Answer four fundamental questions on how to develop the most innovative cancer immunotherapy treatments, starting with screening for lead molecules and ending with evaluation of combination therapies.
Learn about novel cell-based assays that enable improved immunotherapy drug development. See case studies utilizing checkpoint receptors such as PD-1, VISTA, and NIK.
Identify Compounds that Rescue Disease Relevant Mutant Membrane ProteinsDiscoverX Corporation
Learn about diseases caused by protein misfolding and how you can screen for compounds, known as pharmacochaperones, that rescue misfolded proteins and could be used as therapeutics.
Learn about a powerful new cell-based assay for specifically measuring target cancer cell death in co-cultures. Very useful in the development of immunotherapy drugs.
Breaking the Status Quo: Using Mass Spectrometry to detect Host Cell ProteinsMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3b3Tbcd
Measurement of host cell proteins is vital to ensuring a biotherapy's purity and a patient's safety. Biotherapies treat diseases with products produced by living organisms, as a result, host cell components must be characterized and controlled. We'll review new methods within product characterization for detection.
Trace amounts of host cell proteins can be present after the production and purification of any biopharmaceutical. Detection of these species requires highly specific techniques to accurately quantify even low levels of contamination. Host cell protein impurities, present at PPM-levels in biotherapies, are a major immunogenicity risk because they can elicit an unpredictable immune response in patients. Their complex and diverse nature makes them challenging to detect or monitor. With acceptance criteria for host residual DNA usually set at a very low level (often =1.0 pg of DNA per mg of drug substance), effective removal techniques and sensitive methods of detection are critical.
Antibody-based techniques, like the enzyme-linked immunosorbent assay (ELISA), have been used to assess the HCP load of biotherapeutics before and after process changes. However, these techniques do not necessarily detect qualitative changes in the HCP population. In this webinar, we will discuss how mass spectrometry (MS)-based approaches coupled with ELISA methods help detect qualitative and quantitative differences in HCP populations.
In this webinar, you will learn:
• Comprehensive HCP ID and semi-quantitation
• HC agnostic process
• Creation of process specific database
• Differential clearance of specific HCPs throughout purification steps
• Monitoring of problematic species e.g. immunogenic (PLBL2), lipases and proteases
• Explanation about why 90% of BLAs filed included this HCP MS data
Oncology Immunotherapy - Nivolumab and other PD-1/PD-L1 Targeted Agents (061213)Will Roettger
This is a short briefing on the oncology immunotherapy PD-1/PD-L1 targeted agents currently under development. In this briefing we look at the competitive landscape, PD-1/PD-L1 product profiles, positioning, strategy, as well as a development timeline and SWOT on the BMS PD-1 blocker nivolumab. Updates to this briefing will come as newer information is discovered.
Historically, genetic toxicology has been comprised of bacterial and cell based in vitro assays such as the Ames assay (a bacterial mutagenicity assay), Micronucleus and Chromosomal Aberration assays (mammalian cytogenetic assays), and Mouse Lymphoma Assay (in vitro mammalian cell gene mutation assay). These were routinely used for safety evaluation and are still part of the standard core battery. The emergence of new technologies has facilitated the development of in vitro methods for safe and effective drug and chemical testing.
This BioReliance® toxicology services webinar will explore alternative models, including 3D skin models that comply with the EC Scientific Committee on Consumer Safety (SCCS) recommendations. It will also discuss how the 3Rs (Replace, Reduce, Refine) Principle advocates the exploration of such alternative methods while achieving required goals.
In this webinar, you will learn:
• About in vitro alternatives to animal toxicity testing in pharma, chemical, tobacco, and personal care products.
• How the 3Rs (Replace, Reduce, Refine) Principle advocates exploring alternative methods without compromising the required goals.
• Alternatives to comply with the 7th Amendment to the EC Cosmetics Directive.
Learn about novel cell-based assays that enable improved immunotherapy drug development. See case studies utilizing checkpoint receptors such as PD-1, VISTA, and NIK.
Identify Compounds that Rescue Disease Relevant Mutant Membrane ProteinsDiscoverX Corporation
Learn about diseases caused by protein misfolding and how you can screen for compounds, known as pharmacochaperones, that rescue misfolded proteins and could be used as therapeutics.
Learn about a powerful new cell-based assay for specifically measuring target cancer cell death in co-cultures. Very useful in the development of immunotherapy drugs.
Breaking the Status Quo: Using Mass Spectrometry to detect Host Cell ProteinsMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3b3Tbcd
Measurement of host cell proteins is vital to ensuring a biotherapy's purity and a patient's safety. Biotherapies treat diseases with products produced by living organisms, as a result, host cell components must be characterized and controlled. We'll review new methods within product characterization for detection.
Trace amounts of host cell proteins can be present after the production and purification of any biopharmaceutical. Detection of these species requires highly specific techniques to accurately quantify even low levels of contamination. Host cell protein impurities, present at PPM-levels in biotherapies, are a major immunogenicity risk because they can elicit an unpredictable immune response in patients. Their complex and diverse nature makes them challenging to detect or monitor. With acceptance criteria for host residual DNA usually set at a very low level (often =1.0 pg of DNA per mg of drug substance), effective removal techniques and sensitive methods of detection are critical.
Antibody-based techniques, like the enzyme-linked immunosorbent assay (ELISA), have been used to assess the HCP load of biotherapeutics before and after process changes. However, these techniques do not necessarily detect qualitative changes in the HCP population. In this webinar, we will discuss how mass spectrometry (MS)-based approaches coupled with ELISA methods help detect qualitative and quantitative differences in HCP populations.
In this webinar, you will learn:
• Comprehensive HCP ID and semi-quantitation
• HC agnostic process
• Creation of process specific database
• Differential clearance of specific HCPs throughout purification steps
• Monitoring of problematic species e.g. immunogenic (PLBL2), lipases and proteases
• Explanation about why 90% of BLAs filed included this HCP MS data
Oncology Immunotherapy - Nivolumab and other PD-1/PD-L1 Targeted Agents (061213)Will Roettger
This is a short briefing on the oncology immunotherapy PD-1/PD-L1 targeted agents currently under development. In this briefing we look at the competitive landscape, PD-1/PD-L1 product profiles, positioning, strategy, as well as a development timeline and SWOT on the BMS PD-1 blocker nivolumab. Updates to this briefing will come as newer information is discovered.
Historically, genetic toxicology has been comprised of bacterial and cell based in vitro assays such as the Ames assay (a bacterial mutagenicity assay), Micronucleus and Chromosomal Aberration assays (mammalian cytogenetic assays), and Mouse Lymphoma Assay (in vitro mammalian cell gene mutation assay). These were routinely used for safety evaluation and are still part of the standard core battery. The emergence of new technologies has facilitated the development of in vitro methods for safe and effective drug and chemical testing.
This BioReliance® toxicology services webinar will explore alternative models, including 3D skin models that comply with the EC Scientific Committee on Consumer Safety (SCCS) recommendations. It will also discuss how the 3Rs (Replace, Reduce, Refine) Principle advocates the exploration of such alternative methods while achieving required goals.
In this webinar, you will learn:
• About in vitro alternatives to animal toxicity testing in pharma, chemical, tobacco, and personal care products.
• How the 3Rs (Replace, Reduce, Refine) Principle advocates exploring alternative methods without compromising the required goals.
• Alternatives to comply with the 7th Amendment to the EC Cosmetics Directive.
ASCO 2015 Melanoma Immunotherapy
Thomas Olencki, DO Division of Medical Oncology Department of Internal Medicine The Ohio State University Wexner Medical Center Columbus, Ohio
Learn about how to create your own cell lines for cytotoxicity assays for use in immunotherapy drug development. Specifically measure target cell death.
Vaccine Cell Bank and Virus Seed CharacterizationMilliporeSigma
In this webinar, you will learn:
- about the importance of characterising cell banks and virus seed stocks in order to meet worldwide regulatory requirements.
- the difference between guidance documents from different organizations worldwide
- new technologies for determining the identity of cell substrates and virus seed stocks
- detecting adventitious agent contamination
Community Oncology Clinical Debates: Advanced Melanoma
Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge.
Review a downloadable slide deck by Antoni Ribas, MD, PhD, covering the most clinically relevant new data reported from Community Oncology Clinical Debates: Advanced Melanoma.
Target Audience
This educational activity has been designed to meet the unique learning needs of oncologists involved in the treatment of patients with advanced melanoma.
Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
BioMAP® Systems for Investigative Toxicology & Safety Assessment. Presentation for the California Environmental Protection Agency’s 21st Century Toxicology Seminar Series, October 29, 2014, Sacramento, CA. Ellen Berg
This is Part 1 of a presentation on Genetic Toxicology that was given by Dr. David Kirkland to scientific staff at Health Canada in Sept. 2010. Part 2 is availabile in ppt
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van GoolAlain van Gool
Tutorial lecture explaining real case stories of oncology drug development, passing on lessons learned from my pharma days to an audience of research professionals.
ASCO 2015 Melanoma Immunotherapy
Thomas Olencki, DO Division of Medical Oncology Department of Internal Medicine The Ohio State University Wexner Medical Center Columbus, Ohio
Learn about how to create your own cell lines for cytotoxicity assays for use in immunotherapy drug development. Specifically measure target cell death.
Vaccine Cell Bank and Virus Seed CharacterizationMilliporeSigma
In this webinar, you will learn:
- about the importance of characterising cell banks and virus seed stocks in order to meet worldwide regulatory requirements.
- the difference between guidance documents from different organizations worldwide
- new technologies for determining the identity of cell substrates and virus seed stocks
- detecting adventitious agent contamination
Community Oncology Clinical Debates: Advanced Melanoma
Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge.
Review a downloadable slide deck by Antoni Ribas, MD, PhD, covering the most clinically relevant new data reported from Community Oncology Clinical Debates: Advanced Melanoma.
Target Audience
This educational activity has been designed to meet the unique learning needs of oncologists involved in the treatment of patients with advanced melanoma.
Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
BioMAP® Systems for Investigative Toxicology & Safety Assessment. Presentation for the California Environmental Protection Agency’s 21st Century Toxicology Seminar Series, October 29, 2014, Sacramento, CA. Ellen Berg
This is Part 1 of a presentation on Genetic Toxicology that was given by Dr. David Kirkland to scientific staff at Health Canada in Sept. 2010. Part 2 is availabile in ppt
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van GoolAlain van Gool
Tutorial lecture explaining real case stories of oncology drug development, passing on lessons learned from my pharma days to an audience of research professionals.
Target Validation Academy Of Medical Sciences 1 Dec 2006Mike Romanos
An overview of the issues and approaches in selecting the best targets for drug discovery and validating them. Given at the Drug Discovery Forum held at the Royal Society, London and organised by the Academy of Medical Sciences
2014 11-27 ODDP 2014 course, Amsterdam, Alain van GoolAlain van Gool
Presentation as part of a comprehensive oncology drug development course, to discuss a pharmaceutical approach to identify, validate and develop biomarkers for personalized medicine for melanoma.
Long Acting Injectables - A New Dimension for Proteins and PeptidesMilliporeSigma
Access the recording: https://bit.ly/2xAaMba
Abstract:
Long acting injectables (LAI) have been around for decades for the delivery of small molecules and peptides to treat chronic and site-specific diseases. However, when it comes to more sensitive biological therapeutics the classical polylactide and polylactide/glycolide based systems suffer from several limitations (e.g. uncontrolled release kinetics, in situ pH drop, protein degradation) making them unsuitable. The SynBiosys® biodegradable polymeric microparticle technology combines all the features required for LAI formulations for biologics. In two case studies we will showcase sustained release formulations for peptides and proteins and demonstrate their potential via extensive in vitro and in vivo characterization.
Long Acting Injectables - A New Dimension for Proteins and PeptidesMerck Life Sciences
Access the recording: https://bit.ly/2xAaMba
Abstract:
Long acting injectables (LAI) have been around for decades for the delivery of small molecules and peptides to treat chronic and site-specific diseases. However, when it comes to more sensitive biological therapeutics the classical polylactide and polylactide/glycolide based systems suffer from several limitations (e.g. uncontrolled release kinetics, in situ pH drop, protein degradation) making them unsuitable. The SynBiosys® biodegradable polymeric microparticle technology combines all the features required for LAI formulations for biologics. In two case studies we will showcase sustained release formulations for peptides and proteins and demonstrate their potential via extensive in vitro and in vivo characterization.
Human Cell Systems Biology for Drug Discovery and Chemical Safety. Presentation at the 7th Brazilian Symposium on Medicinal Chemistry, November 12, 2014, Campos do Jordao-SP, Brazil. Ellen Berg.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
2. 2
The Cancer-Immunity Cycle & Targeted Therapies
Multiple potential intervention steps to develop anti-cancer therapies
Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity. 39 (1): 1-10
3. 3
Fundamental questions for drug development
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
How do I screen for a functionally active lead molecule?
How can I determine efficacy in a human tumor microenvironment (TME)?
Is my drug active outside the context of the TME?
How does my drug act in a combination therapy?
Translating Discoveries into Drugs
4. 4
Target-based & Phenotypic Assays from DiscoverX
Products and services to support drug development
0% KinasesGPCRs Interleukins Pathways Epigenetics Checkpoint
100%
Primary Cell Profiling
DepthofCoverage
284
410
40
35
34
6
5. 5
From drug discovery to clinical combinations
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
Enabling Anti-cancer Immunotherapies
PathHunter®
Checkpoint Assays
PathHunter® Bioassays for
QC Lot Release Testing
BioMAP®
Oncology Systems
BioMAP
Diversity PLUS™
BioMAP®
Combo ELECT
6. 6
Challenges:
Requires specific cell-based assays for each target
Requires human cells with complex TCR signaling
Donor variability
Longer assay times and complicated protocols
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
How Do I Screen for Functionally Active Lead Molecules?
7. 7
Cancer Cell
Immune Cell
EFC Technology
PD-1 Signaling Assay
PathHunter® Checkpoint Assays
Ideal for screening and lead optimization
8. 8
1 0 -1 0
1 0 -9
1 0 -8
1 0 -7
1 0 -6
1 0 -5
1 0 -4
0
2 0 0 0 0
4 0 0 0 0
6 0 0 0 0
8 0 0 0 0
A n ti-P D -1 D ru g [g /m L ]
RLU
P e m b ro lizu m ab
N iv o lu m ab
HillSlope
IC50
Pembrolizumab
-2.010
6.630e-009
Nivolumab
-1.921
9.398e-009
Robust Screening & Lead Optimization Platform
1 0 -1 1
1 0 -1 0
1 0 -9
1 0 -8
1 0 -7
1 0 -6
1 0 -5
1 0 -4
0
1 0 0 0 0 0
2 0 0 0 0 0
3 0 0 0 0 0
4 0 0 0 0 0
RLU
C o m p o u n d [M ]
X L -2 8 8 0
D a s a tin ib
HillSlope
IC50
Dasatinib
-1.979
5.762e-009
XL-2880
-1.045
4.740e-007
Screen Biologics in
the PathHunter PD-1 Assay
Screen Small Molecule Inhibitors in
the PathHunter PD-1 Assay
PathHunter® assays support both biologics and small molecules
9. 9
PD-1
OX40
CD40
HVEM
VISTA
TIM3
Biologically relevant responses for co-stimulatory & co-inhibitory agents
Easy protocol with results in <5hrs
Supports development of biologics and small molecules
Screen confidently with highly sensitive response
Applicable for QC lot release of biologic drug
Summary for PathHunter® Checkpoint Assays
1 0 -1 2
1 0 -1 1
1 0 -1 0
1 0 -9
1 0 -8
1 0 -7
1 0 -6
1 0 -5
0
5 0 0 0 0
1 0 0 0 0 0
1 5 0 0 0 0
O X 4 0 S ig n a lin g A s s a y
O X 4 0 L [g /m L ]
RLU
+ O X 4 0
n o O X 4 0
Assays currently available
Enabling screening & lead optimization for co-stimulatory & co-inhibitory molecules
10. 10
Challenges:
In vitro assays do not mirror the complexity of TME
Animal-xenograft models are not high throughput
Lack of appropriate response biomarkers
How Can I Determine Efficacy in a Human TME?
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
11. 11
Large or Small
Molecules and
Combinations
BioMAP® Models of Human Disease Biology
Validated systems that provide predictive results
BioMAP Data &
Knowledgebase
56+ BioMAP
co-culture systems
Human Primary Cells
12. 12
Development of BioMAP® Human TME Models
BioMAP systems mirror intratumoral immune suppression
48h Assay Incubation
18. 18
Both Large And Small Molecules Can Be Tested
Screen and prioritize drug candidates
Anti-CD73 antibodies and Paclitaxel show increased immune cytokine production
CD87/uPAR
CEACAM5/CD66e
CollagenI
CollagenIII
Keratin20
P
PBMCCytotoxicity
sGranzymeB
sIFNg
SRB
sVEGF
tPA
uPA
CD40
CD87/uPAR
CEACAM5/CD66e
CollagenIV
Keratin20
PBMCCytotoxicity
sGranzymeB
sIFNg
SRB
Profiles
Paclitaxel, 14 nM
,
StroHT29 VascHT29
sIFNg
sTNFa
sVEGF
uP
sIFNg
Profiles
Paclitaxel, 14 nM
,
sIFNg
sTNFa
sVEGF
uP
sTNFa
sIFNg
StroHT29 VascHT29
Anti-Human CD73 was profiled as part of a collaborative study with MedImmune/AZ
Protein Biomarker Readouts
RelativeExpressionLevels
|Log10ratio|drug/vehiclecontrol)
19. 19
Challenges:
Current approaches rely on single cell or organ types
Bias towards specific targets and target pathways
Less complex and often isolated biology
Limited testing of broad-scale human biology with drug
Is My Drug Active Outside the Context of the TME?
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
20. 20
F
P
f
P
F
f
f
K
P
tP
P
P
C
K
P
tP
P
F
P
P
f
C
P
f
P
P
P
LogRatio
Profiles
Erlotinib, 1.1 uM
Erlotinib, 370 nM
3C 4H LPS SAg BT BF4T BE3C CASM3C HDF3CGF KF3CT MyoF lMphg
uPAR uPAR
P
tPA
uPA
uPAR
EGFR
F
P
f
P
F
f
f
K
P
tP
P
P
C
K
P
tP
P
F
P
P
f
C
P
f
P
P
P
LogRatio
Profiles
Erlotinib, 1.1 uM
Erlotinib, 370 nM
3C 4H LPS SAg BT BF4T BE3C CASM3C HDF3CGF KF3CT MyoF lMphg
uPAR
Eot3
uPAR
IL1a
MMP1
MMP9
P
tPA
uPA
uPAR
EGFR
IL8
Evaluation of Erlotinib Effects Outside the TME
Biomarker activity of EGFR-inhibitors
• Inform mechanism of action
• Identify biomarkers of efficacy
Activities detected at both concentrations are annotated
RelativeExpressionLevels
|Log10ratio|drug/vehiclecontrol)
Monocyte
Activation
T cell
Activation
B cell
Activation
Macrophage
Activation
Matrix-modulation, fibrosis, tissue remodeling
responses
Vascular EC
Inflammation
Epithelial Inflammation and Matrix
Remodeling
Vascular SM
Inflammation
21. 21
F
P
f
P
F
f
f
K
P
tP
P
P
C
K
P
tP
P
F
P
P
f
C
P
f
P
P
P
LogRatio
Profiles
Paclitaxel, 41 nM
Paclitaxel, 4.6 nM
3C 4H LPS SAg BT BF4T BE3C CASM3C HDF3CGF KF3CT MyoF lMphg
TF uPAR
uPAR
sIgG
F
P
f
P
F
f
f
K
P
tP
P
P
C
K
P
tP
P
F
P
P
f
C
P
f
P
P
P
LogRatio
Profiles
Paclitaxel, 41 nM
Paclitaxel, 4.6 nM
3C 4H LPS SAg BT BF4T BE3C CASM3C HDF3CGF KF3CT MyoF lMphg
TF uPAR
IL8
uPAR
VEGFR2
sIgG
CD69
Proliferation
Proliferation
Proliferation
Evaluation of Paclitaxel Outside the TME
Biomarkers for cardiovascular AE, anti-angiogenic and anti-metastatic potential
• Inform mechanism of action
• Identify activities that may highlight potential for adverse events
Activities detected at both concentrations are annotated
RelativeExpressionLevels
|Log10ratio|drug/vehiclecontrol)
Monocyte
Activation
T cell
Activation
B cell
Activation
Macrophage
Activation
Matrix-modulation, fibrosis, tissue remodeling
responses
Vascular EC
Inflammation
Epithelial Inflammation and Matrix
Remodeling
Vascular SM
Inflammation
22. 22
F
P
f
P
F
f
f
K
P
tP
P
P
C
K
P
tP
P
F
P
P
f
C
P
f
P
P
P
LogRatio
Profiles
Pembrolizumab, 2000 ng/ml
Pembrolizumab, 400 ng/ml
3C 4H LPS SAg BT BF4T BE3C CASM3C HDF3CGF KF3CT MyoF lMphg
F
P
f
P
F
f
f
K
P
tP
P
P
C
K
P
tP
P
F
P
P
f
C
P
f
P
P
P
LogRatio
Profiles
Pembrolizumab, 2000 ng/ml
Pembrolizumab, 400 ng/ml
3C 4H LPS SAg BT BF4T BE3C CASM3C HDF3CGF KF3CT MyoF lMphg
Evaluation of Pembrolizumab Outside the TME
Anti-PD1 antibodies are not inherently inflammatory
• Confirm selectivity
• Determine on/off target effects and even target related secondary effects
• Inform mechanism of action
• Nivolumab has an identical profile in this panel
Monocyte
Activation
T cell
Activation
B cell
Activation
Macrophage
Activation
Matrix-modulation, fibrosis, tissue remodeling
responses
Vascular EC
Inflammation
Epithelial Inflammation and Matrix
Remodeling
Vascular SM
Inflammation
No activities detected
RelativeExpressionLevels
|Log10ratio|drug/vehiclecontrol)
23. 23
Challenges:
Pre-clinical testing is technically challenging
Current models are poorly predictive & expensive
Often directly tested in patients
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
How Do My Drugs Act in Combination Therapy?
24. 24
Combination Matrix
Enhanced Immune Response with Combinations
RelativeExpressionLevels
|Log10ratio|drug/vehiclecontrol)
Protein Biomarker Readouts
Pembrolizumab plus Paclitaxel combination enhances cytokine production
25. 25
Lead Molecule:
PathHunter® assays can help identify and optimize a lead candidate
Efficacy:
BioMAP® Oncology Systems determine drug efficacy in a human TME model
Safety:
Diversity PLUS™ evaluates drug activity outside the context of the TME
Combinations:
Combo ELECT tests the impact of drug interactions in a human TME model
Summary
Screening &
Lead
Optimization
Efficacy &
Biomarker
Selection
Safety &
Pre-clinical
Studies
Clinical
Combination
Strategies
26. 26
DiscoverX: Enabling Testing to Therapy
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