Eftilagimod alpha: Difference between revisions
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}}</ref>. Shortly after this, in 2001, Triebel formed a biotechnology company called Immutep SA in 2001 in order to develop the therapeutic potential of LAG3 including soluble LAG3. By 2010 there was a large body of evidence of the efficacy of IMP321 in cancer,<ref>http://www.immutep.org/ProductDevelopment/KeyPublications</ref> |
}}</ref>. Shortly after this, in 2001, Triebel formed a biotechnology company called Immutep SA in 2001 in order to develop the therapeutic potential of LAG3 including soluble LAG3. By 2010 there was a large body of evidence of the efficacy of IMP321 in cancer,<ref>http://www.immutep.org/ProductDevelopment/KeyPublications</ref>. Key papers included: |
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* A March 2006 online paper in the journal ''[[Vaccine (journal)|Vaccine]]'' showing, in animal models, that IMP321 could immunopotentiate [[Vaccine therapy|therapeutic vaccines]]<ref>{{cite journal |
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|author=Fougeray S, Brignone C, Triebel F. |
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|title=A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: Preclinical evaluation of IMP321 |
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|journal=Vaccine |
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|volume=24 |
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|issue=26 |
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|pages=5426-33 |
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|date=June 29, 2006 |
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|pmid=16621192 |
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|url=http://www.ncbi.nlm.nih.gov/pubmed/16621192 |
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}}</ref>. |
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* A March 2007 paper in the ''Journal of Immune Based Therapies and Vaccines'', showing that IMP321 could increase T cell response potentiation in 48 healthy subjects being administered the hepatitis B surface antigen [[HBsAG]]<ref>{{cite journal |
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|author=Brignone C, Grygar C, Marcu M, Perrin G, Triebel F |
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|title=IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study |
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|journal=J Immune Based Ther Vaccines |
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|volume=5 |
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|issue=5 |
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|date=March 29, 2007 |
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|PMCID=PMC1852106 |
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|doi= 10.1186/1476-8518-5-5 |
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|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852106/ |
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}}</ref>. |
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* An April 2007 online paper, also in ''Vaccine'', showing a similar T cell response potentiation, this time with 20 healthy subjects being administered an influenza vaccine<ref>{{cite journal |
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|author=Brignone C, Grygar C, Marcu M, Perrin G, Triebel F |
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|title=IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: a single-blind phase I study. |
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|journal=Vaccine |
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|volume=25 |
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|issue=24 |
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|pages=4641-50 |
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|date=June 11, 2007 |
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|pmid=17493710 |
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|doi= |
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|url=http://www.ncbi.nlm.nih.gov/pubmed/17493710 |
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}}</ref>. |
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* A September 2007 paper in the ''[[Journal_of_Immunology|Journal of Immunology]]'', showing that IMP321 could induces the activation of a large range of human effector T cells.<ref>{{cite journal |
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|author=Brignone C, Grygar C, Marcu M, Schäkel K, Triebel F. |
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|title=A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells |
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|journal=J Immunol. |
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|volume=179 |
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|issue=6 |
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|pages=:4202-11 |
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|date=September 15, 2007 |
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|pmid= 17785860 |
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|doi= |
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|url=http://www.ncbi.nlm.nih.gov/pubmed/17785860 |
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}}</ref>. |
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* A June 2008 paper in ''[[Clinical Cancer Research]]'' demonstrating that IMP321 at low doses can be used as a T cell [[adjuvant]] for cancer vaccines<ref>{{cite journal |
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|author=Li B, VanRoey M, Triebel F, Jooss K |
|author=Li B, VanRoey M, Triebel F, Jooss K |
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|title=Lymphocyte activation gene-3 fusion protein increases the potency of a granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy |
|title=Lymphocyte activation gene-3 fusion protein increases the potency of a granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy |
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|doi= 10.1158/1078-0432.CCR-07-5200 |
|doi= 10.1158/1078-0432.CCR-07-5200 |
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|url=http://www.ncbi.nlm.nih.gov/pubmed/18519788 |
|url=http://www.ncbi.nlm.nih.gov/pubmed/18519788 |
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}}</ref> |
}}</ref>. |
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== Mechanism of action == |
== Mechanism of action == |
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Revision as of 23:42, 30 April 2015
An editor has nominated this article for deletion. You are welcome to participate in the deletion discussion, which will decide whether or not to retain it. |
IMP321 is a large molecule cancer drug being developed by the clinical stage biotechnology company Prima BioMed (Nasdaq: PBMD). The drug is Prima's lead compound.
IMP321 is a soluble version of the immmune checkpoint molecule LAG3, used as an activator of antigen presenting cells in order to increase an immune response to tumours. IMP321 has been in Phase II clinical testing. Currently the main indication for the drug is metastatic breast cancer.
Background
IMP321 is a soluble dimeric recombinant form of LAG-3, being a fusion protein with immunoglobulin, designed to activate antigen presenting cells. LAG3 is expressed on various cells in the immune system including activated T cells, Natural Killer cells, B cells and dendritic cells, being a ligand for MHC class II molecules. On T cells LAG-3 is an inhibitory receptor. However on dendritic cells LAG-3 is an activator, causing increased antigen presentation when it binds to MHC Class II. IMP321 is designed to harness this activation capacity as a 'chemo-immunotherapeutic', increasing antigen presentation in the wake of tumor debris created by chemotherapy.
History
Soluble LAG3 was first established as a dendritic cell activator in the late 1990s. Frédéric Triebel, who discovered LAG3 in 1990,[1] worked through the 1990s at his laboratory at the Institut Gustave Roussy, in collaboration with INSERM and Merck Serono, to elucidate LAG-3’s role in the immune system. Triebel et. al. had successfully produced a soluble fusion protein of LAG3 and immunoglobulin around 1994 or 1995[2] and had initially evisaged its use as an immunosuppressant, but in March 1999 a key paper in the Journal of Immunology from scientists at the University of Montreal, on which Triebel was listed as a co-author, demonstrated soluble LAG3's role as a dendritic cell activator[3]. Shortly after this, in 2001, Triebel formed a biotechnology company called Immutep SA in 2001 in order to develop the therapeutic potential of LAG3 including soluble LAG3. By 2010 there was a large body of evidence of the efficacy of IMP321 in cancer,[4]. Key papers included:
- A March 2006 online paper in the journal Vaccine showing, in animal models, that IMP321 could immunopotentiate therapeutic vaccines[5].
- A March 2007 paper in the Journal of Immune Based Therapies and Vaccines, showing that IMP321 could increase T cell response potentiation in 48 healthy subjects being administered the hepatitis B surface antigen HBsAG[6].
- An April 2007 online paper, also in Vaccine, showing a similar T cell response potentiation, this time with 20 healthy subjects being administered an influenza vaccine[7].
- A September 2007 paper in the Journal of Immunology, showing that IMP321 could induces the activation of a large range of human effector T cells.[8].
- A June 2008 paper in Clinical Cancer Research demonstrating that IMP321 at low doses can be used as a T cell adjuvant for cancer vaccines[9].
Mechanism of action
When IMP321 engages with MHC Class II molecules on dendritic cells, APC activation takes place resulting in an increase in antigen presentation to cytotoxic CD8+ T cells.
Manufacture
IMP321 is manufactured in CHO cells. Prima BioMed's contract manufacturer is the Shanghai-based WuXi PharmaTech[10].
Phase Ib study in renal cell carcinoma, 2009
Immutep's first serious clinical study of IMP321 was an open label study in 21 metastatic renal cell carcinoma patients, with the drug being used as a monotherapy. This study, which initiated in late 2005[11], saw sustained CD8+ T-cell activation, plus a greater percentage of effector-memory CD8 T cells in all patients at doses above 6 mg / injection. Moreover 7 of 8 evaluable patients dosed at 6 mg had stable disease at 3 months compared with only 3 of 11 at lower dose. This result had statistical significance (p = 0.015). The results were published online in the journal Clinical Cancer Research in September 2009[12].
Phase IIa study in metastatic breast cancer, 2010
A 30-patient Phase IIa open label study in HER2-negative metastatic breast cancer 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.[13]
Planned clinical studies
Prima plans to initiate a Phase IIb study of IMP321 in HER2-negative metastatic breast cancer, as well as a Phase I study in conjunction with an existing approved checkpoint inhibitor, in 2015. The Phase II will be a randomised, double-blind placebo-controlled Phase IIb study in first-line metastatic breast cancer. This trial, comparing IMP321+placlitaxel vs paclitaxel alone, will mainly take place in the European Union. The Phase I will mainly take place in US.[14]
Licensing in China
Immutep granted the rights to IMP321 in mainland China, Hong Kong, Macao and Taiwan in October 2013 to Eddingpharm, a privately-held Chinese pharemaceutical company[15].
References
- ^ Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. (May 1, 1990). "LAG-3, a novel lymphocyte activation gene closely related to CD4". J Exp Med. 171 (5): 1393–405. PMID 1692078.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ WO application 1995030750, Florence Faure, "LAG-3 protein soluble polypeptide fractions, method of production, therapeutic composition and anti-idiotype antibody", published 1995-12-2, assigned to Institut Gustave Roussy, INSERM, Merck Serono
- ^ Avice M, Sarfati M, Triebel F, Delespesse G, Demeure CE. (March 1, 1999). "Lymphocyte activation gene-3, a MHC class II ligand expressed on activated T cells, stimulates TNF-alpha and IL-12 production by monocytes and dendritic cells". J Immunol. 162 (5): :2748–53. PMID 10072520.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ http://www.immutep.org/ProductDevelopment/KeyPublications
- ^ Fougeray S, Brignone C, Triebel F. (June 29, 2006). "A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: Preclinical evaluation of IMP321". Vaccine. 24 (26): 5426–33. PMID 16621192.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Brignone C, Grygar C, Marcu M, Perrin G, Triebel F (March 29, 2007). "IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study". J Immune Based Ther Vaccines. 5 (5). doi:10.1186/1476-8518-5-5.
{{cite journal}}: Unknown parameter|PMCID=ignored (|pmc=suggested) (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Brignone C, Grygar C, Marcu M, Perrin G, Triebel F (June 11, 2007). "IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: a single-blind phase I study". Vaccine. 25 (24): 4641–50. PMID 17493710.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Brignone C, Grygar C, Marcu M, Schäkel K, Triebel F. (September 15, 2007). "A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells". J Immunol. 179 (6): :4202-11. PMID 17785860.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Li B, VanRoey M, Triebel F, Jooss K (June 1, 2008). "Lymphocyte activation gene-3 fusion protein increases the potency of a granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy". J Clin Cancer Res. 14 (11): 3545–54. doi:10.1158/1078-0432.CCR-07-5200. PMID 18519788.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ http://www.immutep.org/news/WuXi%20agreement
- ^ http://www.immutep.com/News/PR5.pdf
- ^ Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. (October 1, 2009). "A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma". J Clin Cancer Res. 15 (19): 6225–31. doi:10.1158/1078-0432.CCR-09-0068. PMID 19755389.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Brignone C, Gutierrez M, Mefti F, Brain E, Jarcau R, Cvitkovic F, Bousetta N, Medioni J, Gligorov J, Grygar C, Marcu M, Triebel F (July 23, 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. PMID 20653948.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ http://www.primabiomed.com.au/media/presentation_pdf/PrimaBiomeddetailedpresentation20150227.pdf
- ^ http://www.eddingpharm.com/content.aspx?id=6
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