HOW TO ACCELERATE AND DE-RISK DRUG DEVELOPMENT IN ONCOLOGY - Right Biology, Right Target, Right Biomarkers - Biognosys
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Proteomics for Precision Medicine
HOW TO ACCELERATE AND
DE-RISK DRUG DEVELOPMENT
IN ONCOLOGY
Right Biology, Right Target, Right Biomarkers
White Paper, May 2022
WHY DOES ONCOLOGY LEVERAGING PROTEOMICS ACROSS
DRUG DEVELOPMENT FAIL? THE ONCOLOGY PIPELINE
Fewer than one in 20 new cancer drugs ever make it to market.1 By enriching the Biognosys offers a unique suite of proteomics research platforms for every
understanding of target biology, proteomics can de-risk the drug development application, from discovery to clinic.
process and increase the likelihood of success.
Despite more than a century of dedicated research, By uncovering the right biology, right target, and right
cancer remains one of the leading causes of death.2 biomarkers, Biognosys’ TrueDiscovery™, TrueTarget™,
Recent years have seen significant advances in treat- and TrueSignature™ proteomics platforms can gener- Novel Drug Target Identification
ment, however, there is still much to be done to ensure ate the insights needed to support the next generation and Validation
that scientific developments result in clinically mean- of cancer diagnostics, therapeutics, and clinical bio-
DISCOVERY
ingful improvements. On average, only 3% of oncology markers. Applications
drugs ever make it to market1, and many of those that DRUG TARGET DECONVOLUTION
do make a limited difference to quantity or quality of life Biognosys can lead you from the earliest stages of DRUG TARGET VALIDATION
for patients.3,4 compound characterization through to identifying and
validating biomarkers and developing the next genera-
The reasons for these failures can broadly be separated tion of game-changing immunotherapies. We make it
into three categories: easy to interpret your data to help you get the insights
you need. And our facilities are Good Laboratory Prac-
• Incomplete understanding of underlying biology tice (GLP) certified and Good Clinical Practice (GCP)
(‘wrong biology’): Genomic and transcriptomic compliant, making us the first global large-scale pro-
data does not always reveal the true underlying teomics service provider able to support you from the
Unbiased Biological Insights
complexity of cancer, leading to incomplete insights beginning to the end of your drug development journey.
from Tissue and Biofluids
into the biological processes in tumors.
• Incorrect target (‘wrong target’): Several cancer
PRE-CLINICAL
Applications
drugs do not act on their intended target. Analysis BIOFLUID BIOMARKER DISCOVERY
of oncology drugs in clinical trials found several TISSUE BIOMARKER DISCOVERY
cases of efficacy being achieved through off-target (a) Probability of Success of Clinical Trial Phases in Oncology
MECHANISM OF ACTION STUDIES
effects5 which can result in toxicity and side effects. 80 PHOSPHOPROTEOME PROFILING
• Lack of effective biomarkers (‘wrong biomark- IMMUNOPEPTIDOME PROFILING
60
ers’): A lack of effective biomarkers prevents effec-
40
tive patient identification and stratification, while P1 to P2
hampering efforts to monitor treatment response in 20 P2 to P3
P3 to Approval
the clinic. 0 Overall
Oncology
Although there are initiatives to de-risk the drug devel- Custom Panels for Absolute
opment process, continually applying the same tools b) Probability of Success of Clinical trials in Different Protein Quantification
Therapeutic Areas, Including Oncology and Without
and approaches is unlikely to lead to innovative, first- or Oncology
Applications
CLINICAL
best-in-class targets and transformative progress.
80
PHARMACODYNAMIC BIOMARKERS
60 CLINICAL BIOMARKER PANELS
40
20
Fig 1. a) & b). Source: Chi Heem Wong, Kien Wei Siah, Andrew W Lo.
“Estimation of clinical trial success rates and related parameters.” 0
Biostatics 20(2): April 2019, Pages 273-286. Published online: 31 Overall Overall Excluding Oncology
January 2018. DOI: 10.1093/biostatics/kxx069
2 / Proteomics for Precision Medicine, White Paper, May 2022 Proteomics for Precision Medicine, White Paper, May 2022 / 3
TRUEDISCOVERY™: TRUETARGET™:
INSIGHTS INTO THE RIGHT BIOLOGY HIT THE RIGHT TARGET
Biognosys’ TrueDiscovery™ platform can identify and quantify proteins in tissue and Powered by our patented LiP-MS technology, TrueTarget™ identifies on- and
biofluids, offering unprecedented specificity at scale. Our integrated solutions function off-target drug binding. This can help identify the mechanism of action and
across the entire drug development pipeline and can be performed in a GLP-certified and reveal unexpected side effects early on, accelerating and de-risking the drug
GCP-compliant environment. development process.
The journey to developing a new cancer therapy begins Phenotyping colorectal cancer Target validation is a crucial part of the drug discovery TrueTarget can help you:
with understanding the underlying biology. To do this, it Colorectal cancer is highly heterogeneous,6 with molec- journey. Our proprietary TrueTarget platform offers a • Understand if and where your drug is binding to the
is helpful to look at the proteome – the ultimate output ular signatures frequently varying between patients. unique way of probing drug-target interactions, provid- expected target
of the genome – to really understand what is going on In collaboration with precision oncology experts ing an in-depth characterization of lead candidates to • Identify off-target binding and allosteric effects
inside cells, tissues, and tumors. Indivumed, we performed large-scale proteome profil- increase confidence in your drug target. • Establish the mechanism of action
ing of colorectal cancer patient biopsies and healthy • Identify potential issues with specificity and toxicity
Genomics-based approaches, while useful, cannot be control tissue to obtain deeper functional insights into TrueTarget is based upon Limited Proteolysis cou- • De-risk the drug development process
relied upon to give a complete picture of cancer biology. the biology of the cancer.7 We analyzed more than 900 pled with Mass Spectrometry (LiP-MS), a technique • Increase the chances of success in clinical trials
This is because genomics and transcriptomics alone tissue samples in total, using just 5-10 mg of tissue in invented by Professor Paola Picotti at ETH Zurich and and accelerate the journey to market
cannot determine the presence or expression level of each case, and profiled more than 7,000 proteins and co-developed by Biognosys. Unlike other approaches,
proteins, or provide information about protein function 20,000 phospho-peptides. LiP-MS does not require compound modification or Target identification of a CDK9 inhibitor
and structure. By contrast, proteomics can quantify and labeling, affinity-based purification, or prior knowledge Working together with AstraZeneca, we applied
identify all proteins present in a sample, as well as pro- By integrating this data with Indivumed’s multi-omics of the compound’s mode of action. TrueTarget to profile a novel inhibitor of CDK9, a
viding functional data in the form of post-translational database, we generated new insights into key mole- cyclin-dependent kinase with essential roles in cancer
modifications, structural changes and degradation. cules and clinically relevant signaling pathways in col- TrueTarget generates unique peptide signatures that development.
orectal cancer. These insights could help to identify new reveal drug binding sites at peptide-level resolution
Biognosys’ TrueDiscovery platform, powered by our therapeutic targets and advance progress in precision across the entire proteome, whether in the intended tar- De-regulation of CDK9, one of the best characterized
patented Hyper Reaction Monitoring (HRM) mass medicine for colorectal cancer. get or elsewhere. This approach can also be combined transcriptional CDKs, leads to a loss of cell cycle control
spectrometry technology, offers unbiased identification with our deep learning algorithms to optimize your drug and tumor growth, making it an important therapeutic
and quantification of thousands of proteins from any Beyond pure quantification, our proprietary HRM tech- discovery journey further, identifying and ranking drug target. We found that 80% of the top 10 peptide targets
sample type – cells, tissue and biofluids. We are contin- nology also provides valuable information on mecha- target binding sites across species and a wide range of of the CDK9 inhibitor were members of the CDK fam-
ually achieving new breakthroughs in depth. Our Tissue nism of action across a range of species and sample compound classes for rapid target deconvolution and ily, with CDK9 confirmed as the strongest target of the
Biomarker Discovery service can now quantify 13,000 types. We can offer detailed insights into biological validation.8 inhibitor. Thanks to the peptide-level resolution provided
proteins per tissue or tumor sample, while our Biofluid mechanisms inside cells and tissues during tumor by TrueTarget, we were also able to investigate the
Biomarker Discovery service can detect 3,000 proteins development and in response to drugs or other experi- exact binding site of the drug. This revealed that the
per sample of plasma and 5,000 proteins in cerebrospi- mental interventions. CDK9 CDK1 inhibitor binds within the ATP pocket of CDK9, as well
nal fluid (CSF) and urine. TrueDiscovery analyzes thou- as CDK4 and CDK6, consistent with modeling predic-
sands of samples simultaneously, making it suitable We can also provide important functional insights tions.
for a breadth of studies from target-focused precision through the analysis of post-translational modifications,
studies right through to large-scale drug screening. which play a critical role in regulating protein and cellu- Together with other mass spectrometry techniques,
lar function but cannot be inferred from genomic data these insights helped define the selectivity and mode
TrueDiscovery can help you: alone. For example, our phosphoproteome profiling of action of the inhibitor, including mapping the bind-
• Profile the entire proteome, to unprecedented service offers in-depth, quantitative insights into the ing sites and identifying off-target effects.9
CDK4 CDK6
depth and in an unbiased manner kinases, phosphatases, and signaling cascades at work
• Analyze post-translational modifications and other in cancer cells, revealing new targets for drug discovery.
proteoforms
• Perform discovery proteomics on a large scale TrueDiscovery provides an unrivaled opportunity to
Fig 2. Representation of LiP data showing the CDK9 inhibitor
• Generate reproducible data that are easily transfer- understand cancer biology in new depths, discover binding to its target proteins. CoM = center of mass. Taken from:
able to clinical assays novel biomarkers, and establish the mechanism of Hendricks, J.A. et al (2021). Mechanistic Insights into a CDK9 Inhibitor
• Deliver proteomics in a GLP-certified and action. Via Orthogonal Proteomics Methods. ACS Chemical Biology, 17(1),
pp.54–67.
GCP-compliant environment ATP Binding Site LiP-Quant Peptides Peptide CoM
4 / Proteomics for Precision Medicine, White Paper, May 2022 Proteomics for Precision Medicine, White Paper, May 2022 / 5TRUESIGNATURE™: PROTEOMICS FOR BIOMARKER
DEVELOP THE RIGHT BIOMARKERS DISCOVERY AND VALIDATION
TrueSignature™ provides highly precise and customizable Our high throughput proteomics workflows can be applied to fresh-frozen or
proteomics panels for pharmacodynamic readouts and clinical formalin-fixed tissue and tumor samples, blood plasma, and other biofluids,
biomarker monitoring. including urine and CSF. Here are just a few examples of our technology in action.
Clinical trials that use biomarkers for patient selection You can customize panels down to amino acid reso- Searching for biomarkers in blood plasma Biomarkers for companion diagnostics
are more likely to succeed than trials that don’t.1 You lution, and panels are also transferable across sam- Blood plasma analysis (‘liquid biopsy’) offers an easily Companion diagnostics provides information essential
can rely on Biognosys’ TrueSignature platform to estab- ple types and species, providing flexibility across the accessible way of monitoring cancer within the body. for the safe and effective use of a drug, for example,
lish effective biomarkers for your clinical research. drug development pipeline from preclinical to clinical Plasma can be sampled at regular intervals, provid- identifying which patients are most likely to benefit
research. ing an ongoing overview of health and therapeutic from a particular drug.11
Powered by Parallel Reaction Monitoring mass spec- response over time. Biognosys has pioneered an indus-
trometry, TrueSignature provides customizable pro- Clinical biomarker panels try-leading approach to profiling the proteome, using We are combining our discovery proteomics tools with
teomics panels for pharmacodynamic readouts and TrueSignature is used by our global biopharma partners automated depletion of the most abundant proteins to Siemens Healthineers’ diagnostic assay development
clinical biomarker monitoring. Your custom TrueSig- to de-risk their clinical research. Our clinical biomarker achieve unprecedented depth, and in a fully unbiased and commercial expertise to help you develop compan-
nature panels can be guided by insights from earlier panels can help you reliably validate and monitor bio- manner. ion diagnostics for your novel therapy.
TrueDiscovery studies. markers to ensure the success of your therapeutic
agent. Panels are flexible in size, can be multiplexed, Identifying tumor agnostic biomarkers We can streamline the progress of your companion
Unlike affinity-based proteomics methods, our mass and are customizable across species and indications. We recently demonstrated the power of our novel diagnostic from the initial stages of biomarker discov-
spectrometry technology doesn’t rely on the availabil- Our technology offers unbiased proteomic profiling at plasma proteomics workflow for oncology by analyz- ery right through to assay development and commer-
ity of specific reagents such as antibodies. Panels can unprecedented depth and scale, without the limitations ing plasma samples from 180 people with lung, breast, cialization. Whether applied to early-stage research
also be developed quickly, ready for you to use within a of affinity-based approaches and reagent availability, colorectal, pancreatic and prostate cancer. We detected or patient profiling for clinical trials, our unbiased pro-
matter of weeks. alongside robust and reliable quantification. over 2,700 proteins and categorized people by cancer teomics solutions are transferable across species and
type and stage using their plasma protein profiles. We suitable for all stages of the drug development pipe-
TrueSignature can help you: We provide you with reproducible and comparable data also identified several predictive biomarker candidates, line. Furthermore, our facility is GLP certified and GCP
• Take insights from preclinical research all the way across thousands of samples and multiple time points, including known biomarkers such as STAT3 in colorec- compliant, ensuring that any preclinical or clinical data
through to clinical studies making TrueSignature ideal for large-scale clinical trials. tal cancer, as well as biomarkers with novel biological you collect has the quality and traceability required by
• Build highly precise, customizable protein bio- significance.10 regulators for market authorization.
marker panels
• Simultaneously quantify up to 100 proteins,
including post-translational modifications and other Pharmacodynamic biomarkers for protein degradation
proteoforms therapeutics
• Identify and quantify pharmacodynamic biomark- Clinical-stage biopharma company Kymera Therapeu-
Fig 3. Stage Classification Across Cancer Types. In our cross-tumor biomarker study, GTR1 was differentially abundant across all cancers and
ers for new therapeutics tics is developing cutting-edge therapeutics that har-
could be used to predict stage. a) Boxplot visualization of log-transformed GTR1 quantities across stage and cancer type. Taken from: Tognetti, M.
• Gather GCP-compliant data for clinical trials ness targeted protein degradation pathways to tackle et al (2021) Biomarker Candidates for Tumors Identified from Deep-Profiled Plasma Stem Predominantly from the Low Abundant Area. bioRxiv.
autoimmune conditions, inflammatory diseases, cancer DOI: https://doi.org/10.1101/2021.10.05.463153
Pharmacodynamic biomarkers and more.
TrueSignature can be applied to qualitative and quan-
Breast Colorectal Lung Pancreatic Prostate
titative identification of pharmacodynamic biomark- Building on our long-standing preclinical partnership, Breast
Breast
Cancer
Breast
Cancer
Cancer
Breast
Breast Colorectal
Cancer Colorectal
Cancer Colorectal
Cancer
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Colorectal Lung
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Cancer
Lung
Cancer Cancer
Cancer
Lung
Lung Pancreatic
Cancer Pancreatic
Cancer Pancreatic
Cancer
Cancer
Cancer
Pancreatic
PancreaticProstate
CancerProstate
CancerProstate
Cancer
Cancer
Cancer
Prostate
Prostate
Cancer
Cancer
c c c c c
ers, which are essential for validating the efficacy and we developed custom TrueSignature proteomics pan-
intensity
16
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safety of new therapeutics. TrueSignature can speed up els to provide a pharmacodynamic readout of protein
intensity
log2 GTR1 intensity
log2 GTR1 intensity
log2 GTR1 intensity
log2 GTR1 intensity
15 15 15 15 15
the decision-making process in the early stages of drug degradation in discovery research and clinical studies.
GTR1
14
14 14 14 14 14
GTR1
development and ensure the success of your drug in These panels allow Kymera to monitor and quantify
logLog2
13 13 13 13 13
future clinical trials. protein degradation across all stages of their drug
2
12
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development pipeline. Early
Late
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6 / Proteomics for Precision Medicine, White Paper, May 2022 Proteomics for Precision Medicine, White Paper, May 2022 / 7DEEP INSIGHTS IN IMMUNO-ONCOLOGY CASE STUDIES
Immunotherapy has revolutionized the way we treat cancer: a more targeted form of Here is a selection of case studies that highlight the potential of Biognosys
treatment that has generated survival benefits for a range of patients. Proteomics is proteomics workflows in oncology research. Proteomics is a powerful tool for
advancing immunotherapy even further by identifying new therapeutic targets and understanding the underlying biology and discovering actionable biomarkers to
matching the right immunotherapy to the right patient. speed up and de-risk the oncology pipeline.
So far, we have outlined some of the major pitfalls Immunopeptide profiling for next-generation Predicting treatment response in pancreatic cancer
of drug development in oncology: understanding the immunotherapy Pancreatic ductal adenocarcinoma (PDAC) is the most We found that patients treated with nivolumab had
underlying biology of cancer, identifying the correct Immunopeptidomics is the profiling of the small common form of pancreatic cancer, a disease with higher levels of proteins associated with type II inter-
therapeutic target, and finding informative biomarkers fragments of proteins presented on the surface of a five-year survival rate of around 11%.18 There is an feron response, immune cell migration and T cell activa-
for patient stratification and monitoring. cells by Major Histocompatibility Complex (MHC) or urgent need for new therapeutics and precision med- tion, and reduced levels of immunomodulatory proteins.
Human Leukocyte Antigen (HLA) receptors, which act icine biomarkers in PDAC, to better understand which By contrast, patients treated with sotigalimab had
All of these challenges – right biology, right target, and as signals to orchestrate the activity of the immune patients would be most likely to benefit from which higher levels of proteins associated with mature anti-
right biomarkers – come together in the fast-develop- system. treatments. gen-presenting cells (APCs) and the activation of CD4+
ing field of immuno-oncology. T cells, B cells, and monocytes.
Mass spectrometry is the only technology that can reli- As part of the Phase II PRINCE trial led by the Parker
Immunotherapy has been revolutionary for cancer treat- ably quantify and identify immunopeptides in biological Institute for Cancer Immunotherapy (PICI),19 Biognosys’ We therefore showed that these two immunothera-
ment, generating survival benefits across several can- samples at scale. Biognosys’ immunopeptidome pro- unbiased mass spectrometry proteomics workflow was pies generate unique immune responses. With further
cer types.12,13,14 However, significant challenges remain. filing service is a semi-automated mass spectrometry used to investigate the effects of two immunotherapies development, these biomarker signatures could help
Many patients do not respond to existing immunother- workflow that can robustly identify immunopeptides for PDAC: nivolumab and sotigalimab, in combination to identify PDAC patients who may benefit most from
apies, highlighting the need to find better biomarkers from small amounts of cultured cells and tissue sam- with chemotherapy. particular drug combinations.
to stratify patients. And while these treatments can be ples.
curative for those who do respond, there are others for Understanding the side effects of immunotherapy
whom the transformative effects of immunotherapy Immunopeptidomics has the potential to accelerate the In research presented at the 2021 American Associ- to better overall response and higher survival benefit
do not last. There can also be significant side effects, development of the next generation of immunothera- ation for Cancer Research congress, we discovered from immunotherapy, including two with prognostic
which can limit the utility of immunotherapy. pies in oncology through the detection of neoantigens, proteomic signatures associated with immune-related value.
immunopeptides that reflect tumor-specific muta- adverse events (irAEs) in people receiving PD-1 check-
A deeper understanding of the underlying biology of tions. Immunopeptidome analysis can also be used for point inhibitors for non-small cell lung cancer (NSCLC). We also performed functional analysis, revealing a net-
cancer and how this interacts with the immune system patient profiling, revealing more about the role of the work of five proteins involved in immune, inflammatory,
and tissue microenvironment is essential to identify immune system in tumorigenesis and potential thera- We performed deep proteome profiling on plasma sam- vesicle transport, and acute phase related responses.
new ways to improve the effectiveness and durability of peutic targets. Our immunopeptidome profiling pipeline ples from NSCLC patients before therapy and 8-weeks These insights could lead to new biomarkers to help
immunotherapy. can reliably identify and quantify 10,000 MHC Class I after treatment initiation. We found 82 proteins asso- clinicians better predict and manage toxicity during
and 10,000 Class II immunopeptides in just 15 mg of ciated with irAEs. We also identified 13 proteins that immunotherapy.20
tissue, making it suitable for high-throughput, large- were associated with low-grade toxicity, which is linked
scale preclinical and clinical applications as well as
smaller research studies.
Immunopeptidome profiling in lung cancer
We recently demonstrated the power of our immuno- • MMP11, an important remodeller of the cancer
Fig 4. High Throughput Immunopeptidomics From Needle-size Biopsies. We measured a cohort of 12 cancerous and matched healthy lung peptidomics workflow in lung cancer, generating MHC microenvironment and potential therapeutic target
biopsies, identifying 11,000 MHC Class I and 9,000 MHC Class II immunopeptides from as little as 15 mg tissue. immunopeptide profiles from needle biopsies of 12 lung in lung cancer
cancer and matched healthy tissue samples.21 • CHEK, a cell cycle checkpoint kinase
n = 12 • TNC, an extracellular membrane protein that is
2,000
On average, we were able to identify more than 11,000 upregulated during neovascularization
Modified Peptides
Class I and more than 9,000 Class II immunopeptides • SET, a proto-oncogene that is highly overexpressed
from each sample. Around 3,000 of the identified Class in lung tumors
I immunopeptides were upregulated in the lung cancer
0
2.5 5 10 15 45 135 samples, with significant enrichment of proteins related
Healthy Cancerous 11,000 MHC 9,000 MHC
Lung Tissue Lung Tissue 25 x 106 cells 10 – 15 mg Class I Class II Tissue Input (mg) to lung cancer development including:
8 / Proteomics for Precision Medicine, White Paper, May 2022 Proteomics for Precision Medicine, White Paper, May 2022 / 9NOVEL INSIGHTS TO ACCELERATE References
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org/10.1101/2021.10.05.463153
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10 / Proteomics for Precision Medicine, White Paper, May 2022 Proteomics for Precision Medicine, White Paper, May 2022 / 11KEY TAKEAWAYS
• Oncology drug development fails due to poor understanding of the under-
lying biology of cancer (wrong biology), insufficient target validation (wrong
target), and a lack of effective biomarkers for patient stratification (wrong
biomarkers).
• There is an urgent need for new approaches to de-risk the oncology drug
development pipeline and increase the likelihood of clinical trial success.
• Next-generation proteomics can fill this gap by providing fresh insights into
cancer biology at unprecedented scale and depth.
• Biognosys provides unbiased proteome-wide profiling of cells, tissue, blood
plasma, and other biofluids. Our proteomics technologies accelerate and val-
idate each stage of the drug discovery and development pipeline:
TrueDiscovery™ - Understand the right biology
TrueTarget™ - Hit the right target
TrueSignature™ - Develop the right biomarkers
• Biognosys also provides large-scale immunopeptide profiling to support the
development of next generation personalized immunotherapies.
• Rapid advances, including integration with other omics technologies and
clinical data, are rapidly making proteomics an indispensable tool in the drug
development pipeline.
At Biognosys, we believe that deep proteome insights hold the key to breakthrough
discoveries that can dramatically improve human health. We enable life science
researchers and drug hunters to look at the proteome from every angle with our
versatile portfolio of proprietary next-generation proteomics services, software, and
kits, including the TrueDiscovery™, TrueTarget™, and TrueSignature™ platforms and
flagship software Spectronaut™. These solutions provide a multi-dimensional view of
protein expression, function, and structure in all biological species and sample types.
Biognosys’ unique, patented technologies utilize high-resolution mass spectrometry
to quantify thousands of proteins across thousands of samples with industry-lead-
ing precision, depth, and throughput. Through advanced data analytics, Biognosys
translates data into actionable insights for R&D and clinical research.
Contact us at services@biognosys.com to discuss your specific study needs with
one of our scientific consultants.
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