The science behind Betalutin : why is it unique? Roy H. Larsen PhD Sciencons AS, Oslo, Norway

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 2

Antibody-radionuclide conjugates 3

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 4

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 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 5

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 cellsurface 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 conjugate 6

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 60 100 μm Radium selectively concentrates in bone lesions Harrison MR et al. Cancer Manage Res. 2013;5: 1 14 7

Xofigo (Radium-223) has seen clinical and commercial success 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 EMA: European Medicines Agency; FDA: Food and Drug Administration 8

Betalutin 9

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 10

Betalutin : a new radioimmunoconjugate against CD37 Betalutin is an ARC designed to target the CD37 protein on the surface on NHL cells HH1 antibody that targets CD37 + Lutetium-177 (Lu-177) a beta-particle emitting radionuclide with a 6.7 day half-life + DOTA linker 177 Lu ARC: antibody-radionuclide conjugate; NHL: non-hodgkin lymphoma 11

CD37 is a validated target for non-hodgkin lymphoma CD37 is one of the many potential antibody targets for cancers such as NHL 1 CD37 is well expressed in NHL 1 CD37 is expressed on the same cell subset as CD20, mainly mature B cells and B-cell malignancies 2 3 NHL, non-hodgkin lymphoma 1. 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 4008 Blood: Journal of the American Society of Hematology by American Society ofhematology; Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) 12

Pre-clinical and clinical data supporting CD37 targeting 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 rituximab 1 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 rituximab 2 Survival of mice treated with Betalutin was significantly higher than those treated with rituximab 3 Clinical Treatment of refractory NHL patients with the 131 I-MB-1 anti-cd37 antibody 4 4 patients achieved complete tumor remission 1 patient treated with an anti-cd20 achieved partial response Radioimmunotherapy with 131 I-MB-1 anti-cd37 antibody 5 6 of 10 patients achieved tumor response Much lower doses of 131 I than in the previous study ADC: antibody-drug conjugate; NHL: non-hodgkin lymphoma; TRU-016: otlertuzumab 1. 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 13

Lutetium-177 is well suited for non-hodgkin lymphoma treatment Properties of Lu-177 T ½ (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 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 Imaging possible? Yes ICRP: International Commission on Radiological Protection; kev: kiloelectronvolt; MeV: megaelectronvolt 14

Betalutin : summary Different targeting antibody focusing on a different antigen vs rituximab (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 16

Nordic Nanovector s pipeline Indication FL, 3rd line FL, 2nd line DLBCL, ineligible for ASCT DLBCL, conditioning Other NHL FL, 1st line Leukemia Multiple myeloma Product candidate Discovery Preclinical Phase 1 Phase 2 Phase 3 Betalutin Betalutin + CD20 Betalutin Betalutin Betalutin + CD20 177 Lu-chHH1 ARC 177 Lu-chHH1 ARC Affilutin* *Collaboration with Affibody ARC: 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 17

Betalutin treatment may improve rituximab efficiency 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 MCL: mantle cell lymphoma 18

Pre-clinical results: CD37 (HH1) vs CD20 (rituximab) Internalized antibody (fg/cell) 20 15 10 5 0 HH1 tetulomab rituximab 0 20 40 60 80 100 120 140 160 180 200 Antibodies bound to CD37 (HH1) are internalized Antibodies bound to CD20 (rituximab) are not internalized Time after start of incubation (min) Betalutin is designed for internalization and high retention in cancer cells, which causes greater cancer cell death 19

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 tumor xenografts, and strong cytotoxicity of chhh1 ARC in vitro In vivo efficacy/toxicity studies are ongoing ARC: antibody-radionuclide conjugate; chhh1: chimeric HH1 antibody 20

Overview of Affilutin Affibody-radionuclide conjugate based on an affibody molecule 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 Affibody molecule Lu-177 Affilutin 21

Summary 22

Betalutin : a first-in-class antibody-radionuclide conjugate Tumor-seeking monoclonal anti-cd37 antibody + conjugated radionuclide (Lu-177) Effective therapeutic payload and multi-cell kill approach Specifically designed for the treatment of B-cell tumors 23