UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): May 14, 2015
AGENUS INC.
(Exact name of registrant as specified in its charter)
DELAWARE | 000-29089 | 06-1562417 | ||
(State or other jurisdiction of incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
3 Forbes Road Lexington, MA |
02421 | |
(Address of principal executive offices) | (Zip Code) |
Registrants telephone number, including area code: 781-674-4400
N/A
(Former name or former address, if changed since last report.)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
¨ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
¨ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
¨ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
¨ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Item 7.01 | Regulation FD Disclosure. |
Agenus Inc. (Agenus) is presenting a corporate slide presentation on May 14, 2015 at its Research and Development Day event in New York City. A copy of this slide presentation, dated May 14, 2015, is attached as Exhibit 99.1 to this Current Report on Form 8-K.
The information responsive to Item 7.01 of this Form 8-K and Exhibit 99.1 hereto shall not be deemed filed for purposes of Section 18 of the Securities Exchange Act of 1934 (the Exchange Act) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933 or the Exchange Act, except as expressly set forth by specific reference in such a filing.
Item 8.01 | Other Events. |
On May 14, 2015, Agenus issued a press release titled, Agenus Announces Oral Presentation at ASCO Highlighting Improved Survival with Prophage Immunotherapy in Brain Cancer Compared to Historical Controls (the Press Release). A copy of the Press Release is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
Exhibit |
Description of Exhibit | |
99.1 | Presentation dated May 14, 2015. | |
99.2 | Press Release dated May 14, 2015. |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
Date: May 14, 2015 | AGENUS INC. | |||||
By: | /s/ Christine M. Klaskin | |||||
Christine M. Klaskin | ||||||
VP, Finance |
EXHIBIT INDEX
Exhibit |
Description of Exhibit | |
99.1 | Presentation dated May 14, 2015. | |
99.2 | Press Release dated May 14, 2015. |
Exhibit 99.1
|
Agenus R&D Day May 14th 2015
Driving the immune a system to fight cancer and infectious disease
|
Note Regarding Forward-Looking Statements
This presentation contains forward-looking statements. These forward-looking statements are subject to risks and uncertainties, including the factors described under the Risk Factors section of our Quarterly Report on form 10-Q filed with the Securities and Exchange Commission on May 1, 2015 and made available on our website at www.agenusbio.com. When evaluating Agenus business and prospects, careful consideration should be given to these risks and uncertainties. These statements speak only as of the date of this presentation, and Agenus undertakes no obligation to update or revise these statements. This presentation and the information contained herein do not constitute an offer or solicitation of an offer for sale of any securities.
2 |
|
|
Introduction Garo Armen, PhD
Immuno-Oncology Overview Bob Stein, MD, PhD
Tumor Recognition John Castle, PhD
Glioblastoma (GBM) Orin Bloch, MDNW U
Agenus / 4-Antibody Robert Burns, PhD
Monoclonal Antibodies Marc van Dijk, PhD
Checkpoint Modulators (CPMs) Nicholas Wilson, PhD
Combination Immunotherapy Charles Drake, MDJHU
Science Wrap-up Bob Stein, MD, PhD
Discussion Q&A All
Closing Remarks Garo Armen, PhD
|
Three Synergistic Immune-Modulating Platform
Poised to Create Best-in-Class Immunotherapies
+ Ph 2 in ndGBM
+ Ph 2 w HerpV
Heat Shock Protein-Based Vaccines
QS-21 Checkpoint Stimulon® Modulators
+ Ph 3 Malaria Adjuvant (CPMs)
+ Ph 3 Shingles
4 |
|
|
Merck/Agenus CPM Collaboration: Focus on Oncology
Established April 2014
Uses Agenus monoclonal antibody platform
Two undisclosed targets
Financial considerations
Merck pays all R&D costs
Up to $100 MM milestones per successful compound Mid-single digit royalties
5 |
|
|
Incyte/Agenus Immuno-Oncology Collaboration
Established February 2015 Initial focus on 4 CPM targets:
GITR and OX40 agonists
TIM-3 and LAG-3 antagonists
Financial considerations
$60M upfront (with equity investment) Up to $350M in milestones for lead programs
Royalty bearing products (TIM-3, LAG-3): 6%-12% royalty rate 50:50 cost and profit share programs (GITR, OX40)
6 |
|
|
Agenus Pipeline
Partnered Not Partnered
7 |
|
|
QS-21 Stimulon® Saponin Adjuvant
Generates strong antibody and cell-mediated immune responses Safe & well tolerated in >50,000 people
8 |
|
|
Robust Phase 3 Results with Shingles Vaccine
GSK Merck
Efficacy: 97% 50-70%
1 |
|
out of 3 people will get shingles in their lifetime |
Target population: 370M
9
|
R&D Day
Introduction Garo Armen, PhD
Immuno-Oncology Overview Bob Stein, MD, PhD
Tumor Recognition John Castle, PhD
Glioblastoma (GBM) Orin Bloch, MDNW U
Agenus / 4-Antibody Robert Burns, PhD
Monoclonal Antibodies Marc van Dijk, PhD
Checkpoint Modulators (CPMs) Nicholas Wilson, PhD
Combination Immunotherapy Charles Drake, MDJHU
Science Wrap-up Bob Stein, MD, PhD
Discussion Q&A All
Closing Remarks Garo Armen, PhD
|
The Immune System defends from enemies from without
11
|
The Immune System defends from enemies from without & within
12
|
Immunological Surveillance
Macfarland Burnet (1957): It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provide an effective immunological reaction with regression of this tumor and no clinical hint of its existence.
13
|
Accumulated Mutations Drive Cancers
Various carcinogens (sun, smoke, gamma
Approximately 1% rays, etc.) of mutations produce stochastic produce mutant mutations proteins (<0.03% of genome)
A handful hit growth- A fraction of these related genes, driving produce potential T-cell malignancy neo-epitopes potential (5-10) basis for immune rejection (1-20+)
14
|
Cancer- In Limbo between Self & Non-Self
Mutational Heterogeneity in Cancer
Taking off brakes may be enough
May need agonists, Unclear how widely vaccines, adjuvants, etc.
Immuno-Rx will work
Lawrence MS et al. Nature 2013; 499: 214-18
100 mutations per Mbase = 0.01% of genome
15
|
Agenus R&D Day
Heat-Shock-Protein (HSP)-based Vaccines
A strategy for Tumor-Specific Immuno-education
Pre-Clinical Overview
|
The Immune System Can Defeat Cancer
The Observations that led to Agenus
TUMOR A TUMOR A or B CELLS INJECTED CELLS INJECTED
Tumor mass is resected
from mouse Mouse cured of tumor A immune to tumor A
Naïve mouse Mouse forms Mouse Cured tumor mass Of Tumor A
Mouse cured of
Requires immune system tumor A NOT
immune
Requires T Cells & NK Cells to tumor B
Mouse Cured
Of Tumor A
Adapted from Srivastava 2002 Ann Rev Immunol 20:395
17
|
Immunity is Individually Tumor Specific
10 different methylcolanthrene-induced murine fibrosarcomas
Tumors Used to Immunize
A BB C C D D E E FF G H H I I J A A + -
e
ng B B+
l e C
C + -
al
Ch D D + to E E + -Used F F +
G
rs G +
o H
m H +
u
T II + -J J +
Basombrio 1970 Cancer Res. 30:2458
18
|
Heat Shock Protein Fractions Confer Immunity
hsp70 hsp90 hsp110 gp96 grp170
CRT
Tumor cell Proteins liberated Proteins tested in Heat Shock Proteins (HSP) from tumor cell tumor rejection assays elicit anti-cancer immunity
Tumor
Rx Rx
Challenge
Tumor DAY 0 7 14 size
MONITOR TUMOR GROWTH Days post tumor
challenge
19
|
Heat Shock Proteins (HSPs)
Quality Control for the Intracellular Proteome
Cellular Peptides Chaperoning by HSPs
Mutated / Normal
Abundant class of intracellular proteins Constantly sample intracellular proteome Sense and manage misfolded proteins Natural role in immune recognition of damaged cells, non-self antigens
20
|
Prophage Mechanism of Action
Cell
D8+ T Cell
IL-12 NK Cell
TNF? MCP-1 IL-1?
MIP-1á
GM-CSF
RANTES NO
Modified from
21
|
Heat-Shock-Protein (HSP)-based Vaccines
Personalized Immuno-education
Clinical Overview
Agenus R&D Day
|
Prophage confers tumor-specific immunity
Tumor Heat Shock Protein bound tumor antigens
Prophage
Intradermal injection
23
|
Prophage: Sporadic Efficacy in Previous Studies
Patient remains disease-free at 10+ years
Before 16 Months 32 Months Prophage Post-Treatment Post-Treatment
Belli F et al., J Clin Oncol 2002;20:4169-4180
24
|
Prophage Clinical Summary
Autologous Cancer Vaccine Practical logistics Cost-effective manufacture Pharmaceutically tractable Well-tolerated
Promising efficacy signal in newly diagnosed GBM Phase 3 ready program with near-term registration opportunity Potential synergy with CPMs
25
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD
Tumor Recognition John Castle, PhD
Glioblastoma (GBM) Orin Bloch, MDNW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherapy Charles Drake, MDJHU Science Wrap-up Bob Stein, MD, PhD Discussion Q&A All Closing Remarks Garo Armen, PhD
|
Agenus R&D Day
Immunological Recognition and Rejection of Tumors
The genetic basis of patient-specific immunity
|
Next-Generation Sequencing (NGS)
Tumor DNA sequence data
28
|
Next-Generation Sequencing (NGS)
Tumor DNA sequence data
Terabytes of data
29
|
Next-Generation Sequencing (NGS)
Tumor DNA sequence data
Terabytes of data
EFKHIKAFDRTFANNPGPMVVFATPGM Protein-changing EFKHIKAFDRTFADNPGPMVVFATPGM mutations
30
|
Genome Sequencing Costs Have Plummeted!
The first human genome cost $3 billion and took 10 years. A genome can now be sequenced in one week for $3 thousand
31
|
We Can Now Determine Tumor Genomes
Reoccurring tumor mutation
Genes Patient tumors
Each dot is a tumor mutation
Patient-specific tumor mutations
PJ Stephens et al. Nature, 1-5 (2012)
32
|
Tumors Typically Have 10 To 500 Protein-changing Mutations
a m a e o m l l b a l l c o e m r n c o e a i h i o l c s c s p l l y o k r u og e r n c a o e c a a l i e c m r m l l a c o m o d i i rn n a r a a o p r a a h r l e t a t c s l d h e u d g n t e l s e a a n c r d q m i tc ac ap e e m a e a s o o s l r i a t a n l l l m n r n u i c a d n r a a e r s e a b a o r i c o t v d m g g a L y n w a r n o n d n l c r a d n n l M r e e v o d e l i e t e o e e e o l a e h o r n a t u u A T B R L O P A R G R E U P C R C H S B L L M
1000
750
Mutated Mutated
500
proteins proteins
250
0
9 14 28 29 33 39 39 43 47 51 52 52 57 67 73 78 92 99 123 163 183 215 266
Median per tumor
J. Castle, Agenus proprietary analysis of TCGA tumor profiles
33
|
Tumor Mutations
Tumors typically have between 10 and 500 protein mutations Over 98% mutations are unique to the specific tumor
DNA Tumor cells mutations
34
|
Tumor Mutations
Tumors typically have between 10 and 500 protein mutations Over 98% mutations are unique to the specific tumor
Identify immunogenic mutations
DNA Tumor cells mutations
35
|
How Can The Immune System See Mutations?
Many challenges to become an effective neo-antigen
DNA mutation in protein Transcribed to RNA Translated to protein Processed by proteasomes Transported to the ER Loaded onto MHCs (must fit) Transported to the cell surface
Stay on patients MHCs Be sufficiently non-self
Be recognized by a TCR that has not been deleted or tolerized
36
|
Cells Displaying Neo-antigens Recognized as Non-self by CD8+ T Cells Can Be Destroyed
37
|
Immunogenic Mutations in Patients
GBM patient 020-002 GBM patient 020-006
HLA types HLA types
HLA-A*02:01 HLA-A*29:02 HLA-B*35:03 HLA-B*44:03 HLA-C*16:01
HLA-A*01:01 HLA-A*68:01 HLA-B*37:01 HLA-B*51:01 HLA-C*06:02 HLA-C*15:02
Mutations
101 protein mutations
50 expressed
23 HLA presented (immunogenic)
Mutations
127 protein mutations
50 expressed
27 HLA presented (immunogenic)
38
|
Tumors With Many Immunogenic Mutations Respond to Inhibitory CPMs Like anti-PD-1 and anti-CTLA-4
Predict response to CTLA4 & PD1 therapies
Identify immunogenic mutations
DNA Tumor cells mutations
39
|
Tumors With Many Immunogenic Mutations Respond to Inhibitory CPMs Like anti-PD-1 and anti-CTLA-4
Predict response to CTLA4 & PD1 therapies
Identify immunogenic mutations
DNA Tumor cells mutations
|
Mutant Protein Vaccination For Patients With Fewer Immunogenic Mutations
Predict response Use mutant to CTLA4 & PD1
proteins for therapies vaccination
Identify immunogenic muteins
DNA Tumor cells mutations
41
|
Mutant Peptide Vaccination
Melanoma 563 expressed 50 of 50 B16F10 cells missense confirmed mutations
Exploiting the Mutanome for Tumor Vaccination Castle et al., 2013
42
|
Mutant Peptide Vaccination
Melanoma 563 expressed 50 of 50 Immunize with B16F10 cells missense confirmed mutation peptide mutations
Exploiting the Mutanome for Tumor Vaccination Castle et al., 2013
43
|
Mutant Peptide Vaccination
ELISPOT Wild type & mutated
16 of 50 mutations immunogenic
Melanoma 563 expressed 50 of 50 Immunize with B16F10 cells missense confirmed mutation peptide mutations
Exploiting the Mutanome for Tumor Vaccination
Castle et al., 2013
44
|
Mutant Peptide Vaccination
ELISPOT Wild type & mutated
16 of 50 mutations immunogenic
Melanoma 563 expressed 50 of 50 Immunize with B16F10 cells missense confirmed mutation peptide
mutations Tumor challenge
40% mice survive
Exploiting the Mutanome for Tumor Vaccination
Castle et al., 2013
45
|
Humans and Tumors Are Unique
The immune system recognizes mutated proteins
Tumors harbor a unique set of mutations
Mutated proteins are recognized by HSPs
Prophage vaccines target tumor- and patient-specific mutations
46
|
HSP-based Vaccines Target Multiple Mutations And Function As Personalized, Patient-specific Immunotherapies
Prophage
Patient individualized tumor vaccine
Purify heat-shock proteins (HSPs) complexed with muteins
47
|
Benefits
Prophage inherently captures the individuality of tumors and patients
By understanding the process, we:
Identify patients who will respond to our therapies Enable immuno-monitoring of patients in our clinical trials Can synthesize fully recombinant individualized vaccines
Identify immunogenic mutations
DNA Tumor cells mutations
48
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MDNW U
Agenus / 4-Antibody Robert Burns, PhD
Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherapy Charles Drake, MDJHU Science Wrap-up Bob Stein, MD, PhD Discussion Q&A All Closing Remarks Garo Armen, PhD
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MDNW U Agenus / 4-Antibody Robert Burns, PhD
Monoclonal Antibodies Marc van Dijk, PhD
Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherapy Charles Drake, MDJHU Science Wrap-up Bob Stein, MD, PhD Discussion Q&A All Closing Remarks Garo Armen, PhD
|
Agenus Integrated Antibody Discovery Dedicated to Making Best in Class Antibody Drugs
Target Retrocyte Display Yeast Display (SECANT®) Phage Display
Fully human repertoire Display of full length IgG through ScFv or Fab format binding displayed on mouse pre-B cells biotin attachment Massive diversity >1010
109 Antibody library 5x109 Antibody library Differentiated screening options
Fc-engineering Computational Biology
Effector Modulation of effector functions Bioinformatics
Functions DuoBody® bi-specific technology Integrating structure and function data to understand MOA; Structure-guided optimization; Epitope analysis
Immuno-Biology Development
MOA / Immunological assays can Expertise be leveraged across Extensive internal Product multiple TAs to and used to development expertise determine appropriate isotype formats for product development
Currently accessed through CRO
Key components profiled
51
|
Key Components Retrocyte Display
Retroviral transduction of human heavy and light chain antibody genes
huIgG VH
á
â Ig
Ig -Ig Igá â
Mouse pre-B cells huIgG
Multi- Top Leads VL Natural folding, parameter pairing, and Fully human high screening anchoring diversity stable methods antibody libraries
Iterations to identify high quality lead
52
|
Key Components SECANT® Yeast Display
Biotinylated antibody is secreted and captured by the avidin on the surface of the same cell
Biotin Ligase
53
|
Key Components SECANT® Yeast Display
A library of yeast cells displaying captured antibodies is exposed to fluorescently labeled target antigen. Yeast cells displaying an antibody recognizing the target are isolated by FACS
Multiple parameter
FACS selection
54
|
Key Components SECANT® Yeast Display
After selection by FACS the isolated yeast cell will continue to grow, causing avidin to progressively disappear and antibody to be released into the medium
Biotin Ligase
55
|
Key Components Phage Display
Phage Display Highlights
Use of VH and VL gene repertoires in well-established Workhorse technology phage-display screening cycle Very large libraries to provide maximum diversity
Flexible selection conditions (pH, temperature)
Primary utility generation of hit panel
ScFv or Fab format
Currently accessed through CRO
56
|
Key Components Bi-specific Format
Mix & screen technology, product-ready format
Single-point mutant, homodimeric formats expressed and mixed under permissive conditions allows recombination into bi-specific formats with high efficiency
Application
combinations are key in immuno-oncology Generates new MoA
Next generation compounds
57
|
Modular Platform Components Interchangeable and Complementary
Key Antibody Discovery Deployable Agenus Platform Objective Process Steps Components
Lead Retrocyte SECANT® Speed & Phage Display Generation Display Yeast Display Diversity
Retrocyte Efficacy, Lead Fc Engineering Differentiation Display Optimization Developability
Candidate Cell line & CMC
Development Product development Validation
Product Development
58
|
Agenus Integrated Discovery Platform
Retrocyte Display Yeast Display (SECANT®) Phage Display
Fully human repertoire Display of full length IgG through ScFv or Fab format displayed on mouse pre-B cells biotin attachment Massive diversity >1010
109 Antibody library 5x109 Antibody library Differentiated screening options
Fc-engineering Computational Biology
Modulation of effector functions Bioinformatics
DuoBody® bi-specific technology Library design; Integrating structure (Genmab research License) and function data to understand MOA; Structure-guided optimization; Epitope analysis
Immuno-Biology Development
Immunological assays can Expertise be leveraged across Extensive internal multiple TAs to and used to development expertise determine appropriate isotype formats for product development
Currently accessed through CRO
59
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MDNW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD
Checkpoint Modulators (CPMs) Nicholas Wilson, PhD
Combination Immunotherapy Charles Drake, MDJHU Science Wrap-up Bob Stein, MD, PhD Discussion Q&A All Closing Remarks Garo Armen, PhD
|
Targets Across the Spectrum of Tumor Immunity
Equipped to treat a range of human cancers
Modified Chen et al., 2013
*Anti-OX40
*Anti-GITR
*Anti-TIM-3 *Anti-LAG-3
Novel Platforms
Vaccine
Platforms Anti-PD1
Anti-CTLA-4
Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies
61
|
Antibody Discovery at Agenus
Antibody Discovery Platforms Key Filters: Examples:
Target Binding Recombinant proteins, cell lines (over-expressing, endogenous) Species cross-reactivity Human/NHP/rodent Many Hits Target selectivity Related family members
(100s+)
CDR diversity from panning Sequencing (NGS)
Blocking/non-blocking Flow cytometry (cell lines), recombinant proteins (Luminex)
Cross-competition/Affinity Reference antibodies (Flow cytometry
(EC50), affinity (SPR)) Functional evaluation Reporter gene assay(s)
Mechanistic evaluation Primary human/NHP functional assays
Developability assessment Tm, pI, yield, aggregation, IP, immunogenicity risk, PTM evaluation/stress test etc
62
|
Antibodies Are Naturally Bifunctional
Variable region defines interaction with target antigen IgG Fc region dictates half-life, antibody dependent cellular cytotoxicity (ADCC), CDC, phagocytosis (ADCP)
Activating Inhibitory Activating
Modified: Pietersz et al., Nature Review Drug Discovery 2012
63
|
Two Functionally Distinct Classes Of Fc? Receptors: Activating And Inhibitory
Example: Rituxan
Clynes et al., Nat Med 2000
Nimmerjahn and Ravetch Nat. Rev. Imm. 2008
64
|
Inhibitory Fc?RIIB Mediates Receptor Forward Signaling By Anti-TNFR Antibodies
Cross-linking (Forward signaling)
E.g: Anti-CD40/DR5
Wilson NS et al., Cancer Cell, 2011 Li et al., Science 2011 White et al., JI 2011
Nimmerjahn and Ravetch Nat. Rev. Imm. 2008
65
|
Canonical View of GITR Forward Signaling in T Cells
Naïve GITR -L
T cell
GITR expression
upregulated
Initial 24-72 hrs
priming
Activated
mature DC
No GITR
stimulus GITR
Secondary engagement
expansion
Effector phase
Reduced T cell Enhanced effector T cell
expansion/survival expansion/survival
Decreased Increased proinflammatory
cytokine production cytokine production
Adapted from: Current Opinion in Immunology 2012
66
|
Model for GITR Agonist Immunotherapy of Cancer
Cohen & Schaer et al. PloS ONE 2010 May 3;5(5) Schaer et al. Cancer Immunology Research 2013 Nov 5
Schaer, Murphy & Wolchok Current Opinion in Immunology 2012, 24:217224
67
|
Fc? Receptors Contribute To The Activity Of Antibodies Targeting Immune Regulatory Molecules
TNFRs
?
Modified: Mellman et al., Nature 2011 Modified: Pietersz et al., Nature Review Drug Discov 2012
Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies
68
|
Preclinical: Anti-OX40 (OX86) and Anti-GITR (DTA-1) Require Intact Fc?R Interactions to Exert Anti-Tumor Activity In Vivo
Colon26 model Control DTA-1 mIgG2a DTA-1 (N297A)
700 700 700 600 600 600
3 |
|
) |
(mm 500 500 500
Anti-GITR
400 400 400
Volume 300 300 300 200 200 200 100 100 100
0 0 0
0 3 6 9 12151821 0 3 6 9 12151821 0 3 6 9 12151821
Control OX86 mIgG2a OX86 (N297A)
700 700 700 600 600 600
)
3 |
|
500 500 500 |
Anti-OX40 (mm
400 400 400
Volume 300 300 300 200 200 200 100 100 100
0 0 0 Bulliard et al., JEM 2013
0 3 6 9 12151821 0 3 6 9 12151821 Bulliard et al., ICB 2014
0 3 6 9 12151821
Days
69
|
Old Paradigm: Activating Fc?Rs Enhance Cytotoxic Antibodies, Inhibitory Fc?RIIB Facilitates Antibody-Mediated Forward Signaling
Anti-CD20 Anti-CD40 Anti-EGFR Anti-DR4 Anti-Her2 Anti-DR5
Anti-FGFR3 Anti-CD27 Anti-CD19 Anti-CD30
Other Anti-CD95
Modified from: Nimmerjahn F and Ravetch, J Cancer Immunol. 2012
70
|
Activating Fc?Rs Are Required for Anti-tumor Activity of Agonist GITR and OX40 Antibodies
Anti-GITR Anti-OX40 Bulliard et al., JEM 2013
Colon26 tumor model
Bulliard et al., ICB 2014
Control
Wild type
100% CR
|
GITR and OX40 Are Expressed By Multiple Immune Cell Subsets Within The Tumor Microenvironment
Croft et al., Ann. Rev. of Immunol. 2010 Restifo et al., Cancer Res 2012
Cell type GITR OX40
B cells ++ +/- Naive CD4 T cells +Naive CD8 T cells +Regulatory T cells ++++ +++ Activated CD4 T cells +++ ++ Activated CD8 T cells +++ ++ Macrophages +NK cells ++ + NK T cells ++ + DCs (lymphoid/myeloid) -/+Monocytes/Macrophages ++
Granulocytes/Neutrophils+/-
Colon26
Qualitative summary only. Differences in human and mouse expression are not accounted for.
72
|
Intra-Tumoral Regulatory T Cells Express High Levels of GITR and OX40. Antibody Treatment Leads to Depletion
Bulliard et al., JEM 2013 Colon26 model Bulliard et al., ICB 2014
GITR expression OX40 expression
Tregs
Tregs
73
|
Preclinical: Selective Intratumoral Treg Depletion is Rapid, and Requires Fc?R Co-engagement
Colon26 model Kinetics of Tregs depletion (within the tumor)
7.0
Control
CD4+ 6.0 DTA-1 mIgG2a
Tumor
5.0 DTA-1 N297A
FoxP3+ cells 4.0
T
of 3.0
node
2.0 28-fold
Lymph Density 1.0
0.0
0 1 2 3 4 5 6
Days post-treatment
Bulliard et al., JEM 2013
Bulliard et al., ICB 2014
Comparable results obtained with anti-OX40 surrogate antibody (clone OX86)
74
|
Translation to Human Tumors:
Intratumoral Regulatory T Cells Overexpress OX40
Mouse Healthy Donor Tumor Colon tumor model (CT26) PBMCs TILs
Tconv Treg Tconv Treg
A D B E C F
Bulliard Y et al., JEM 2013 Waight et al., Agenus unpublished data
75
|
Antibody Co-Engagement of Fc?Rs Depletes Intra-Tumoral Regulatory T Cells (Examples: GITR & OX40)
GITR & OX40 agonist antibodies deplete intratumoral Tregs Smyth M. et al., ICB 2014 Bulliard Y. et al., ICB 2014 Bulliard Y. et al., JEM 2013 Simpson et al., JEM 2013
Shelby et al., Can. Immunol. Res. 2013
GITR & OX40 agonist
GITR & OX40 agonist antibodies promote antibodies drive Teff Teff resistance to activation/expansion Treg suppression
76
|
Targets Across the Spectrum of Tumor Immunity
Equipped to treat a range of human cancers
Modified Chen et al., 2013
*Anti-OX40 *Anti-GITR
*Anti-TIM-3 *Anti-LAG-3
Novel Platforms
Vaccine
Platforms Anti-PD1
Anti-CTLA-4
Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies
77
|
Clinical Candidate: Anti-GITR Agonist Antibody (Planned IND 2015)
Goal: Differentiated mechanism of action for best-in-class potential
Example: Enhanced poly-functional T cell response by GITR agonism
Donor ID#XXXX Isotype
CD4+ 3% 3% 0% 1% T cells
12% 2%
10% 11% 3% 3% CD8+ T cells
ã
IFN
12% 5%
Reference: Agenus unpublished data
78
|
Clinical Candidate: Anti-OX40 Agonist Antibody (Planned IND 2016)
Goal: Differentiated mechanism of action for best-in-class potential
Example: Anti-OX40 antibody-mediated T cell modulation
n 8 i o nduct 6
I e i n 4 k o Cyt 2 ld o 0 F
y e12 s d p b b u o t y A A n i b o f f e t s e e g n I A a R R o
N Reference: Agenus unpublished data
79
|
Generating High-quality Antibodies is a Great Start Understanding the Target Biology is also Critical (e.g., TIM-3)
Complex biology Preclinical data
?
Days post tumor implantation
Sakuishi K et al. JEM 2010
The complexity is both a challenge and an opportunity!
80
|
Checkpoints The Beginning of Understanding
B7-1/CD80 4-1BB/CD137 TIM3 2B4/CD244/SLAMF4 B7-2/CD86 4-1BB Ligand GAL-9 BLAME/SLAMF8 B7-H1/PD-L1 CD27 CD2 CD2
B7-H2/B7RP1/ICOS-L CD27 Ligand/CD70 CD7 CD2F-10/SLAMF9 B7-H3 CD30 CD53 CD48/SLAMF2 B7-H4 CD30 Ligand CD82/Kai-1 CD58/LFA-3 B7-H5/VISTA CD40 CD90/Thy1 CD84/SLAMF5 CD28 CD40 Ligand CD96 CD229/SLAMF3 ICOS HVEM CD160 CRACC/SLAMF7 PD-L2/B7-DC LIGHT CD200 NTB-A/SLAMF6 PDCD6 DR3 OX-2R (CD200R) SLAM/CD150 B7-H6 TNF-alpha CD300a/LMIR1Integrin alpha 4 beta 1 B7-H7 TNF-beta CRTAM Integrin alpha 4 beta 7/LPAM-1 BTLA (CD272) TNF RII DAP12 TCL1A
KIRs BAFF/BLyS Dectin-1/CLEC7A TCL1B
DNAM-1 (CD226) BAFF R DPPIV/CD26 TIM-1/KIM-1/HAVCR VSIG4 RELT EphB6 TIM-4 CD31 (PECAM-1) TACI HLA-DR TSLP
PILR-? (FDF03)TL1A Ikaros TSLP R
PILR-? TNRFSF25 Integrin alpha 4/CD49d A2AR
SIRP? TIGIT ( WUCAM, Vstm3) Siglec-5 (CD170) RNF125/TRAC-1 CD47 CD155 Siglec-7 (CD328) CD5 LAIR-1 (CD305) CEACAM1 (CD66a) ILT2 MAFA
BT3.1 CD33 ILT4 NKG2A
BT3.2 EP4 (PGE2 receptor) EP2 (PGE2 receptor) NKG2B BT3.3 NKG2D
Over 100 potential checkpoint proteins
AGENUS HAS ADDITIONAL UNDISCLOSED CPM PROGRAMS
81
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MDNW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherapy Charles Drake, MDJHU
Science Wrap-up Bob Stein, MD, PhD
Discussion Q&A All
Closing Remarks Garo Armen, PhD
|
CPM Combinations
83
|
Combination Therapies Likely Key to Success
With CTLA-4 and PD-1 antagonists, different patients respond differently
Differences in responses to each CPM or combo
Differences in time course of response
Reflects mutational burden, in part
Studies with proxy TAAs such as NY-ESO-1 demonstrate heterogeneity of immune education
Implies that patients have different baseline degrees of Immune Education and different degrees and types of mechanisms of effector evasion
Redundancy of Inhibitory CPs suggests need for or benefit from patient-specific combination CPM use
Optimal therapy will tailor combination use of CPMs and potentially vaccines to match needs of individual
84
|
Cancer- In Limbo between Self & Non-Self
Mutational Heterogeneity in Cancer
Taking off brakes may be enough
May need agonists, Unclear how widely vaccines, adjuvants, etc.
Immuno-Rx will work
Lawrence MS et al. Nature 2013; 499: 214-18
100 mutations per Mbase = 0.01% of genome
85
|
Checkpoints and Vaccines Synergize
OX40 agonist and vaccine in mice Vaccine + CTLA-4 inhibitor (ipilimumab) better than either alone in prostate cancer
Jensen et al., 2010 Semin Oncol. 37(5):524-32.
Ipi monotherapy failed in Ph 3 (no stat. sign. vs. placebo)
Importantly: 20% of patients alive at 80 months on
PROSTVAC+ipi 10mg/Kg
Source: 2015 Genitourinary Cancers Symposium, abstract no. 172; Bavarian Nordic press release
86
|
HSPPC-96 + Anti-CTLA-4 Ab in Mouse SM1 Therapy
Set-up gp96 gp96 gp96 gp96 gp96 gp96
Day 0 3 4 6 7 9 10 12 15 18 Monitor
tumor growth
SM1 Tumor Ab Ab Ab Challenge (ID)
Results
SM1 (breast cancer)
Buffer Antibody gp96 Antibody + gp96
(mm) 25 25
0/7 (0%) 1/7 (14%) 1/6 (17%) 6/7 (86%)
20 20
15 15 diameter 10 10
5 |
|
5 tumor 0 0 |
. 0 7 12 16 21 25 28 32 36 0 7 12 16 21 25 28 32 36 0 7 12 16 21 25 28 32 36 0 7 12 16 21 25 28 32 36
Avg
Days post tumor challenge
Agenus data
87
|
Realizing New Optimized Combination Strategies
An armamentarium to tackle a range of human malignancies
Example: PD-1 and CTLA-4 combination Agenus diverse I-O portfolio
Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies
Postow M et al., NEJM 2015 SMIs
88
|
Translational Medicine in Immuno-Oncology
What is the initial pathobiology?
Has the patient seen the tumor as non-self?
What immuno-suppressive mechanisms are blunting recognition of tumor? What checkpoint processes will block tumor killing?
Those already in place and those induced by therapy
What choice of therapy is implied?
What combination of immuno-education strategies and CPMs should we try?
Have we achieved the desired pharmacological effects?
Have our interventions produced their effects?
Will we achieve clinical benefit?
Will the interventions lead to tumor control?
Are we heading toward immune side effects?
Should we alter the clinical intervention?
89
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MDNW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherapy Charles Drake, MDJHU Science Wrap-up Bob Stein, MD, PhD
Discussion Q&A All
Closing Remarks Garo Armen, PhD
|
R&D Day
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MDNW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherapy Charles DrakeMD JHU Science Wrap-up Bob Stein, MD, PhD Discussion Q&A All
Closing Remarks Garo Armen, PhD
|
Three Synergistic Immune-Modulating Platform
Poised to Create Best-in-Class Immunotherapies
+ Ph 2 in ndGBM
+ Ph 2 w HerpV
Heat Shock Protein-Based Vaccines
QS-21
Checkpoint Stimulon® Modulators
+ Ph 3 Malaria Adjuvant (CPMs)
+ Ph 3 Shingles
92
|
Agenus R&D Analysts Day
May 14th. 2015
Driving the immune a system to fight cancer and infectious disease
Exhibit 99.2
Agenus Announces Oral Presentation at ASCO Highlighting Improved Survival
with Prophage Immunotherapy in Brain Cancer Compared to Historical Controls
Improved median Overall Survival and Progression Free Survival observed for Prophage-treated patients with Lower PD-L1 expression on peripheral blood monocytes at baseline
LEXINGTON, MA May 14, 2015 Agenus Inc. (NASDAQ: AGEN), an immunology company developing innovative treatments for cancers and other diseases, today announced that data on continuing survival from a Phase 2 study of its Prophage vaccine in glioblastoma multiforme (GBM) has been selected for an oral presentation at the 2015 ASCO Annual Meeting, to be held May 29 June 2, 2015 in Chicago. The presentation, abstract #2011 entitled Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy, will be presented during the Clinical Science Symposium at 8:48am CST by Orin Bloch, MD, Khatib Professor of Neurological Surgery and Assistant Professor of Neurological Surgery and Neurology at Northwestern University Feinberg School of Medicine.
Study Highlights
| Patients treated with Prophage added to Standard of Care (SOC) showed significantly longer progression free survival and overall survival compared to historical data for patients receiving SOC alone |
| Patients in the study showed a degree of elevation of PD-L1 on their peripheral blood monocytes and in tumor infiltrating macrophages |
| In patients who had less PD-L1 on monocytes at baseline, the median Overall Survival (mOS) was approximately 45 months, with a significant proportion of patients alive without progression for more than 3.5 years |
| In patients who had more PD-L1 on monocytes at baseline, the mOS was 18 months, still better than expected from historical data |
These are impressive results in a disease that has few effective treatments or promising candidates in development, commented Orin Bloch, M.D. Were particularly gratified to observe the very impressive survival data in the half of our patients with lower PD-L1 monocyte expression at baseline. Not only is the median Overall Survival much better than expected, but there is a significant proportion of patients who are living longer than expected without progression. We are also intrigued by the possibility that blocking the PD-1 / PD-L1 axis in conjunction with Prophage in patients with elevated PD-L1 may allow the outcomes observed in the lower PD-L1 group to extend to these patients as well.
Study Details
The Phase 2 single-arm trial enrolled forty-six adult patients newly diagnosed with GBM from eight centers in the U.S. Each patient received standard treatment of surgical resection followed by chemoradiation. Within five weeks of completing radiotherapy, patients received weekly Prophage
injections for four weeks followed by monthly Prophage injections, and adjuvant temozolomide until the depletion of vaccine or tumor progression. Expression of PD-L1 has been shown to be elevated in patients with GBM, and each patient was also evaluated for PD-L1 expression as a predictor of survival.
The primary endpoint of the trial was overall survival. Median progression-free survival in the trial was 17.8 months (95% CI, 11.3 21.6), and median overall survival was 23.8 months (95% CI, 19.8 30.2). This compares to a historical overall survival of 14.8 18.8 months for patients receiving standard of care alone. The vaccine was well-tolerated in the study with no severe adverse events attributed to the treatment.
The median overall survival for patients with high PD-L1 expression (above the median, 54% of monocytes) was 18.0 months (95% CI, 10.0 23.3). Median overall survival for patients with low PD-L1 expression was 44.7 months (95% CI not calculable).
These data continue to impress, and were gratified they were selected by ASCO for an oral presentation, commented Dr. Robert Stein, Chief Scientific Officer of Agenus. Prophage monotherapy, in patients with low PD-L1 expression in peripheral blood monocytes at baseline, appears to show a substantial increase in survival compared to historical controls. Registrational study planning is underway for Prophage, and we will provide further updates later this year.
About Agenus
Agenus is an immunology company developing a series of Checkpoint Modulators for the treatment of patients with cancer, infectious diseases, and other immune disorders, heat shock protein (HSP)-based vaccines, and immune adjuvants. These programs are supported by three synergistic technology platforms. Agenus internal and partnered checkpoint modulator programs target GITR, OX40, CTLA-4, LAG-3, TIM-3, PD-1 and other undisclosed immune-modulatory targets. The companys proprietary discovery engine Retrocyte DisplayTM is used to generate fully human and humanized therapeutic antibody drug candidates. The Retrocyte Display platform uses a high-throughput approach incorporating IgG format human antibody libraries expressed in mammalian B-lineage cells. Agenus recently acquired a powerful yeast antibody display platform termed SECANT, developed by Celexion, LLC. SECANT allows rapid generation of soluble, full-length human antibodies. SECANT and Agenus mammalian antibody display platform have complementary strengths and further bolster Agenus abilities to generate and optimize fully human monoclonal antibodies. Agenus heat shock protein-based vaccines have completed Phase 2 studies in newly diagnosed glioblastoma multiforme, and in the treatment of herpes simplex viral infection; the heat shock protein-based vaccine platform can generate personalized as well as off the shelf products. The companys QS-21 Stimulon® adjuvant platform is extensively partnered with GlaxoSmithKline and with Janssen Sciences Ireland UC and includes several candidates in Phase 2 trials, as well as shingles and malaria vaccines which have successfully completed Phase 3 clinical trials. For more information, please visit www.agenusbio.com, or connect with the company on Facebook, LinkedIn, Twitter and Google+; information that may be important to investors will be routinely posted in these locations.
Forward-Looking Statement
This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding the upcoming presentation at ASCO, the potential application of the Companys product candidate in the remediation of GBM, and
2
potential future clinical trial plans. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or annual report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement.
Contacts:
Media
Brad Miles
BMC Communications
646-513-3125
bmiles@bmccommunications.com
Investors
Andrea Rabney/ Jamie Maarten
Argot Partners
212-600-1902
andrea@argotpartners.com
jamie@argotpartners.com
3
I'Z>BB(!3*X6X7G.X]M1..>&V,BGK>046KPK9%M#[B
MF0=88]=5V?9>;"TFDD$_$QA*5$KT<5VMGZ+,CN9;1%.F>>BG2EHR1,\M5Y?`
M\&Q76>&XS@&$4T3'L2Q"FA4-!306TMQH-=`:)IE!$DNKK[G0UNNJ,W'G5*6L
MS4HS.FN*T/GS@L-[FX_ST-I*3*UAED)Y9$1*<8A95%>C-&KIZDTY8.&DC]"[
MC^Z+6W]V?6J;CWH]2;GQTRG9?!SC"\\HUK+4^/L=ROB;<0GXC1?W&F4E_P!@
MAR_M)3XOV<-TA&D5[O/\E/X@<:%="-19UL`B49%W)2K&J;N2D_B25&@C,OI,
MB^X),?/Z&MN3='PZ_F$:L_;!LK]_^0#&3WBO)*`-&RE9GQ)3Y;;@DI2DOZ\-
M2?1)$DNI[+JC,^A="ZF9]1//N?0C_A?2NI%\/[I_^)B!(\@*T'GWQ?)CRWCI
MFORTIS#2Q_-L4*6@G%PX>4.V%3;E&>[2-MB595+)J:Z]%.IBK(NO88GP3$6U
MGDBS5FU-(YLQ>++R4ZB;U3@O&?=5Y6ZXR_!8C>+X/E-V^U`P_,J),EPZ:#*N
M75)A4.2P&7BCJ1*4TQ+2VE;;AN*4V3-&MYM7DTP7B*Q2>::_;6L,*WUJS,M5
M9JTNSPK8N.2:2U572&423@3VT.1[*IG*:DL,SH;R6Y,5_L<2AYM"R(^G00+#
MGM>X55:VP/#->43]A)I,&Q>BQ&GD6TAN59O5>.UD:I@.6$EIF,U(F*BQ$>XM
M+:"4KJ9)+X`.X```````````````````````````````````````````````
M`````````````````````````````````````````````````````````C(\
MBGDUU%P`QVIBWU5+V#MS,(S\O"-8TL]B!(>@-.'%7DN56KC<@L=QAJ8DVD.^
MT[(ENI6AAM78XI'*;#8WW>LQ/36(GLYZ=W[O[[ZE_++^4KYA?F<\:SXO`)C8
M>3=E?'3=[^U9M6N3+/LXJ4KI:]]-+6TF*TK,6M,1I$Q6Z$Y#^:KR/PE9WJ"T
MU-Q4T7+F2(5=FTG%&92+-+#BVY18P]DD++,FRU4%Q)M+ELQH,`WDJ2EPEI-)
M7\M/#-E6:WC7-/*)XS/T<(C[/I?7?S.^57Y#?RJ[K_\`%_.EO&?/GS&QTQSE
MV^+<5Q8L?5[T9,N":4Q6CMI:;7F)CA$<7/>4[3F\=*>*'(<=Y"\B+GDKL6RY
M$X#>2\ZM*2-CD2!72W7X]?C=-3Q7'41JZM^56OO,R4ZZ^M1DDNA%ML,V#/O_
M`/P^/HCICNC^'7NX?NN+_)9YQ\A^=/SN>&^,?+KP#%Y9\IT\$\1QTV=,ML\S
M,;>TSDR9;>U:\\N[TN5_5I?7CKR/_EPJ?W@4XA\?_IE?5^ZY'_%NG7YQ^69C
ME_\`C\_UK,LJI^']T_\`Q,<#/-^3]/=^F?O?F^VV\RZRZA+C3K:VW6UEU0XV
MM)I<0HCZ]4K09D8PW4M-YZNV!XS><&,YNQ6G.Q.EV$]L?5=D;R&H.8X%(LW4
MVN+NO]3.';P*JU=JY3:R(T+4AY/ M=QCL-16&(S"$MLQVFV66TD24MMM()MM"2+T)*4)(B_8'PYDO;+>V2\ZW
MM,S/KGC+UN*UK$5K$16.3]AHR```````````````````````````````````
M``````````````*X'FWI:[)>17!_&KA+BJC))USCULEE9MO*K+S86MZJP)EQ
M)DI#IPY:^U1>I*Z&+6WX4M*#-SA#E4V.5\$.:K /#CVLVF-*S
MHRSF?&;CC3C,J<^RG
MV)TF?A5U--!'V1)RK"5`6ZKHA#J8Z#/JX0FQ7F)Z8Y2AR4BTQ,OJ\+?-K'Z>
MI=XB[,NXM1).VFW.E+6TE$Q#L#N'E3+W7_S+ZR98L2LUN3:ULS+YGWWF4GWI
M;0K?/2(]N.UC%:=9IV0LA"LG``!K?S$=;9XG\DW'5I;;3H[:!&M9DE)&K#;A
M"2,S^E2E$1?LF`KF>!M24\I-FH4I*5N:(G$VDU$2EFWF^'FOM+KU5V$9&?3X
M"?/[T(J^]"V&($JK]Y]%H/;G'=LE)-:==9HM2",NY*%9-5)2HR^))4IM1%]T
MR%K;^[/K5-Q[T>I--XWNG]1;C%T,CZ:NJ2]#(_4I,TC+T^DC+H8AR_M)3XOV
M<-VQ&D0'^?+'+&;IG0N5,,.+J\>VA>U-B\E"E(8?R7%7%UQNK(NB">71N(3U
M^*C(OB)\'O3ZD6:TUKK'>S+X1]D4.3\0%X#&GL*R36&P-^<=U/B.YMBVTS,TMIQX@^>OS$^![7:>&X=WAC2:WKIV<^J.[NEZ9\NI
MTW%XUYTGZ>4K%(^0WKH`````````````````````````````````````````
M````````````````````````````````````````````````````````````
M``````````````````````"*CRKU>30-2U6QJ_+(&+XQAZ+AG)79:'%.=;*.
MW]GR6UDZAMMIEQA9.*,EJ]2Z$74S'T'^7OQ38X/,M_"MUMOC7S1U1;JB(K%8
MTTF)B====>QT/SUM+Y]E7)%^FL:QR^E6DP?8NUW]H4_(C,MN8GDO%/*,%M,4
MA:E92_)R._M*Q:HD3+I'4NQN---#QLI(S41-].OJ/K[Q+'U>+6V^SCX-:<8F
M-)_A3#QF)PX]IDV]M;;BVO'E&FG=SUU]+J*LGT^[QJV)DV9J:OZ6?G35SAU9
MET1J.UCTG$YTE^DHJDB)#I1G9AQW$]Q*3U^)&)HVU\>;\1EMU8XK.M=.
8/H74A+AMU4C7G'!'DKTW]$K7O"+?S7)CB_J7;+DAM[(+3'&:;
M-VD+2I<7.L86JBRI#J4D7M%,M(*Y;23]?EY#9_`Q3R5Z+S7L6:6ZJQ+:T:-D
M!'D+\L>;:NVC8<;>*=5666P:6RAXYE^?654G)50
7:>R@GEIIG'TD1/G/Q*=+IY"BZDF='`VUA\UE/UNIUC$Y5D^V?J
MEF$Z1]#(Q3I2;9.F>SG]"Q:T13J:_P#AQXXNZ5XJP=@9#$=:SSD#-8V);O3$
M+38,XB3+D;`($E3A$LSD5+SMJ?T^Y:K(_4AMGMU7TCE#&*NE=>V4M`A2````
M````,=;2U3@VY<.M,%V#2,7=!;,FTZA71N9$7U2I$NNF$DWH4QE:"4EQ'J1E
MZ]1R/AGB_B?@VX_%>%9\F#/IIK6?OB=8GZ8X=BIN]CL]_C^%O,=
CA3XUK
M6DW(H'+-V&F1-J8E@2R^:=@K):%J2GH2D]#(OB/A3Q[R!XWX#AR[K=UB,%+6
MTXZS-(G2+3Z9YZ=GV/HO9>.;;=VIBI$]=HCZ].+<(=%
SGI%O\`BK13KQZ"Y>3-AW,V$JIF%J3\W=7MDXW&C-]2(
MW'"-1I02E%M6LVGICFQ:T5C6>2B5R3WYGW)O<&6[FV*XXW;Y6^A5/3H6\JLQ
M?$HJW6\=QBB]TD]U551#,O=21?-25/2%=7'5F.0I6*5Z84[6FTZROZXM_LSC
MO^@JC_5\<<:N1R5/_,'Q^N=8[\UAEUUNG8^RY>[)IWZSGU$*(T$E)>GH.#\Y>?(\;^)BK;^;F9X?7Z'8/"_!9\/QTZH_G*Q$2D
ML8S)KM[3?ZI[TK]%?5):3-1*3T]#+J?_`&=!XM&VQ3FG)I'&9=JKFUC3T.?A
M98E9$CY@R,UH5U-1(Z&E!MH,U%T(DI[C/U]"5ZCC
)[_`'V6^EIX8L<6FN'!2/X./!BBF*E8Y5K';K*DGY#>-;W%?E=L
M?7+=O*OJ"]?1LO$+>Q?5)N)..9U.LIZ(UW)6:G)5O4W$>9#=D*^M*)A+Y]#=
M,B[/L\_XC;UORM'"?7#^BK\JWS=Q_.OY(^$^;;8*;7Q/;5GP_=8L<=.*N?9T
MQTFV&L<*XLN*V++6D<,OK\K<=M,TDPV"1'4VMBM8DR'7SBJZ(:+,Q:
!+M
M4=[7O-6^MJ3["YCMVPW9,X+&J"UK>E9S:7N:1H1FN+JH;XY')*XNZTEM;R
M##SQ%DBT426(8O`0[WH+9X'\N;W^V5U?97]P=.^5ZNZ;MRM&VPIQR%2\`;V^
MT[#CD#A2NUJUJ%M+6B8XJZ%@1M`91,#W%=^*F&>:8<<9H(S!_J&P-'_:O>Z$
MI8E-'[:&-,`I208)2EN7JTU4G"`T`A'IBMMZ71B@G6OD`/VE>1:UKYA_WM!]
M]+S)(Y7$+526P9BQQR-1-E*52B;S!X;HXPMZ1"066L>WUZ=U:9L:DHAZ^9AI
MYP2P;%^HL#7>V^ZGU+.TL*A2#V( OQ.DB_X;FJO(8PPY2W4+;[C/GV])'*`D+@.I
M"2/GNL A_99:_!CD;$A*R9)IL+W^@E.DNR`[WK6Q^=ZP)E
MO+H>AN9(2&R>BKDK.CH`-X0QXJ96K-(_!8V>_N92M0WLB=WD:]O1J'9:G0'F
M%)P#$<,L@P>@_$`MZ"%;A]BO!_/\!@%H7)UWS[`(#:[,ADE725[M"*_AV/''
M).%4BD4$*1.*M9+F`],8$?YJ`I0F"$0=B'KSKR$QT-T?074D#3V?SC
(1D"!M/26L^ID)C>GC+8X%&`)1J#PZ7;/.+T#8O@,`<>WO99RE3$]E=\`
M(IY*I%7FDXK1-JRI;'M)BJO2DC2H`+"D,(C;RSQQ26DW]IJ<9PE!(-;^PL.]
M;U@7D8WILD;*T2%E5:6L[\UM[TTK=%'D:5MCHD*7(%6B%)1*DG2A*>`?P,``
M8?/@0=;\ZP*AV][`^5*+FTXK>R+%4-4\@+7"7%TB;=%)7('YW4V(6Z'Q"/0]
MK86=P63*4.B1H.4"0-H%!Z5-H)RC116]#P,WYHZ\HKK6*R65TU)US@7"7PV-
M3F/R://4,E\*?"B1*--\GC$D1-[HUC/3`$,L8@;*,T`8="^99@0!!<1]I7&5
M@3"I8'!+"D$QE%RNY;1&FZ/5Y.7#3(8KD+K&6A9/%1;%I+!F^0.3*H$A,<1D
M;4)`:5:#I.()NPR&Z_8]RQ1RQ#^L!.@@#K0=
M8$7\Q<&
3N4\=9''
MW1P<'L#TJLMP<7&8A<%3DI4*C4KH-T-*T3H02R4WQ*+T$``ZT$:\O\*<\\?G
M28RE&B9("I,A3LXV^5V--9NT,+`E7+'(J/Q1HD[TY-D<:1+UQAIH4Q035`_C
MLT8_CKP$&J?49Q@-W?E+2QVU$8G*7=6^2&J(/?5NPRI'5Q<3/M<1G02.2UN:
MTZ9>/>]&)R/J3Z!OX!`$&M!T%N9KS'35@22@91)8P<>NYD>CY!3:-$\.[:S1
MIU-8"HRG4'LZ)82A>=-C00$"0*L!P4XM?(&M"WO>P[.8\^5=/;CJ2^)2RK7*
MQJ.135%6SAMZ=B&MCU8#80SR948P$*RV=Q<%3:G"46>H),,(UYV7L._UT'B\
M<]U8_7W#^EW9D6++<@4!?ZUB;V-Z=M-K1%Y.XA
QC7QT,/5L7W;9WB+.S*K1/+,^H3%1H_S"C]'G"/
M-^X1FCC=##!:*]?_`#]S_.T-FQD^VYE/&=J<6./2*W+JLRT38RU.Y`4KDDCS
M;+9(O9&O:Q&'1(CBTOW_`$^0:'H(A:$$WW[