Helix Biopharma Corp. · TSX:HBP
Helix Biopharma — Precision Lung Cancer Summit 2016
36 slides from Helix Biopharma's conference presentation, September 2016
Slide 1: Therapeutic Strategy Against Tumor Acidity Induced Immune-Suppression: L-DOS47
Therapeutic Strategy Against Tumor Acidity Induced Immune- Suppression: L-DOS47 a Clinical Candidate for Lung Cancer Precision Lung Cancer Summit Boston USA Sept 2016
Slide 2: Forward-looking Statements
Forward-looking Statements This presentation document contains certain forward-looking statements and information (collectively, “forward- looking statements”) within the meaning of applicable securities laws. Forward-looking statements are statements and information that are not historical facts bu
Slide 3: The Hallmarks of Cancer
The Hallmarks of Cancer Cell 2011 144, 646-674 3
Slide 4: Metabolic Reprogramming
Metabolic Reprogramming Cancer Cell 2008, 13 472-482 4
Slide 5: Cancer Hallmarks Link to Metabolism
Cancer Hallmarks Link to Metabolism Cancer Cell 2008, 13 472-482 5
Slide 6: Dysregulated pH is Emerging as a Hallmark of Cancer
Dysregulated pH is Emerging as a Hallmark of Cancer 6 Nature Reviews Cancer 11, 671-677 (September 2011)
Slide 7: Cancer cell pH is regulated by a number of mechanisms
Cancer cell pH is regulated by a number of mechanisms • Cancer cells upregulate Glut1 and Glut2 to import glucose for glycolysis • Excess proton and lactate are excreted by monocarboxylate transpoters (MCTs); Na/Proton exchangers (NHEs); and proton pump vacuolar ATPase (V- ATPase) • Other proteins t
Slide 8: Acidosis and Tumor Progression
Acidosis and Tumor Progression Nature Communications 6:8752 2015 8
Slide 9: Low pH and Tumor Invasion
Low pH and Tumor Invasion (A) The Tumor edge has an increased expression of NHE-1 (small thin arrows) and GLUT1 (large arrows), which is indicative of acidification caused by an increase in glycolysis. This is consistent with microenvironmental acidosis observed in vivo leading to subsequent invasio
Slide 10: Lactate Lowers Tumor pH and Polarizes Macrophages
Lactate Lowers Tumor pH and Polarizes Macrophages Macrophages integrate metabolic and environmental signals to promote Tumor growth. Tumor lactate which lower pH polarizes macrophage and up-regulate Arg1. Area within dotted rectangle indicates proposed mechanisms of action. ARG, arginase; HIF, hypox
Slide 11: T Cell Loss of Function from Low pH and Elevated Lactate Level
T Cell Loss of Function from Low pH and Elevated Lactate Level Several factors in the inflammatory microenvironment (e.g., oxygen concentration, pH, lactate, fatty acids and ROS) can influence the function of T cells and other immune cells on a number of levels and determine the outcomes of the Am J
Slide 12: T Cell Loss of Function from Low pH
T Cell Loss of Function from Low pH CD8+ T cells isolated from pmel mice transgenically express a TCR specific for the melanocyte-associated peptide, Gp100(25-33) while remain viable in low pH, has lower IFNg secretion upon stimulation (A,B). The effect can be reversed by re-stimulation in higher pH
Slide 13: Acidity Affects Adoptive T cell Therapy
Acidity Affects Adoptive T cell Therapy Effect of bicarbonate on adoptive T-cell transfer. A, Tumor growth after adoptive transfer of T cells or controls in combination with or without buffer therapy. Group mean differences between T cells vs. T cells vs bicarbonate were not significant. However, the
Slide 14: Tumor pH and Check-Point Inhibitors
Tumor pH and Check-Point Inhibitors Buffer therapy enhances efficacy of anti-immunotherapy in B16 melanoma. C57BL/6 14 Cancer Res; 76(6) March 15, 2016
Slide 15: Therapeutic Strategy Against Acidosis
Therapeutic Strategy Against Acidosis • Inhibitors (small molecules or antibodies) to target: – Carbonic anhydrase isoforms – V-ATPase inhibitors and proton pump inhibitors – Na+/HCO3− co-transporters, anion exchangers and Na+/H+ exchanger 1 – Monocarboxylate transporter inhibitors • Targeting a spe
Slide 16: DOS47: Targeting the Tumor Acidic Barrier
Targeting the Tumor Acidic Barrier DOS47 16
Slide 17: DOS47
DOS47 • DOS47 is a technology that changes the Tumor microenvironment from acidic to alkaline using the enzyme ‘urease’ • Alkalinizing the Tumor has the potential to – To exert direct cytotoxic effect on Tumors – to increase the action of certain chemo-therapies – to correct an impaired immune micro
Slide 18: L-DOS47: Helix First Clinical Drug Candidate
Helix First Clinical Drug Candidate L-DOS47 18
Slide 19: L-DOS47
L-DOS47 • L-DOS47 is a conjugate of urease with a proprietary camelid single domain antibody specific for CEACAM6 • CEACAM6 is a cell surface Tumor antigen highly expressed on lung, colon, pancreatic and other cancer cells • L-DOS47 is in clinical studies for the treatment of non- squamous, non-smal
Slide 20: L-DOS47 – Dual Function
L-DOS47 – Dual Function Antigen: CEACAM6 Enzyme substrate: urea • Urea is a natural metabolite • Ammonia/ Ammonium produced from urea hydrolysis is toxic to cells • Apoptotic enzymes caspase • Glycosylated 90 kDa (286aa) GPI- linked membrane protein 2 and 3 (A549 lung cell) and • Intercellular adhes
Slide 21: Specific Delivery to Tumors
Specific Delivery to Tumors Tumor specific localization Full Body Scan A549 Tumor (8 x 7 mm) L-DOS47-Cy5.5 Filtered Scan L-DOS47-Cy5.5 Cy5.5 emission max @710nm 21
Slide 22: L-DOS47 Affects Metabolism
L-DOS47 Affects Metabolism 1H-NMR anatomical imaging 32P-NMR microenvironment control Treatment NMR imaging on A549 xenograft mice showing a change in energy metabolism (Pi/Pcr) as a result of L-DOS47 treatment 22
Slide 23: L-DOS47 Cytotoxic to CEACAM6-Positive Tumor Cells
L-DOS47 Cytotoxic to CEACAM6-Positive Tumor Cells Cell lines Binding assay Cytotoxicity assay A549 Lung carcinoma ++ + H460 Lung carcinoma - ND H647 Lung carcinoma + ND H23 Lung adenocarcinoma - + BxPC-3 Pancreatic adenocarcinoma +++ +++ Capan-1 Pancreatic adenocarcinoma +++ ++ MIA PaCa-2 Pancreatic
Slide 24: L-DOS47 Inhibits Tumor Growth in Lung and Pancreatic Models
L-DOS47 Inhibits Tumor Growth in Lung and Pancreatic Models 350 300 %Change in Tumor 250 Volume 200 150 100 50 0 0 5 10 15 20 Days A549 (lung) BxPC3 (Pancreatic) L-DOS47 (10,20,35U/kg) L-DOS47 (7,35,175ug/kg) Cisplatin control Paclitaxel control Tian et. al. Bioconjug Chem. 2015 Jun 17;26(6):1144-55
Slide 25: L-DOS47 Binds to CEACAM6 Positive Cancer Patient Tissues
L-DOS47 Binds to CEACAM6 Positive Cancer Patient Tissues Age-matched Tumor Tissue Samples Normal Tissue Positive Negative Negative Kidney carcinoma 12/12 12/12 Parathyroid adenoma 1/1 n/a Plaenta, umbilical cord, allantois n/a 1/1 Myofibroblastic Tumor 1/1 n/a Prostate carcinoma 4/4 4/4 Thyroid carc
Slide 26: Tumor Formation Inhibition
Tumor Formation Inhibition 26
Slide 27: Enhances Other Chemotherapeutics
Enhances Other Chemotherapeutics ➢ L-DOS47 enhances chemo drugs The cytotoxic effect of weakly basic drugs is directly related to the solution pH (left panel). At an acidic Tumor pH (<6.8), the effectiveness of these drugs is significantly reduced. L-DOS47 can dramatically raise the effectiveness of
Slide 28: L-DOS47 Enhances Pemetrexed and Carboplatin
L-DOS47 Enhances Pemetrexed and Carboplatin A549 (No Pemetrexed) (2.5M Pemetrexed) (12.5M Pemetrexed) 100 No L-DOS47 1g/mL L-DOS47/4mM urea 80 %Survival 60 40 20 0 0 25 50 100 200 0 25 50 100 200 0 25 50 100 200 Carboplatin (M) Carboplatin (M) Carboplatin (M) A549 cells were treated with vario
Slide 29: L-DOS47 Clinical Update
L-DOS47 Clinical Update • L-DOS47 Phase I / II Trial (LDOS002) – Monotherapy in advanced NSCLC patients – Currently enrolling Phase II patients • L-DOS47 Phase I with Expansion Trial (LDOS001) – Combination with pemetrexed and carboplatin – Currently enrolling in cohort 2 • L-DOS47 Phase II (LDOS003
Slide 30: L-DOS47 Phase I / II Trial (LDOS002)
L-DOS47 Phase I / II Trial (LDOS002) • Monotherapy treatment protocol in NSCLC patients that have not responded to other treatments; • Stage IIIb / IV, metastatic, and progression after several lines of chemo, rad, surgery or chemo-naïve patients that have refused other lines of therapy; • Dosed onc
Slide 31: Demography and NSCLC Baseline Characteristics
Demography and NSCLC Baseline Characteristics (up to 12 Cohorts) Total NSCLC Total Demography (N=40) History (N=40) Adeno = 38 (95%) Age Mean = 61.2 Tumor Large Cell = 1 (2.5%) Min, Max (34, 83) Histology Unknown = 1 (2.5%) Weight Mean = 69.1 Tumor Stage IIIB = 7 (17.5%) (kg) Min, Max (48, 95) Stagi
Slide 32: Clinical Observations Up to Cohort 12
Clinical Observations Up to Cohort 12 • 21/40 patients had an overall response of SD at cycle 2 • 10/40 patients had an overall response of SD at cycle 4 • Patient 01-047 enrolled in cohort 9 (1.84µg/kg) was progression free for 10 cycles (approx. 7 months) • None of the patients treated to-date hav
Slide 33: L-DOS002 Phase I
L-DOS002 Phase I • Currently has completed 16 cohorts (13.55 ug/kg) • One Dose Limiting Toxicity (DLT); • No safety issues beyond those observed in pre-clinical toxicology studies or expected in the population of patients being studied; • Immunogenicity consistent with what was observed pre- clinica
Slide 34: L-DOS47 Phase I with Expansion Trial (LDOS001)
L-DOS47 Phase I with Expansion Trial (LDOS001) • Combination therapy in first-line treatment of NSCLC: – Stage IIIb / IV, metastatic, and chemo-naïve; – Given in combination with standard pemetrexed/carboplatin treatment; – Dosed continuously each week; – Monitor radiologically every 6 weeks; • Cond
Slide 35: DOS47: Breaking Down Tumor Acidic Barrier
DOS47: Breaking Down Tumor Acidic Barrier • L-DOS47 is the only targeted enzymatic approach to combat Tumor acidosis • L-DOS47 is being studied as monotherapy and chemo combo in the clinic • A second DOS47 candidate that targets VEGFR2 is in preclinical development • Active R&D work are exploring DO
Slide 36: Acknowledgement
Acknowledgement • Helix Polska Poland • The Maria Sklodowska-Curie Institute of Oncology Poland • Military Institute of Health Institute Poland • Mazovian Centre of Pulmonary Diseases and Tuberculosis in Otwock Poland • Poznan University of Medical Sciences Poland • National Tuberculosis and Lung Di