multimmune GmbH

..........delivering innovative cancer theranostics

mi-THERAPEUTICS PIPELINE

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 strategy 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, Pre-clinical product); 
  • Specific direct targeting of tumors using an antibody against the membrane form of the Hsp70 molecule (mi-TUMEXtx, Pre-clinical product);
  • Inducing the tumor-specific 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-iv has the potential to be effective against ~50-70% of all tumors, it could therefore command a substantial market share and incur dramatically lower pipeline development and delivery costs.


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 surface-bound heat shock protein 70 (Hsp70). Surface-bound Hsp70 is a tumor-specific marker which is expressed on about 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 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.

Phase I Clinical Pilot Study
Feasibility and safety of ENKASTIM-ev (ex vivo), has been proven in patients with colorectal and lung carcinomas in a Phase I Clinical Pilot Study at the University Hospital of Regensburg (Krause et al, 2004).

Phase II Clinical Study
A multi-centre Phase II trial of ENKASTIM-ev in patients with non-small lung cell carcinoma following radio(chemo)therapy is currently recruiting (follow links on right for description of trial).

For this ongoing Phase II Clinical Trial, 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 tumor-specific marker expressed on about 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 of apoptosis in Hsp70-positive tumors and metastases, sparing healthy cells. 

Indication

All tumors and metastases on which surface-bound Hsp70 is present. mi-APO can be applied in immunosuppressed patients i.e. after radio-chemotherapy.  


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, colon, pancreas, leukaemia (see mi-APO link on right).


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 expressed on about 50-75% of various cancer entities, e.g. lung, colon, breast, pancreas.


The administration of mi-TUMEXtx, a unique monoclonal antibody which recognises the membrane form of Hsp70, induces Antibody-Dependent Cellular Cytotoxicity (ADCC) of membrane Hsp70-positive tumors and metastases, while sparing healthy cells. 


Furthermore, the product can 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. Preclinical development in colorectal cancer is ongoing, and further studies in pancreatic and lung cancer are planned.


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.