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L-DOS47L-DOS47A phase I/II lung cancer candidate
that uses tumour alkalization as a
therapeutic approach
Safe Harbor Statement
This presentation contains certain forward-looking statements and information
(collectively, “forward-looking statements”), regarding the development of our
new drug candidate, L-DOS47, and include statements regarding our planned
Phase I/II programs and submission of a European study for regulatory approval.
Certain material assumptions have been made in making these forward-looking
statements, including successful and timely completion of pre-regulatory
submission activities; receipt, on a timely basis of all regulatory approvals and
appropriate financing; and sufficient patient enrolment. These forward-looking
This presentation contains certain forward-looking statements and information
(collectively, “forward-looking statements”), regarding the development of our
new drug candidate, L-DOS47, and include statements regarding our planned
Phase I/II programs and submission of a European study for regulatory approval.
Certain material assumptions have been made in making these forward-looking
statements, including successful and timely completion of pre-regulatory
submission activities; receipt, on a timely basis of all regulatory approvals and
appropriate financing; and sufficient patient enrolment. These forward-lookingappropriate financing; and sufficient patient enrolment. These forward-looking
statements are subject to risks and uncertainties that may cause actual events or
results to differ materially from such statements, including without limitation, our
need for further financing, which may not be available; the delay or denial of
regulatory approvals needed; that future events, including patient enrolment,
may not proceed or be completed as planned or within expected timelines; and
that the planned studies may not be completed or achieve expected results.
appropriate financing; and sufficient patient enrolment. These forward-looking
statements are subject to risks and uncertainties that may cause actual events or
results to differ materially from such statements, including without limitation, our
need for further financing, which may not be available; the delay or denial of
regulatory approvals needed; that future events, including patient enrolment,
may not proceed or be completed as planned or within expected timelines; and
that the planned studies may not be completed or achieve expected results.
Tumour Microenvironment
Robert A. Gatenby and Robert J. Gillies
Nature Reviews Cancer 4:891 2004
License:2601421317277
Acidic and Hypoxic Environment
Robert A. Gatenby and Robert J. Gillies
Nature Reviews Cancer 4:891 2004
License:2601421317277
Acidosis and Hypoxia
�Increase radio-resistance
�Resistance to chemotherapeutics
�Increase metastases
�Increase migration and invasion
DOS47 – Proposed MOA
�Reverse Tumour Acidity
�Apply Natural Metabolic Toxin
�Induce Chemo-optimized Environment
Urea 2NH4+ + OH- + HCO3
-
3H2O
Urease
Effects of pH on cell survival
60
80
100
% S
urvi
val
7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.50
20
40A549MB231
pH
% S
urvi
val
2h @ 37oC
pH and Ammonium
NH4+ + OH-H2O + NH3
Ammonia Ammonium
75
100
125pH 7.4
pH 8.4
pH 9.0
pH 9.6
% S
urvi
val
A549
0 10 20 30 40 50 60 70
0
25
50
75 pH 9.6
pH 10.0
[NH4Cl] mM
% S
urvi
val
DOS47- Cell Proliferation Inhibition
40
60
80
100
8.6
8.8
9.0
pH
% C
ell P
rolif
erat
ion
Inhi
bitio
n
0 50 100 150 200
0
20
40
% Inhibition
pH
8.0
8.2
8.4
% C
ell P
rolif
erat
ion
Inhi
bitio
n
[Urea] mM
DOS47 Activity Inhibition
60
80
100
% S
urvi
val
Acetohydroxamic acid (AHA)
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
20
40No Urea
5 mM Urea
25 mM Urea
25 mM Urea (no DOS47)
[AHA] mM
% S
urvi
val
acid (AHA)
DOS47 MCF7 and A549 Xenograft
MCF-7
A549
Journal of Experimental Therapeutics and Oncology
(volume 5, number 2, pp. 93-99) – DOS47
Antigen Identification
(kDa)
10377
50
1 2 3 1 2 3
1 = total protein
2 = soluble protein
3 = hydrophobic protein
50
34
29
21 +ES1 -ES1
2nd Ab = rabbit anti-VT1B
3rd Ab = goat anti-rabbit AP
Antigen Identification by MS
carcinoembryonic antigen related cell adhesion molecule 6
(CEACAM6), 344 aa, MW = 37,159. Peptides shown in red.
MGPPSAPPCRLHVPWKEVLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLAHNLPQNRIGYSWYKGERVDGNSLIVGYVIGTQQATPGPAYSGRETIYPNASLLIQHNLPQNRIGYSWYKGERVDGNSLIVGYVIGTQQATPGPAYSGRETIYPNASLLIQNVTQNDTGFYTLQVIKSDLVNEEATGQLHVYPELPKPSISSNNSNPVEDKDAVAFTCEPEVQNTTYLWWVNGQSLPVSPRLQLSNGNMTLTLLSVKRNDAGSYECEIQNPASANRSDPVTLNVLYGPDGPTISPSKANYRPGENLNLSCHAASNPPAQYSWFINGTFQQSTQELFIPNITVNNSGSYMCQAHNSATGLNRTTVTMITVSGSAPVLSAVATVGITIGVLARVALI
L-DOS47 Imaging
Tumour specific localization
Full Body ScanA549 tumour (8 x 7 mm)
L-DOS47-Cy5.5
Filtered ScanL-DOS47-Cy5.5
Cy5.5 emission max @710nm
L-DOS47 Imaging
80
100
120
No
rma
lize
d F
luo
resc
en
ce I
nte
nsi
ty
12hrs
24hrs
48hrs
72 hrs
0
20
40
60
Time post injection (hours)
No
rma
lize
d F
luo
resc
en
ce I
nte
nsi
ty
72 hrs
L-DOS47 A549 Xenograft
200
250
300
350VehicleCisplatinL-DOS47 (35U/kg)L-DOS47 (20U/kg)
%C
hang
e in
Tum
our
Volu
me
0 5 10 15 20
0
50
100
150
200 L-DOS47 (20U/kg)L-DOS47 (10U/kg)
Days
%C
hang
e in
Tum
our
Volu
me
Human Cancer Tissue Screening
Positive Negative NegativeKidney carcinoma 12/12 12/12Parathyroid adenoma 1/1 n/a
Plaenta, umbilical cord, allantois 1/1Myofibroblastic tumor 1/1 n/a
Prostate carcinoma 4/4 4/4Thyroid carcinoma 2/2 2/2
7/57 weak8/57 v. weak
Neuroendocrine tumors 9/9 n/a
Brain, heart muscle, testis, spleen 30/30n/a
Samples
Pancreas adenocarcinoma 42/57
Age-matched Normal Tissue
Tumour Tissue
n/a
25/25
Brain, heart muscle, testis, spleen 30/30Testis - teratoma and seminoma 3/3 3/3Parotis tumor 1/1 1/1Cervix squamous carcinoma 2/2 n/a
Thymoma 2/2 n/a
Colon adenocarcinoma 14/24 weak 10/24- lymph node metastasis 3/3
Breast adenocarcinoma 13/13- lymph node metastasis 2/2
Leiomoma - lung metastasis 1/1 n/a
Ovary carcinoma 4/4 n/a
Bladder carcinoma 42/42- lymph node metastasis 1/1 strong- squamous carcinoma metastasis 2/2
Lung - small cell carcinoma 1/1- adenocarcinoma 5/5 strong
Stomach adenocarcinoma 3/3 3/3Liver carcinoma 4/4 4/4Soft tissue tumors 3/3 n/a
Melanoma 48/48- metastasis 18/18
18/18
36/36
24/24
13/13
5/5
Weakly Basic Drug
Mitoxantrone pKa 8.13 Doxorubcin pKa 8.34
Vinblastine pKa 7.4
Vincristine
Vinorelbine
Effect of pH on Drug’s Efficacy
A549 cells
doxorubicin (100 µM), mitoxantrone (75 µM), and vinblastine (150 µM)
Effect of L-DOS47 and Vinorelbine on A549
Vi
% V
iabl
e C
ance
r C
ell
Vinorelbine only
Vinorelbine + L-DOS47
Vinorelbine (µM)
% V
iabl
e C
ance
r C
ell
L-DOS47 Phase I/II Program
� Helix plans to conduct a comprehensive Phase I/II program
� Two parallel, open-label studies are under consideration:
� U.S. Phase I safety study in refractory solid tumours
� European, multi-arm, Phase I/II safety/efficacy study in patients with
Stage III/IV NSCLCStage III/IV NSCLC
� L-DOS47 monotherapy
� L-DOS47 adjunct chemotherapy/radiation therapy regimens
� US Phase I study has been approved by the FDA
� European study to be submitted and subject to regulatory approval
Summary
�A different approach to cancer therapy� Targeting tumour microenvironment
�Specific for lung adenocarcinoma� Unique antibody � Unique antibody � Specific binding to lung cancer tissue
�Clinical program underway� US Phase I recently approved� European Phase I/II planned
Acknowledgement
�Helix BioPharma Corp
�Wah Wong, Carl De Luca, Baomin Tian, Kim Gaspar, Iain Wilson, Sharon Molund, Terri Hinkley, Jill Chapman, Axel Wellmann, John Docherty and Don SegalSegal
�National Research Council of Canada
�Institute of Biological Sciences
�Roger MacKenzie, Jianbing Zhang
�Institute for Bio-diagnostics
�Elda Hegmann, Mike Sowa