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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
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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.
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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
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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
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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
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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
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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
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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.
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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
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