Immutep

Last updated

Immutep Ltd
Company type Public
Nasdaq:  IMMP
ASX:  IMM
Industry Biotechnology
Founded2001
Headquarters Sydney, Australia
Leipzig, Germany
Key people

Marc Voigt
(CEO)
Frédéric Triebel
(Chief Scientific and Medical Officer)
Products IMP321, GSK2831781, CVac LAG-3 Immunotherapy
Website www.immutep.com

Immutep Ltd (formerly Prima Biomed) is a biotechnology company working primarily in the field of cancer immunotherapy using the LAG3 immune control mechanism. The company was originally built on CVac, a therapeutic cancer vaccine. In late 2014 the privately held French immunotherapy company Immutep SA was purchased by Prima Biotech.

Contents

Prima currently has three main products in its pipeline, all acquired with Immutep:

Eftilagimod alpha , (lab name: IMP321) which is recombinant soluble LAG-3, used as an activator of antigen presenting cells. This product has completed a Phase IIa clinical study, where it doubled the expected response rate in HER2-negative metastatic breast cancer.

IMP731, a depleting monoclonal antibody for autoimmune diseases, targeting LAG-3+ activated T cells. This antibody has been licensed to GlaxoSmithKline.

IMP701, an antagonist monoclonal antibody to LAG3 for use in cancer. This product has been licensed to Novartis

History

Immutep (formerly Prima BioMed) originated from four early-stage biomedical research projects which scientists at the Austin Research Institute, a medical research facility then associated with Melbourne's Austin Hospital (and that merged with the Burnet Institute in 2006) were working on in the late 1990s. These projects were packaged together and taken public in July 2001 on the ASX in a reverse takeover of a defunct mineral explorer called Prima Resources. [1] The most advanced of these projects is what became CVac.

CVac

CVac was taken into the Phase II 'CAN-003' study in epithelial ovarian cancer in July 2010. [2] In September 2013 Prima reported top-line interim data from this trial which showed no observed difference between treatment and control group in terms of Progression-free survival (PFS), [3] however in May 2014, when Prima reported final data from CAN-003, it was able to show median PFS for CVac patients in second remission of 12.91 months versus 4.94 months for the control group. This result had statistical significance (p=0.04). [4] After this data was received Prima sought to alter its clinical trial protocols in order to recruit second remission patients, however in February 2015 the company announced that it was no longer recruiting into its CVac studies. [5] Prima reported final Overall Survival numbers for CVac in May 2015 showing that median survival number for second remission CVac patients had still not been reached at 42 months, versus the median for the treatment group of 25.5 months. The p value for this comparison was 0.07. [6]

Immutep acquisition

Since February 2015 Prima's main focus has been on the programs that it acquired with Immutep. Prima had announced the acquisition of Immutep in October 2014 and completed the transaction in December 2014. The final purchase price was US$25m. [7] Immutep, which had been founded in 2001 by Professor Frédéric Triebel, had been built on LAG3, an immune checkpoint molecule known to play a role in switching off an immune response. Triebel had discovered LAG-3 in 1990 [8] and over the course of the next decade, as part of a collaboration between Institut Gustave Roussy and Merck Serono, Triebel et al., established LAG-3's mechanism of action in T cells and dendritic cells. Immutep had called its soluble LAG-3 immune system activation technology 'ImmuFact' (short for 'Immunostimulatory Factors') and its LAG-3 antagonist antibody technology 'ImmuTune'. It also developed a technology platform called ImmuCcine which involved covalently linking an antigen to IMP321 in a fusion protein in order vectorise the antigen to dendritic cells. Currently Immutep are only focus on the ImmuFact and ImmuTune platforms. [9]

Eftilagimod alpha

Eftilagimod alpha (lab names: IMP321 or LAG-3Ig) is a soluble dimeric recombinant form of LAG-3, being a fusion protein with immunoglobulin, designed to activate antigen presenting cells. Immutep established in 2008 that the product could induce activation of dendritic cell and monocytes, resulting in T cell expansion. [10] Phase IIa data in metastatic breast cancer, generated in 2010, has suggested that IMP321 works as a chemo-immunotherapeutic, where chemotherapy creates tumour debris, and IMP321 increases activation of APCs as they take up that debris. In that study, IMP321 increased the response rate according to the RECIST criteria from the 25% rate expected for paclitaxel to over 50% at the six-month mark. [11] There is also evidence (in-vivo) that IMP321 at low doses can be used as a T cell adjuvant for cancer vaccines. [12]

Immutep has initiated a Phase IIb study (2015-2019) of IMP321 in hormone receptor-positive metastatic breast cancer. [13] As of February 2016 Prima has registered a Phase I study in conjunction with an existing approved checkpoint inhibitor pembrolizumab in late stage melanoma. [14]

IMP731

IMP731 is a depleting antibody for autoimmune disease that targets LAG3+ activated T cells. GSK licensed the rights to develop such antibodies from Immutep in December 2010 in a total deal package worth £64m. GSK subsequently developed GSK2831781, its own depleting anti-LAG-3 antibody based on Immutep's original IMP731 antibody. [15] Prima announced a 'single digit' million dollar milestone related to GSK2831781's commencement of a Phase I study in psoriasis in January 2015. [16] There is evidence, in the tuberculin-induced DTH model in primates, that a single injection of a depleting LAG-3 monoclonal antibody can prevent Th1-driven skin inflammation. [17]

IMP701

IMP701 is an anti-LAG-3 antibody which blocks LAG-3-mediated immune down-regulation. The product was originally licensed in 2012 to the American biotech company CoStim. That company was acquired by Novartis in 2014. Novartis remains a licensee of IMP701 but the program is pre-clinical.

Prima stock

Prima has been publicly traded on the ASX since July 2001. The company did its IPO on Nasdaq in April 2012 and trades on that exchange in the form of ADRs. The current conversion rate between Prima ordinary shares and ADRs is 30:1. [18] On 14 May 2015 Prima BioMed announced a A$15 million investment from Ridgeback Capital Investments, a US-based specialist healthcare investor. [19] On 19 and 20 May 2015, just after Prima announced final Overall Survival data for its CAN-003 study of CVac, the company's ADRs experienced a significant two-day increase on Nasdaq. On 19 May the stock increased from US$0.52 per share from the previous session's close to US$1.60. On 20 May the stock opened at US$2.13 and rising as high as US$6.48 per share before closing at US$5.91. On that day 91.46 million ADRs were traded.

Main people

Prima's CEO since July 2014 has been Marc Voigt, [20] a German national who runs the company from its Berlin office. Frédéric Triebel serves as Chief Scientific and Medical Officer, working from the Paris office and laboratory. The Prima board is chaired by Australian-born scientist Russell Howard who took on the role in November 2017 following the resignation of Australian businesswoman Lucy Turnbull after seven years as chairperson.

Locations

Prima BioMed has office space in Berlin on Brandenburgische Straße in the Wilmersdorf district near the Konstanzer Straße U-Bahn station. Immutep had laboratories and office space at Orsay, a southwestern suburb of Paris, and this has been maintained by Prima BioMed. There is also an office on Macquarie Street, Sydney.

Leadership history

Prima BioMed's first two CEOs were Marcus Clark (2001–2006) [21] and Eugene Kopp (2006–2008). In October 2007 the Sydney-based bioentrepreneur Martin Rogers became an executive director and he led the company as managing director or CEO through to 2012. An American named Matt Lehman was CEO to 2014 before he was replaced by the current incumbent, Marc Voigt.

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

This is a list of terms related to oncology. The original source for this list was the US National Cancer Institute's public domain Dictionary of Cancer Terms.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

The following are notable events in the Timeline of immunology:

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

<span class="mw-page-title-main">Tumor-infiltrating lymphocytes</span>

Tumor-infiltrating lymphocytes (TIL) are white blood cells that have left the bloodstream and migrated towards a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ which consist of both mononuclear and polymorphonuclear immune cells, in variable proportions. Their abundance varies with tumor type and stage and in some cases relates to disease prognosis.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span> Protein-coding gene in the species Homo sapiens

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Pelareorep is a proprietary isolate of the unmodified human reovirus being developed as a systemically administered immuno-oncological viral agent for the treatment of solid tumors and hematological malignancies. Pelareorep is an oncolytic virus, which means that it preferentially lyses cancer cells. Pelareorep also promotes an inflamed tumor phenotype through innate and adaptive immune responses. Preliminary clinical trials indicate that it may have anti-cancer effects across a variety of cancer types when administered alone and in combination with other cancer therapies.

<span class="mw-page-title-main">TIGIT</span> Protein-coding gene in the species Homo sapiens

TIGIT is an immune receptor present on some T cells and natural killer cells (NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155 (PVR) on dendritic cells (DCs), macrophages, etc. with high affinity, and also to CD112 (PVRL2) with lower affinity.

CVac, is an immunotherapeutic agent that was 1st developed in Australia.

Frédéric Triebel is a French immunologist who is best known for his 1990 discovery of the LAG3 immune control mechanism. Triebel worked through the 1990s in a collaboration between Institut Gustave Roussy and Merck Serono to establish LAG-3's mechanism of action in T cells and dendritic cells. In 2001 he founded Immutep SA, a biotech company, to develop the therapeutic potential of LAG3. In 2014 this company was acquired by Prima BioMed, where Triebel remains Chief Scientific and Medical Officer.

GSK2831781 is a monoclonal antibody being developed by GlaxoSmithKline (GSK) for autoimmune diseases. The antibody targets the T cell activation marker LAG-3, which is mainly expressed in inflamed tissues. In GSK's March 2015 Product development pipeline document the antibody is listed under 'Immuno-inflammation' candidates. GSK2831781 entered a Phase I clinical trial in psoriasis early in 2015.

Eftilagimod alpha is a large-molecule cancer drug being developed by the clinical-stage biotechnology company Immutep. Efti is a soluble version of the immune checkpoint molecule LAG-3. It is an APC Activator used to increase an immune response to tumors, and is administered by subcutaneous injection. Efti has three intended clinical settings:

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

APC Activators are a type of immunotherapy which leverages antigen-presenting cells (APCs) to drive an adaptive immune response. APC Activators are agonists to APC surface-expressed ligands that, when bound, induce the maturation and activation of APCs. Professional antigen-presenting cells – including dendritic cells, macrophages, and B cells – serve an indispensable role in the adaptive immune response through their unique ability to phagocytose, digest, and present exogenous (circulating) antigens to T cells, facilitating antigen-specific immune responses.

<span class="mw-page-title-main">Cellular adoptive immunotherapy</span> Immunotherapy using T-cells

Cellular adoptive immunotherapy is a type of immunotherapy. Immune cells such as T-cells are usually isolated from patients for expansion or engineering purposes and reinfused back into patients to fight diseases using their own immune system. A major application of cellular adoptive therapy is cancer treatment, as the immune system plays a vital role in the development and growth of cancer. The primary types of cellular adoptive immunotherapies are T cell therapies. Other therapies include CAR-T therapy, CAR-NK therapy, macrophage-based immunotherapy and dendritic cell therapy.

References

  1. ↑ "Immutep Ltd (formerly Prima Resources Ltd) - Reinstatement of securities to Official Quotation" (PDF). Australian Stock Exchange Participant Circular. 6 July 2001. Archived from the original (PDF) on 4 March 2016. Retrieved 1 June 2015.
  2. ↑ "Prima BioMed to Release Interim CVac Clinical Data". Marketwire.
  3. ↑ "Archived copy" (PDF). Archived from the original (PDF) on 16 February 2016. Retrieved 24 April 2015.{{cite web}}: CS1 maint: archived copy as title (link)
  4. ↑ "Prima BioMed's CVac Demonstrates Improvement in Progression-Free Survival in Second Remission Ovarian Cancer". Marketwire.
  5. ↑ "Archived copy" (PDF). Archived from the original (PDF) on 27 February 2015. Retrieved 24 April 2015.{{cite web}}: CS1 maint: archived copy as title (link)
  6. ↑ "CVac Shows Clear Trend for Overall Survival Benefit in Second Remission Ovarian Cancer in Phase II Study" (PDF). Prima BioMed market release. 19 May 2015. Retrieved 1 June 2015.[ permanent dead link ]
  7. ↑ "PRIMA BIOMED". primabiomed.com.au. Archived from the original on 3 March 2015. Retrieved 24 April 2015.
  8. ↑ Triebel F (May 1990). "LAG-3, a novel lymphocyte activation gene closely related to CD4". J. Exp. Med. 171 (5): 1393–405. doi:10.1084/jem.171.5.1393. PMC   2187904 . PMID   1692078.
  9. ↑ "Technology Platforms". www.immutep.org. Immutep. Archived from the original on 1 July 2015.
  10. ↑ Casati C (March 2008). "Human lymphocyte activation gene-3 molecules expressed by activated T cells deliver costimulation signal for dendritic cell activation". J Immunol. 180 (6): 3782–8. doi: 10.4049/jimmunol.180.6.3782 . PMID   18322184.
  11. ↑ Brignone C (2010). "First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity". J Transl Med. 8: 71. doi: 10.1186/1479-5876-8-71 . PMC   2920252 . PMID   20653948.
  12. ↑ Li B (2008). "Lymphocyte activation gene-3 fusion protein increases the potency of a granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy". Clin Cancer Res. 14 (11): 3545–54. doi: 10.1158/1078-0432.CCR-07-5200 . PMID   18519788.
  13. ↑ IMP321 as Adjunctive to a Standard Chemotherapy Paclitaxel Metastatic Breast Carcinoma
  14. ↑ Phase 1 Study of IMP321 Adjuvant to Anti-PD-1 Therapy in Unresectable or Metastatic Melanoma (TACTI-mel)
  15. ↑ "A First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Intravenous (IV) Dose of GSK2831781 in Healthy Subjects and Patients With Plaque Psoriasis". Clinicaltrials.gov. 26 February 2021.
  16. ↑ "PRIMA BIOMED". primabiomed.com.au. Archived from the original on 27 May 2015. Retrieved 27 April 2015.
  17. ↑ Poirier, N; Haudebourg, T; Brignone, C; Dilek, N; Hervouet, J; Minault, D; Coulon, F; de Silly, RV; Triebel, F; Blancho, G; Vanhove, B (2011). "Antibody-mediated depletion of lymphocyte-activation gene-3 (LAG-3+)-activated T lymphocytes prevents delayed-type hypersensitivity in non-human primates". Clin. Exp. Immunol. 164 (2): 265–74. doi:10.1111/j.1365-2249.2011.04329.x. PMC   3087919 . PMID   21352204.
  18. ↑ "BNY Mellon Depositary Receipts - DR Profile". adrbnymellon.com.
  19. ↑ "Prima BioMed announces A$15 million investment from US Healthcare Investor Ridgeback". Prima BioMed. 14 May 2015. Archived from the original on 26 June 2015. Retrieved 30 June 2015.
  20. ↑ http://www.primabiomed.com.au/investor/filings/42qqy1cxbpfqnk.pdf [ dead link ]
  21. ↑ http://www.asx.com.au/asxpdf/20061010/pdf/3yxr68s2zqmhd.pdf [ bare URL PDF ]
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