The science behind Betalutin®: why is it unique? · Speaker credentials •Roy H. Larsen, PhD...
Transcript of The science behind Betalutin®: why is it unique? · Speaker credentials •Roy H. Larsen, PhD...
The science behind Betalutin®:why is it unique?
Roy H. Larsen
PhD
Sciencons AS, Oslo, Norway
Speaker credentials
• Roy H. Larsen, PhD
• >25 years of experience in research on targeted radionuclide therapy
• Main founder of Algeta and inventor of Xofigo®, and approved radionuclide therapy targeting bone metastases in cancer patients (sold by Bayer)
• Main inventor of >15 families of patents/patent applications
• Author of >50 peer-reviewed papers
• Chairman of the Board of Directors of Nordic Nanovector from 2009-2014, and is now a member of the Board of Directors of Nordic Nanovector
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Antibody-radionuclide conjugates
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Targeting cancer cells
• Cancer cells present various proteins on their cell surfaces, which can be exploited therapeutically using targeted therapies
• Traditional monoclonal antibodies such as rituximab (MabThera®) target cell-surface proteins such as CD20 that are present on the surface of lymphoma cells
• These therapies work by recruiting the immune system to kill the cancer cells
• Additionally, other molecules can be linked to these antibodies in order to provide further clinical benefit or an alternative anticancer mechanism
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Antibody-radionuclide conjugates
• Immunoconjugates are antibodies that are joined to a second molecule via a linker
• This second molecule is usually a label, cytotoxic molecule, or radionuclide
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Antibody-drug conjugates (ADCs) Antibody-radionuclide conjugates (ARCs)
An antibody joined to a cytotoxic molecule; these are known together
as an immunotoxin
Examples of ADCs include:Adcetris®
Kadcyla®
An antibody joined to a radionuclide; treatment is often referred to as
radioimmunotherapy
Examples of ARCs include:Zevalin®
Bexxar®
Source: Nordic Nanovector prospectus
Antibody-radionuclide conjugates: mechanism of action
• ARCs provide a way to selectively deliver a radioactive payload to cancer cells
• The binding of the antibody to the cell-surface protein brings the radionuclide in close proximity to the cancer cell
• The emitted radiation kills the target cell along with surrounding cancer cells
ARC: antibody-radionuclide conjugate6
Radionuclides are an accepted part of cancer treatment
• Radium was investigated as a targeted treatment for bone disease due to its chemical similarity with calcium
• Radium is readily available for production and has a 11.4 day half-life that allows easy shipping to end users
• Radium selectively concentrates in bone lesions
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60–100 μm
Harrison MR et al. Cancer Manage Res. 2013;5: 1–14
Xofigo® (Radium-223) has seen clinical and commercial success
EMA: European Medicines Agency; FDA: Food and Drug Administration8
• 3.6 month extended survival led to priority FDA and EMA review, followed by approval in 2013
• Xofigo® was in the top 10 drugs of 2013, with projected 2018 sales of $829 million
Betalutin®
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Intellectual property (IP) protection: Betalutin®
• Betalutin® is protected by the strongest form of IP protection — Composition of Matter
I. Patents already granted/issued in the USA, Europe, China and Japan; patent applications are still being processed in other geographies
II. The patent protects Betalutin® as well as radioimmunotherapies based on other radionuclides and chelators attached to the HH1 antibodies
• Nordic Nanovector also has patent applications on specific versions of humanized and chimeric versions of the HH1 antibody
• The third layer of IP protection for Betalutin® is a Use Patent application regarding the upregulation of tumor antigens by treatment with Betalutin® and subsequent possible enhanced therapeutic effect of immunotherapies like rituximab
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Betalutin®: a new radioimmunoconjugate against CD37
• Betalutin® is an ARC designed to target the CD37 protein on the surface on NHL cells
ARC: antibody-radionuclide conjugate; NHL: non-Hodgkin lymphoma
HH1 antibody that targets CD37
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Lutetium-177 (Lu-177)a beta-particle emitting
radionuclide with a 6.7 day half-life
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177LuDOTA linker
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CD37 is a validated target for non-Hodgkin lymphoma
• CD37 is one of the many potential antibody targets for cancers such as NHL1
• CD37 is well expressed in NHL1
• CD37 is expressed on the same cell subset as CD20, mainly mature B cells and B-cell malignancies2
NHL, non-Hodgkin lymphoma1. Flinn IW. Blood 2011; 118: 4007–4008; 2. Palomba ML, Younes A. Blood 2013; 122: 3397–3398; 3. Figure redrawn from Flinn IW. Blood 2011; 118: 4007–4008Blood: Journal of the American Society of Hematology by American Society of Hematology; Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH)
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Pre-clinical
• In vitro tests with the antibody construct (TRU-016), suggest that CD37-targeted proteins induce cell death by a different mechanism of action vs rituximab1
• Mice inoculated with a CD37-targeted ADC had a superior tumor-free survival time than those given an unconjugated antibody or the anti-CD20 antibody rituximab2
• Survival of mice treated with Betalutin® was significantly higher than those treated with rituximab3
Clinical
• Treatment of refractory NHL patients with the131I-MB-1 anti-CD37 antibody4
• 4 patients achieved complete tumorremission
• 1 patient treated with an anti-CD20 achieved partial response
• Radioimmunotherapy with 131I-MB-1 anti-CD37 antibody5
• 6 of 10 patients achieved tumor response
• Much lower doses of 131I than in the previous study
ADC: antibody-drug conjugate; NHL: non-Hodgkin lymphoma; TRU-016: otlertuzumab1. Zhao X et al. Blood 2007; 110: 2569–2577; 2. Deckert J et al. Blood 2013; 122: 3500–3510; 3. Dahle J et al. Anticancer Res 2013; 33: 85–96;4. Press OW et al. J Clin Oncol 1989; 7: 1027–1038; 5. Kaminski MS et al. J Clin Oncol 1992; 10: 1696–1711
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Pre-clinical and clinical data supporting CD37 targeting
Lutetium-177 is well suited for non-Hodgkin lymphoma treatment
• Half-life long enough to ensure that tumor mass is irradiated
• Mean range of radiation treats ‘bulky’ tumors while limiting damage to health tissue
• Sufficient gamma component to obtain imaging, but low enough to allow safe treatment in an outpatient setting
ICRP: International Commission on Radiological Protection; keV: kiloelectronvolt; MeV: megaelectronvolt14
Properties of Lu-177
T½ (half-life) 6.7 days
Mean b-energy 0.13 MeV
Mean range in tissue 0.67 mm
ICRP radiotoxicity 3
g-yield 17%
g-energies 113 and 208 keV
Imaging possible? Yes
Betalutin®: summary
• Different targeting antibody focusing on a different antigen vsrituximab (CD37 vs CD20)
• Greater anticipated effect in patients not responding to rituximab (CD20)
• Different β-emitting radionuclide with better therapeutic and safety properties
• Longer half-life (6.7 days) than Y-90
• Lower β-energy (mean range 0.67 mm) than Y-90
• Long intracellular half-life
• Low yield of photons (17%), with suitable energy for imaging
• Ready-to-use formulation
Y-90: Zevalin®15
Future opportunities with Betalutin®
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Nordic Nanovector’s pipeline
*Collaboration with AffibodyARC: antibody -radionuclide conjugate; ASCT: autologous stem cell transplant; chHH1: chimeric HH1 antibody; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; NHL: non-Hodgkin lymphoma
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Product candidate Discovery Preclinical Phase 1 Phase 2 Phase 3
DLBCL, ineligible for ASCT
FL, 3rd line
177Lu-chHH1 ARC
Affilutin*
DLBCL, conditioning
Indication
FL, 1st line
Multiple myeloma
Betalutin®
Betalutin®
Betalutin®
Other NHL Betalutin® + CD20
FL, 2nd line Betalutin® + CD20
Leukemia 177Lu-chHH1 ARC
Betalutin® treatment may improve rituximab efficiency
MCL: mantle cell lymphoma18
• Biodistribution of rituximab in the blood and tumor of mice improved after treatment with Betalutin®
• In a preclinical mouse model of MCL, treatment with the combination of Betalutin® plus rituximab appears to be associated with increased survival, compared with rituximab alone
Pre-clinical results: CD37 (HH1) vs CD20 (rituximab)
• Betalutin® is designed for internalization and high retention in cancer cells, which causes greater cancer cell death
Antibodies bound to CD37 (HH1) are internalized
Antibodies bound to CD20 (rituximab) are not internalized
Time after start of incubation (min)
0 20 40 60 80 100 120 140 160 180 200
Inte
rnalized a
ntibody
(fg/c
ell)
0
5
10
15
20tetulomab
rituximab
HH1
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Overview of chHH1-ARC
• chHH1-ARC is based on a chimeric antibody linked to the radioactive Lu-177 nuclide
• Target: CD37
• chHH1-ARC allows:
• Repeated injections over time – making it suitable for first-line use
• Fractionated dosing – making it suitable for chronic lymphocytic leukemia
• Potential for synergistic effect when combined with anti-CD20 antibody – leading to an efficacy profile that can compete with first-line regimens across multiple hematologic cancers
• Status:
• Preliminary studies have shown relevant uptake of chHH1 ARC in normal organs and tumorxenografts, and strong cytotoxicity of chHH1 ARC in vitro
• In vivo efficacy/toxicity studies are ongoing
ARC: antibody-radionuclide conjugate; chHH1: chimeric HH1 antibody20
Overview of Affilutin
• Affibody-radionuclide conjugate based on an affibodymolecule and a Lu-177 radioactive nuclide
• Development in collaboration with Affibody AB and funding from the Eurostars programme
• Target – undisclosed surface antigen
• Indication – multiple myeloma
• Status:
• Initial affibody molecules (hits) have been identified and characterized in cells and the relevant tumor models
• Affinity maturation of lead molecules is ongoing
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Affilutin™
Affibodymolecule
Lu-177
Summary
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Betalutin®: a first-in-class antibody-radionuclide conjugate
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Tumor-seeking monoclonal anti-CD37 antibody + conjugated
radionuclide (Lu-177)
Specifically designed for the treatment of B-cell tumors
Effective therapeutic payload and multi-cell kill approach