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Immuno-Oncology Solutions

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• Our I-O Service Portfolio

• Highlighted Services:

• I-O Biomarker Discovery & Clinical Applications

• Neoantigen Identification & Clinical Applications

• Regulatable CAR-T Development

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ICI Efficacy Prediction

Cancer Vaccine

Checkpoint Inhibitor & drug targeting

Regulatable CAR-T

Neoantigen Identification

Immune Repertoire

• Tumor Mutational Burden• Microbiome• dMMR, MSI-H• Checkpoint Inhibitor

Expression

• Neoantigen• Immune Repertoire• MHC Binding/Prediction• Epigenetic Analysis

• Transcriptome Seq• Exome Seq• Epigenetic Analysis• Immune Repertoire• MHC Binding• scRNA-seq

AptaNxTM RegCAR-TTM

Biomarker Discovery

• Exome Seq• Transcriptome Seq• Epigenetic Analysis • HLA Typing

• Exome Seq• Transcriptome Seq• Epigenetic Analysis• AptaNxTM

• Immune Repertoire• MHC Binding• Checkpoint Inhibitor

Discovery• Exome Seq• Transcriptome Seq• scRNA-seq

Solution

Technology

DiscoveryClinical

Translation

Therapeutics

Immuno-OncologySolutions

Legend

Stem cell Transplantation

• HLA Matching• Transcriptome Seq

Minimal Residual Disease • Transcriptome Seq

• Exome Seq

Tumor Micro-environment

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Distribution and Growth of Cumulative Immuno-Oncology Biomarker

Mentions by Test Purpose 2014 – 17Growth of Cumulative Mentions of Top 30 Immuno-Oncology Biomarkers; 2014 – ’17

https://www.decibio.com

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J Yuan et al. Journal for ImmunoTherapy of Cancer20164:3

Technology

Whole Exome Sequencing

Gene signature/RNA Seq

Epigenetic Analysis

Antigen/Neoantigen Identification

B/T-cell receptor repertoire

Flow cytometry/WES/RNA Seq

Multicolor IHC

Therapeutic strategy

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Putative I-O Biomarkers in the TME

• PD-L1 expression

• Tumor-infiltrating lymphocytes (TILs)

• Mutational load and neoantigens

• Immunosuppressive cell types

• Macrophage and DC polarization

• Immunosuppressive molecules

• Cytokine signatures

Tumor cell Dead tumor cell MDSC CD8+ T cells CD4+ T cells Immature

dendritic cell

Primed

dendritic cell

M1

macrophage

M2

macrophage

PD-L1 PD-1 MHC I CTLA-4 TIM-3 LAG-3 Tumor Neoantigens IDO IFNγ M-CSF T-regulatory cell

antigens

© 2017 American Association for Cancer Research

M1

M2

IFNγ

M-CSF

iDC

CD8+

CD8+

CD8+

MDSC

CD8+

MDSC

MDSC

TIL

TIL

TIL

TIL

IDO

M2

IDO

iDC

Mutational

load

pDC

CD4+

Treg Treg

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Clinical Application Examples

Efficacy Biomarkers of ICI (Immunotherapy Checkpoint Inhibitors)

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Barnhart C. J Adv Pract Oncol. 2015 May-Jun;6(3):234-8.

PD-1 inhibitors:• Pembrolizumab (Keytruda)

• Nivolumab (Opdivo)

PD-L1 inhibitors:• Atezolizumab (Tecentriq)

• Avelumab (Bavencio)

• Durvalumab (Imfinzi)

CTLA-4 inhibitors:• Ipilimumab (Yervoy)

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28%

18%

27%

Melanoma NSCLC Renal-cell cancer

Response rate (Nivolumab)

33%

27%

13%

Melanoma NSCLC PD-L1–positive endometrial

cancer

Response rate (Pembrolizumab)

10.90%

Melanoma

Response Rate (Ipilimumab)

SL Topalian, FS Hodi, JR Brahmer , etal N Engl J Med 366: 2443– 2454,2012

A Ribas, et al. JAMA. 2016 Apr 19. doi: 10.1001/jama.2016.4059

R Hui, EB Garon, et al. Ann Oncol. 2017 Apr 1;28(4):874-881. doi: 10.1093/annonc/mdx008.

Ott et al. Journal of Clinical Oncology 35, no. 22 (August 2017) 2535-2541.

F Stephen Hodi et al. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466.

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• TMB (Tumor Mutational Burden)

• RNA signature

• PD-1, PD-L1 expression

• dMMR, MSI-H

• Microbiome

• Neoantigen

Hugo W. et al. Cell. 2017;168:542. doi: 10.1016/j.cell.2017.01.010.

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Snyder, A. et al. N. Engl. J. Med. 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).

There was a significant difference in mutational load between patients with a long-term clinical benefit and those with a minimal benefit or no benefit.

Our Solution:

TMB analysis by WES (Whole Exome Sequencing) or our OncoGx gene panel

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Hugo W. et al. Cell. 2017;168:542. doi: 10.1016/j.cell.2017.01.010.

Identification of transcriptomic features (IPRES:

innate anti-PD-1 resistance) associated with anti-

PD-1 resistance

Our Solution:

RNA expression signature analysis by RNA-Seq

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Sunshine, J. & Taube, J. M. 23, 32–38, doi:10.1016/j.coph.2015.05.011 (2015).

Association of PD-L1 expression in pre-

treatment tumor specimens with

objective response to anti-PD-1/PD-L1

therapy

Our Solution:

Expression analysis of PD-1 and PD-L1

in tumor tissue by IHC

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Le DT, et al. N Engl J Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596.

Mismatch repair–deficient tumors are more responsive to

PD-1 blockade than are mismatch repair–proficient tumors

Our Solution:

MSI-H and dMMR status testing by our MSI-H/dMMR or

OncoGx gene panels.

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Metagenomics of cancer

patient stools revealed

correlations between clinical

responses to ICI.

Routy B. et al. Science. 2017 Nov 2. pii: eaan3706. doi: 10.1126/science.aan3706.

Our Solution:

Gut microbiome analysis by metagenomics

or our FloraCheck™ assay.

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A peptide signature from the candidate neoepitopes is generated. This set of neoepitopes

defines a signature linked to a benefit from CTLA-4 blockade.

Snyder, A. et al. N. Engl. J. Med. 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).

Our Solution:

Neoantigen signature analysis by WES (whole exome sequencing),

RNA seq, MHC binding prediction and bioinformatics analysis

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Highlighted Service II

Neoantigen Identification & Clinical Applications

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Ton N. Schumacher, Robert D. Schreiber Science 03 Apr 2015: Vol. 348, Issue 6230, pp. 69-74

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H. Hackl, et al. Nature Reviews Genetics 17, 441–458 (2016)

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• Whole-exome sequencing (WES) - identified neoantigen

• RNA-seq - Validate and assess the expression of neoantigen

• HLA binding - predict

• Vaccine synthesize and administration

At a median of 25 months after vaccination

4 patients: no disease recurrence

2 patients with lung metastases: disease recurrence

ICI treatment

complete responses

Ott PA et al. Nature. 2017 Jul 13;547(7662):217-221..

Clinical Application

ConfidentialHinrichs CS. et al. Immunol Rev. 2014 Jan; 257(1): 56–71

Clinical Application

Tumor

Normal TissueWES

RNA Seq

Non-synonymous Mutation

Expression ConfirmHLA Typing

MHC Binding Neoantigen

T-cell Activation

Reintroduce to Patient

TCR Clone/Construct

T-cell Expression

Transfect to T-cell

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Confidential 24

CAR generation 1st 2nd 3rd

Chronology 1989 2002 2009

Li H et al,2017, PMID: 28434147

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Clinical trial 1

63 r/r B-cell ALL

(3-21 yrs old)

Clinical trial 2

101 NHL

(77 DLBCL + 24 TFL/PMBCL)]

CR: complete remission; ORR: objective response rate; NHL: Non-Hodgkin's Lymphoma;

DLBCL: Diffuse Large B-Cell Lymphoma; TFL: transformed follicular lymphoma;

PMBCL: Primary Mediastinal Large B-Cell Lymphoma

Data from public news release

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Clinical Trial 1

63 patients with r/r B-cell ALL

(3-21 yrs old)

Clinical Trial 2

101 patients with NHL

(77 DLBCL + 24 TFL/PMBCL)

CR: complete remission; ORR: objective response rate; CRS: cytokine release syndrome

ALL: Acute Lymphoblastic Leukemia; NHL: Non-Hodgkin's Lymphoma;

DLBCL: Diffuse Large B-Cell Lymphoma; TFL: transformed follicular lymphoma;

PMBCL: Primary Mediastinal Large B-Cell Lymphoma;

Data from public news release

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ON-switch OFF-switch

Li H et al,2017, PMID: 28434147

Dose tuning to reduce CRS and avoid long-term B-cell aplasia while maintaining CAR-T

efficacy (PMID: 26759369; 26759368).

Tagged Ab

Tumor cell

Y

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• Limited options of the split proteins with the capability of

chemical induced dimerization (CID)

• The function of tagged antibodies may be affected by the

tagging position, tagging efficiency and tissue penetration

• The construct is too large to allow multi-layer T-cell

engineering

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ON-Switch ( Turn on CAR by a ligand)

OFF-Switch ( Turn off CAR by a ligand)

AAACAR

AAACAR

AAACAR

AAACAR

Aptazyme-ligand as a switch Potential Advantages

• Control CAR expression at mRNA level, no cell

stress due to constitutive overexpression of

CAR components.

• Aptazymes may be developed against

intracellular and external ligands, allowing

multiple layers of control.

• Aptazyme is small (~100 nt), allowing multiple

layer engineering of CAR constructs.

Aptazyme = Aptamer + Ribozyme

↑

Ligand

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• Admera Health is an advanced life science company focused on personalized

medicine, non-invasive cancer testing, immuno-oncology solution, and digital

health.

• A CLIA- & CLEP- certified and CAP-accredited lab

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For more information, please contact:

Dr. Jun T. Huang

126 Corporate Blvd.

South Plainfield, NJ 07080

908-222-0533 ext. 3443

844-4ADMERA

Web: www.admerahealth.com

Email: BiopharmaSolutions@admerahealth.com