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November 2016 multimmune GmbH Company Profile & Product Pipeline ….delivering innovative cancer theranostics multimmune GmbH …………….delivering innovative cancer theranostics BACKGROUND AND COMPANY PROFILE With current statistics indicating that the lifetime risk of developing cancer is now 1 in 2, it is essential that approaches for diagnosing and treating cancer continue to be improved. Although progress in the development of new cancer therapies for the majority of tumour entities progresses at a pace, key challenges in the management and treatment of aggressive disease remain. Another big challenge relates to the time and cost of drug development, and thereby the ability of the healthcare providers to afford the therapeutics that are developed. The identification of more ‘universal’ targeting structures that are present across different cancer entities will consolidate the costs of developing therapies during the preclinical and early clinical phases. multimmune GmbH is a private, clinical-stage biopharmaceutical company which has developed a unique and proprietary technology platform on the basis of the founding scientists' (Professor Gabriele Multhoff, Dr Claus Botzler) discovery that cell surface-bound Hsp70 is uniquely expressed on a large proportion of cancers (~50-75%), but not on healthy cells. This makes this form of Hsp70 an excellent and broadlyapplicable molecule on which to base the development of innovative imaging platforms, therapeutics and diagnostics (theranostics). VISION & MISSION multimmune's aim is to significantly improve the lives of cancer patients by developing revolutionary products which specifically target primary tumors and aggressive, metastatic disease as quickly as possible. We are developing new diagnostic platforms and more focused therapies which have a higher efficacy and fewer side effects than those that are currently available. Creating value: product and technology platform based on a widely, but selectively expressed tumor-specific marker pipeline of therapeutic, delivery, diagnostic and imaging platforms Commercialization: out-licensing technology to the commercial sector development and delivery of selected co-development partnerships for complementary technologies PLATFORM TECHNOLOGY The company´s proprietary platform technology is based on the discovery of a novel tumor specific marker, a membrane-expressed form of heat shock protein 70 (Hsp70). Membrane Hsp70 is most frequently expressed on a variety of different tumor types including lung, colon, breast, head and neck, stomach, pancreas carcinomas, malignant melanoma, and hematological diseases, but never on the corresponding normal tissues. In addition to primary tumors, metastases, the major cause of death by cancer, present even higher amounts of Hsp70 on their surface membranes. Metastatic disease is responsible for approximately 90% of all cancer-related deaths. Further information at www.multimmune.com 1|P a g e Based on its discovery of membrane Hsp70, multimmune has succeeded in developing a powerful product, termed ENKASTIM which allows, for the first time, a unique and specific activation of human natural killer (NK) cells which are programmed to recognise and kill cancers expressing membrane Hsp70 via the release of a cytotoxic molecule called granzyme B. These cells destroy tumors and metastases that are invisible to the cell killing (cytolytic) consequences of more conventional T cell-based immunotherapies. Hsp70-expressing tumors can also be targeted using a unique monoclonal antibody which can detect the membrane form of Hsp70 (mi-TUMEXtx) and a serine protease (granzyme B, mi-APO) which can selectively kill cancer cells expressing the membrane form of Hsp70. mi-THERAPEUTICS PIPELINE Cancer immunotherapy drugs have captured nearly 50% of the overall oncology drugs market, generating about $41.0 billion in 2014 alone (ReportLinker, 2014). This is by far the fastest-growing segment of the industry. An unusual cell surface localization of Hsp70 has been demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. multimmune´s goal is to build a well-staged pipeline of differentiated products for the diagnosis (dx) and targeted therapy (tx) of cancer. All platforms are based on the widely-expressed tumor specific target - the membrane form of Hsp70. Ex vivo activation of natural killer (NK) cells using a synthetic peptide which mimics Hsp70 (ENKASTIM-ev, End-Phase I and ongoing Phase II product) In vivo activation of natural killer (NK) cells using a synthetic Hsp70 peptide (ENKASTIM-iv, Preclinical product) Specific direct targeting of tumors using an antibody against the membrane form of the Hsp70 molecule (mi-TUMEXtx, Pre-clinical product) Inducing the selective death (apoptosis) of cancer cells / tumors expressing the membrane form of Hsp70 using granzyme B (mi-APO, Discovery and Pre-clinical product) A key observation has been that non-lethal radio- or chemotherapy increase the membrane density of Hsp70 on tumor cells, and thereby their sensitivity to membrane Hsp70-targeted therapies. This means that such therapies can be added to conventional approaches, thereby accelerating the translational process and adoption into clinical practice. ENKASTIM ENKASTIM is based on the activation of immune cells called natural killer (NK) cells that are major players in the body's first line of defence, also called innate immunity. The immune effector cells are activated ex vivo (outside the body; ENKASTIM-ev) or in vivo (inside the body; ENKASTIM-iv). Indication All tumors and metastases on which surface-bound Hsp70 is present. Market Given that ENKASTIM has the potential to be effective against ~50-70% of all tumors, this platform could command a substantial market share and dramatically lower pipeline development and delivery costs. Further information at www.multimmune.com 2|P a g e ENKASTIM-ev: Ex vivo stimulation of natural killer (NK) cells ENKASTIM-ev is an innovative product candidate representing a new class of therapy known as Active Cellular Immunotherapies (ACIs). ACI is a treatment approach which capitalizes on the power of vital human cells to re-engage the patient's own immune system to fight cancer. The product induces a targeted immune response against a membrane form of heat shock protein 70 (Hsp70), a tumor-specific marker which is expressed on 50-75% of various cancer entities, e.g. lung, colon, breast, pancreas. Ex vivo stimulation of ENKASTIM-ev, an Hsp70-based GMP-grade synthetic peptide comprising 14 amino acids (14mer, TKD), results in a specific activation of NK cells with targeting and killing ability towards membrane Hsp70-positive tumors and metastases. Approach Immune effector cells are obtained from patients by blood collection (leukapheresis). NK cells are incubated in culture bags (ex vivo) with Hsp70 peptide/Interleukin-2 for several days in a closed system. Following quality control and sterility testing, the therapeutic is delivered to the patient as an intravenous infusion. Status The efficiency of ex vivo stimulated effector cells in killing tumors has been demonstrated in pre-clinical mouse models and in patients with colorectal and lung carcinomas (see below). Phase I Clinical Pilot Study The feasibility and safety of ENKASTIM-ev in patients with colon and lung cancer has been proven in a Phase I Clinical Pilot Study at the University Hospital of Regensburg (Krause et al., Clinical Cancer Research 2004, 10: 3699-707). Phase II Clinical Trial A multi-centre randomised Phase II clinical trial of ENKASTIMev in patients with lung cancer following radio(chemo)therapy is currently underway. For this, the cellular immunotherapeutic product is obtained from the patient via a standard leukapheresis procedure approximately 4 days before each scheduled infusion. Leukapheresis is centrally performed at the University Hospital Regensburg, Transfusion Medicine and cell processing is performed in a GMP-laboratory at TUMCells, Munich (Professor Martin Hildebrandt). ENKASTIM-iv: In vivo stimulation of natural killer (NK) cells In vivo application of ENKASTIM-iv, an Hsp70-based GMP-grade synthetic peptide comprising 14 amino acids (14mer), results in a specific activation of NK cells which acquire the capacity to recognise and kill membrane Hsp70-positive tumors and metastases. Status Proof of principle has been demonstrated in a pre-clinical mouse colon tumor model. In these studies, three repeated intravenous injections of ENKASTIM (TKD/IL-2) resulted in a 60% reduction in the tumor size. mi-APO: an apoptosis-inducing enzyme mi-APO is a targeted protein product with potential to be used for the treatment of most tumor types. The product targets surface-bound heat shock protein 70 (Hsp70). Surface-bound Hsp70 is a tumorspecific marker expressed on 50-75% of various cancer entities, e.g. lung, colon, breast, pancreas. Application of mi-APO, a recombinant serine protease, results in a specific perforin-independent induction Further information at www.multimmune.com 3|P a g e of apoptosis (cell death) of Hsp70-positive tumors and metastases, while sparing healthy cells (Gehrmann et al., PLoS ONE 2012, 7(7): e41341). Indication All tumors and metastases on which surface-bound Hsp70 is present. mi-APO can be used for the treatment of patients that have been rendered immunosuppressed by radio(chemo)therapy. Market Given that mi-APO has the potential to be effective against ~50-75% of all tumors, it has the potential to command a substantial market share and incur dramatically lower pipeline development and delivery costs. Status Proof of principle has been demonstrated in tumor cell lines of various Hsp70 expressing tumor entities, i.e. breast, prostate, colon, pancreas, leukaemia. mi-TUMEXtx: A therapeutic monoclonal antibody recognising membrane Hsp70 mi-TUMEXtx is a targeted antibody which has the potential to be used for the treatment of most tumor types. The product targets surface-bound heat shock protein 70 (Hsp70), a tumor-specific marker which is expressed on 50-75% of various cancer entities, e.g. lung, colon, breast, pancreas. The administration of miTUMEXtx induces Antibody-Dependent Cellular Cytotoxicity (ADCC) of membrane Hsp70-positive tumors and metastases, while sparing healthy cells (Stangl et al., PNAS 2011, 108: 733-8). The product can also be used in a "magic bullet" approach, as it can be designed to deliver a cytotoxic conjugate directly, and specifically, to tumor cells. Indication All tumors and metastases on which surface-bound Hsp70 is present. Market Monoclonal antibody-based therapeutics for the treatment of cancer generate significant global revenues: e.g. Avastin ($6.3 billion), Herceptin ($6 billion) and Rituxan ($7 billion) alone generated ~$20 billion revenue in 2012 (THE DEAL ROOM - Monoclonal Antibodies Continue to Drive Biotech Investment, 2013). Given that mi-TUMEXtx has the potential to be effective against ~50-75% of all tumors, it could therefore command a substantial market share and incur dramatically lower pipeline development and delivery costs. Status Proof of Principle has been demonstrated in a pre-clinical colon tumor mouse model. In these studies, three repeated injections of the antibody resulted in a 70% reduction in the tumor size. mi-DIAGNOSTICS PIPELINE multimmune´s goal is to build a well-staged pipeline of differentiated products for identifying patients that will respond to membrane Hsp70-directed therapies, for the diagnosis and prognosis of cancer, and for the monitoring of therapeutic responses to anti-cancer therapies. multimmune's lead mi-DIAGNOSTICS (dx) candidates are a patented monoclonal antibody for detecting the presence of tumors expressing the membrane form of Hsp70, and a patented enzyme immunoassay for the detection of lipid-associated Hsp70 in the peripheral circulation. mi-TUMEXdx Using multimmune's unique monoclonal antibody which recognises the membrane form of Hsp70 which is expressed on cancer cells, an Hsp70 membrane-positive phenotype was found in 40% (colon), 37% (gastric), 43% (lower rectal), and 42% (squamous cell) of the analyzed tumor specimens. None of the corresponding normal tissues was found to be Hsp70 membrane-positive. In patients with colon (P = .032) and gastric (P = .045) carcinomas, an Hsp70 membrane expression correlated significantly with an improved overall survival; whereas a negative association was seen in patients with lower rectal (P = .085) and Further information at www.multimmune.com 4|P a g e squamous cell carcinoma (P = .048) (Pfister et al., Cancer 2007, 110: 926-935). High membrane Hsp70 expression on leukemic cells from patients with acute myeloid leukemia has also been shown to be associated with a poorer prognosis (Steiner et al., Leukemia 2006, 20: 2076-2070). mi-lipHsp70dx: An enzyme immunoassay for detecting lipid-associated Hsp70 in the peripheral circulation Elevated levels of the stress-inducible heat shock protein 70 (Hsp70) in the peripheral circulation have been reported for many tumor entities. We have shown that Hsp70 membrane-positive tumor cells actively release Hsp70 in exosome-like lipid vesicles. To quantify free as well as lipid-bound Hsp70 derived from exosomes in the serum of tumor patients, we have developed the novel patented mi-lipHsp70 sandwich ELISA. This assay specifically detects the inducible form of Hsp70 and does not cross-react with the highly homologous constitutive form - Hsc70. The antibody used in this assay recognises free and membranebound Hsp70 on living tumor cells. A comparison of the Hsp70 levels in patients with head and neck, lung, colorectal, pancreatic cancer, glioblastoma or hematological malignancies and healthy human volunteers has revealed significantly higher levels in tumor patients (Breuninger et al., Clinical and Cellular Immunology 2015, 5:5). Furthermore, serum levels of Hsp70 correlate with gross tumor volume in patients with squamous cell and adeno non-small cell lung cancer (Gunther et al., Frontiers in Immunology 2015, 6:556). mi-IMAGING PIPELINE multimmune GmbH's mi-IMAGING pipeline is being developed in collaboration with the Technische Universität München and the Collaborative Research Centre 824 (CRC824) 'Imaging for Selection, Monitoring and Individualization of Cancer Therapies' which is funded by the Deutsche Forschungsgemeinschaft (DFG) - German Research Foundation. multimmune's mi-IMAGING (im) platforms are based on product candidates (mi-TUMEXim - membrane Hsp70-specific monoclonal antibody and miTPPim - tumor penetrating peptide) that detect the membrane form of Hsp70 which is selectively expressed on tumor cells. mi-TUMEXim: Imaging monoclonal antibody mi-TUMEXim provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. mi-TUMEXim might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies (Stangl et al., J Cell Mol Med. 2011, 15: 874-87; Stangl et al., Radiother Oncol 2011, 99: 313-6). Intraoperative detection of CT26 colon carcinoma cell-derived tumors using the miTUMEXim-Cy5.5 monoclonal antibody Further information at www.multimmune.com 5|P a g e mi-TPPim: Imaging tumor penetrating peptide mi-TPPim provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. mi-TPPim might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies (Gehrmann et al., PLoS ONE 2014, 9(8): e105344; Stangl et al., Cancer Research 2014, 74: 6903-12). In vivo imaging of 4T1 mammary tumors (o.t., upper row) and lung metastases (lower row) using the 14-mer tumor penetrating peptide (mi-TPPim) Further information at www.multimmune.com 6|P a g e INVESTMENT OPPORTUNITIES Cancer immunotherapy drugs have captured nearly 50% of the overall oncology drugs market, generating about $41.0 billion in 2014 alone (ReportLinker, 2014). This is by far the fastest-growing segment of the industry. multimmune GmbH is offering a number of innovative funding opportunities for investors to support, and engage with, the timely development and targeted translational delivery and exploitation of its pipeline miTHERAPEUTICS, mi-DIAGNOSTICS and mi-IMAGING platforms. ________________________________________________________ MANAGEMENT & CONTACTS Chief Executive Officer Professor A. Graham Pockley, PhD Tel: +49 89 3398 4822 (DE) - please make contact via eMail in the first instance Tel: +44 114 360 1213 (UK) - please make contact via eMail in the first instance eMail: [email protected] LinkedIn Profile: https://www.linkedin.com/in/grahampockley Founder & Chief Scientific Officer Prof. Dr. Gabriele Multhoff, PhD Tel: +49 89 3398 4822 (DE) - no unsolicited calls please Tel: +44 114 360 1213 (UK) - no unsolicited calls please eMail: [email protected] Further information at www.multimmune.com 7|P a g e