg cell expansion, differentiation and/or function, in particular, but not limited to, measuring Treg suppressive capacity. The assay(s) should allow the detailed analysis of the interaction between Treg and effector/conventional T cells (Tconv) on platform(s) that include high-content imaging and/or transcriptomics/proteomics. One of the main challenges of this task is the limited number of Treg cells that can be isolated from human peripheral blood. This implies that a more scalable approach is desired, while human primary cell-based assay systems are of significant interest, the use of surrogate cell populations such as induced pluripotent stem cells (iPS cells) that can be differentiated into Treg cells for higher throughput screening provide additional advantages. We are also looking for new Treg-specific markers/signatures (signalling and/or transcriptional) to identify bona fide human Tregs. Finally, detailed assessment of small molecule effectors specifically targeting Treg suppressive capacity requires co-culturing Treg cells with Tconv cells. This means that the assays should be able to distinguish the effect of small molecule compounds on Treg versus Tconv cells.

Current knowledge, background, existing comparable assays
Naturally occurring Treg cells (nTreg) are thymic-derived cells that represent a small population (5-7%) of total CD4+ T cells in human peripheral blood, and express CD25 as well as the transcription factor Foxp3 (forkhead box P3), which is critical for their development and function. They possess potent regulatory activity to suppress excessive activation, proliferation and effector functions. They act on a wide range of immune cells in-vitro and in-vivo, including CD4+ and CD8+ T cells, natural killer (NK), Natural Killer T (NKT) cells, B cells, and antigen-presenting cells. Treg cells are indispensable for the maintenance of tolerance and immune homeostasis. Their dysfunction or absence causes fatal autoimmune disease, immunopathology, and allergy (Sakaguchi 2010, Nat. Imm. Rev.).

The markers typically used to identify Treg cells are CD4, CD25, CD45RA, CD127, Foxp3 and the proliferation marker, Ki67. Phenotypically, these cells are CD4+/CD25hi/CD45RA-/CD127lo/Foxp3hi/Ki67-. However, many of these markers are also expressed by Tconv upon activation. Treg and Tconv also produce different cytokines (eg IL-10 vs IL-2 or IFN-g, respectively), which can be measured by intracellular staining or in supernatants after stimulation. Due to the low numbers or frequencies of nTreg in human peripheral blood, in-vitro assays have been developed to generate larger numbers of “induced” Treg (iTreg) cells from naïve CD4+ T cells. This is achieved by culturing CD4+CD25- T cells for several days with TGF-b +/- IL-2. While the majority of cells cultured under these conditions will upregulate Foxp3, it is unclear whether they have a specific phenotype compared to nTreg.

Currently, the functional study of human Treg-mediated suppression is limited to in-vitro co-culture assays. It should be emphasized that there is no direct evidence that in-vitro suppression assays with nTreg or iTreg directly reflect in-vivo suppressive capacities of Treg. cells. That being said, Treg suppressive capacity can be assessed by culturing Treg with Tconv cells and measuring proliferation (thymidine incorporation or by flow cytometry using CFSE dilution) of, and/or cytokine production (e.g. IL-2 production) by, Tconv cells. Our aims are to exploit and adapt such systems to more automated and higher throughput screening formats.

Cellular stress assays

Assay description, desired readouts and end points

High level brief for the call: We are seeking novel cell-based screening methodologies able to distinguish cells undergoing Endoplasmic Reticulum (ER) stress from normal cells, and able to identify compounds that rectify ER stress responses and restore normal cell function. Ideally, these platforms will be developed using primary human cells or cell lines from tissues of interest, such as neuronal, pancreatic, Gastro Intestinal (GI), to maximize translational value, and allow the comparison of patient-derived healthy versus diseased cells.

The assays should be able to identify phenotypic changes associated with increased ER stress responses in an agnostic manner by leveraging high content imaging-based techniques or genetically encoded reporters of multiple pathways to track and characterize, morphological, subcellular, metabolic and pathway adaptations which generate phenotypic profiles suitable for medium- to high-throughput screening.

Potential developments of interest

1. Novel unbiased readouts for cells undergoing stress
  1. Development of biosensors for monitoring misfolded proteins in a cell, by using specific tracer proteins or chaperones; alternatively, developing a method to monitor any improperly folded protein in a cell. The goal would be to screen small molecules for increased clearance of misfolded proteins/aggregates and this could potentially apply to different cellular compartments (i.e. ER, mitochondria, cytosol)
  2. Measurement of the temporal movement and recycling (flux) of mitochondria and ER through autophagosomes, fusion/fission events, subcellular localization (i.e. contact or stress-induced collapse around the nucleus), as the basis of a screen for cell protective molecules. Is the physical location or orientation of the mitochondria/ER altered in response to stress?
  3. High throughput method to monitor ER associated degradation (ERAD) to use as a basis for a screening platform.
  4. ER and mitochondrial calcium perturbations in response to stress. Excess accumulation of mitochondrial calcium is pro-apoptotic and increasing mitochondrial buffering capacity may be protective.
  5. Metabolic changes induced by cellular stress (i.e. metabolic switching and reliance on oxidative phosphorylation versus glycolysis).
  6. Mitochondrial biogenesis readouts.

2. Cell survival assays: Normal screening for cell heath in response to stress is done in short term assays (i.e. 1-2 days). However, monitoring the effects of chronic stress on cellular survival long term would be of great benefit. This would recapitulate sustained physiologic low-level stress. Ideally this could be done across cell lines representative of target organs/tissues of interest and would be adaptable to high throughput screening methodologies.

3. Survey, identify and categorize misfolded proteins associated with a number of disease states to create a fingerprint that may provide the basis of novel screening approaches.

4. Epigenetics: Epigenetic modifications contribute to multiple disease states, though this is not well understood as an adaptation mechanism for cells in response to stress. Readouts for epigenetic modifications in response to stress, and tracking these changes in living cells.

Current knowledge, background, existing comparable assays

Chronic ER stress in response to the accumulation of misfolded proteins and defects in ER-associated protein degradation has been implicated in the pathophysiology of a variety of human disorders, including neurodegeneration, heart disease, inflammatory bowel disease, and immune dysregulation. Cellular stressors may include chemical inducers of ER and mitochondrial stress, genetic interference of protein folding or processing mechanisms, and mutations or physiological conditions associated with disease.

Human bronchoepithelial cell air-liquid assays

Assay description, desired readouts and end points

High-level brief for the call: We are seeking human bronchoepithelial cell (HBEC) air-liquid interface models in 96-well format, which have the potential to be analyzed on a fully automated high-content imaging platform (e.g. Yokogawa, ImageXpress or IN Cell analyzer platforms). These assays will be used to study the interactions of respiratory viruses with HBECs and to test the effect of small molecules on these interactions and associated alterations in inflammatory response.

Protocols of interest could include:

  • novel cell staining methods (nuclei + cell membrane or cell membrane + cell phenotype markers)
  • novel imaging protocols that allow the high-content imaging of these cells with platforms like Yokogawa, ImageXpress or IN Cell analyzer
  • novel methods for culturing these cells

Current knowledge, background, existing comparable assays

Respiratory viruses (Influenza, Respiratory Syncytial Virus (RSV), Rhinovirus…) are a major cause of upper and lower respiratory tract infections, leading to significant morbidity and mortality in humans. For example, viral infections are notorious triggers of symptomatic exacerbations in patients suffering from COPD and asthma.

The human lung epithelium, joining forces with the innate and adaptive immune system, sets up the primary defensive wall against these viral pathogens. However, respiratory viruses have developed strategies to evade the human defense response often leading to severe disease in the infected host. Damage of lung tissue (loss of epithelial cells) ensues from the viral infection itself and the immune response mounted by the host. Epithelial injury and mucus production by epithelial cells impair mucociliary clearance, pave the way for bacterial superinfection and impair gas exchange in the airways, leading to respiratory compromise. Additionally, infected epithelial cells release pro-inflammatory mediators (IL-6, IL-8...) and a damage-associated molecular pattern (DAMP) that can be modulated by the infecting virus. This mechanism contributes further to symptomatic deterioration or eventually respiratory failure. Therefore, there exists a high unmet medical need for novel therapeutics to prevent and treat respiratory viral infections.

The 3-dimensional HBEC air-liquid interface model is a physiologically relevant and established model system to study the effects of respiratory viral infection and is used to test the antiviral activity of RSV inhibitors (1). This model system comprises a multilayered, pseudo-stratified lung epithelial tissue that includes the presence of ciliated epithelial cells, mucus-producing goblet cells, and basal cells; cell types that constitute the bronchoepithelial tissue in humans.

Reference:

  1. Villenave, R., Thavagnanam, S., Sarlang, S., Parker, J., Douglas, I., Skibinski, G., Heaney, L.G., McKaigue, J.P., Coyle, P.V., Shields, M.D. & Power, U.F. (2012). In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo. Proc. Natl. Acad. Sci. U S A. Vol. 109(13): 5040-5045.

Blue Sky - High risk, innovative assay proposals

We are looking for proposals for highly novel, high-risk cell-based assays or small model organisms suitable for phenotypic screening, that can provide a step change in our understanding of human disease, and our approach to curing it.

The emphasis in this call is on novelty. The phenotypic assay should provide a novel way to model a disease-state or monitor a novel disease pathway, that can be probed with large libraries of chemical matter. Complex assays are encouraged, that involve human tisue, complex-cocultures, iPS cell lines, organoids etc..

Apply for a PDi funded assay call

Expressions of interest

This is an open call for expressions of interest for phenotypic assay ideas put forward to NPSC.

This call for expressions of interest is currently open. There is no deadline for submitting EOIs.


Call guidelines - How to apply?

We are interested in knowing about highly innovative phenotypic assay ideas from academia, clinicians, and SMEs*.
Assays can be at various stages of development: from an early concept to a working screening format (96-well / 384-well).
We will contact you if we are interested in pursuing a collaboration with you to develop the assay further.
We will select projects according to characteristics such as scientific quality, novelty, relevance to human health, feasibility for medium to high-throughput high-content screening, value in drug discovery or chemical biology.

How to put your assay proposal forward for consideration?

If you think you have a highly novel phenotypic assay please go to the NPSC online application portal and apply to the call category you are interested in. The site requires registration. The application form is very short and straightforward.

We are looking for non-confidential information only at this stage.
If we are interested in accessing more details we will contact you directly.

Deadline for proposals: This is an open rolling call. Proposals will be selected on a continuous basis.
*SME definition is according to EU commission.

Blue sky assays - Highly innovative phenotypic assay ideas

UK-NPSC is seeking ideas from academia, clinicians and SMEs for phenotypic assays that can be executed within its facilities.

We are looking for proposals for highly novel, high-risk cell-based assays or small model organisms suitable for phenotypic screening, that can provide a step change in our understanding of human disease, and our approach to curing it.

The emphasis in this call is on novelty. The phenotypic assay should provide a novel way to model a disease-state or monitor a novel disease pathway, that can be probed with large libraries of chemical matter. Complex assays are encouraged, that involve human tisue, complex-cocultures, iPS cell lines, organoids etc..

Submit an expression of interest

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