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IMP321

From EverybodyWiki Bios & Wiki


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. The drug is administered by subcutaneous injection. IMP321 has been in Phase II clinical testing. Currently the main indication for the drug is metastatic breast cancer.

Background[edit]

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 (NK 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[edit]

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 1995[2] and had initially envisaged its use as an immunosuppressant after evidence that its interaction with MHC class II molecules leads to the down-regulation of CD4+ antigen-specific T cell clone proliferation and cytokine secretion,[3] and that it inhibited the alloresponses of naive peripheral blood lymphocytes.[4] However 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.[5] 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.[6] Immutep was acquired by Prima BioMed in 2014 and as a result IMP321 became Prima BioMed's lead compound.

Pre-clinical work, 2000-2008[edit]

The years 2000 to 2008 saw a number of demonstrations of IMP321's effectiveness in vitro and in vivo.

  • A June 2000 paper in in the Journal of Immunology showing that IMP321 would act as a vaccine adjuvant when immunizing mice with hepatitis B surface antigen and soluble ovalbumin.[7]
  • An April 2002 paper in the Journal of Immunology showed the mechanism of action in IMP321 in inducing maturation and activation of human monocyte-derived dendritic cells, where the IMP321 binds to MHC class II molecules expressed in plasma membrane lipid rafts on immature dendritic cells and and induces morphological changes such as the formation of dendritic projections, an up-regulation of co-stimulatory molecules, and the production of IL-12 and TNF-α.[8]
  • A February 2003 paper in the journal Vaccine showed that, in human immature monocyte-derived dendritic cells, IMP321 could induce production of the chemokines that would direct the migration of maturing dendritic cells to lymph nodes. Notably, LAG-3-matured dendritic cells were upregulated for CCR7.[9] Later, the same authors showed that soluble LAG-3 would reduce the differentiation of macrophages and dendritic cells from monocytes, suggested that the positive effect of LAG-3 as a dendritic cell activator related to existing dendritic cells.[10]
  • A March 2006 online paper in Vaccine showed, in animal models, that IMP321 could immunopotentiate therapeutic vaccines by inducing dendritic cell maturation.[12]
  • An April 2006 paper in Cancer Research showed, in vitro, that IMP321 would induce an antigen-specific CD8+ T-cell response in human PBMCs, with the T cells thus created being cytotoxic and capable of producing Tc1 cytokines. Moreover this LAG-3-related adjuvant effect depended on direct activation of antigen presenting cells. For this paper Triebel collaborated with scientists at the Istituto Nazionale dei Tumori in Milan.[13]
  • 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, resulting in the production of IFN-γ and TNF-α among other cytokines. The investigators found that effector and effector memory but not naive or central memory T cells could be induced by IMP321 to a full Tc1 response [14]
  • A March 2008 paper in the Journal of Immunology, again in collaboration with the Instituto Nazionale dei Tumori, showing in vitro that IMP321 could induce the maturation of monocyte-derived dendritic cells to produce chemokines and TNF-α, and that, when it was given with CD40/CD40L, it could induce full functional activation of such dendritic cells so that they could produce high levels of IL-12. That cytokine is required for the induction of IFN-γ, which in turn is critical for the induction of Th1 cells.[15]
  • A June 2008 paper in Clinical Cancer Research demonstrated that IMP321 at low doses could be used as a T cell adjuvant for cancer vaccines. For this work Triebel collaborated with Cell Genesys, a cancer vaccine company based in South San Francisco. That company's lead product, called GVAX, was whole tumor cells genetically modified to secrete GM-CSF.[16] When mice that had been inoculated with the B16 mouse melanoma cell line received both GVAX and only 0.1 μg of soluble LAG-3, the result was a 7 day median survival advantage (47 days to 54) for the mice that got both, over those which just received GVAX at day 3. Correlated with this survival, the investigators noted higher levels of tumor-infiltrating lymphocytes for the combination group, and a higher number of antigen-specific CD8+ T cell responses. There was also a notable IgG1 humoral response.[17][18]

Early proof-of-concept studies, 2007[edit]

Immmutep conducted two Phase I studies with IMP321 designed to evaluate the safety as well as immune response profile of IMP321 in humans

  • A March 2007 paper in the Journal of Immune Based Therapies and Vaccines, showed that IMP321 could increase T cell response potentiation in healthy subjects being administered the hepatitis B surface antigen HBsAg. This randomised and controlled study, conducted in Paris in 2005, saw 40 people immunized with 10 μg of HBsAg, and then given either saline (8 subjects) or ascending doses of IMP321 up to 100 μg (32 subjects). An additional 8 subjects received a conventional Hepatitis B vaccine, the Engerix-B product of GlaxoSmithKline. Subjects who got IMP321 had higher levels of HBsAg antibody in their blood as well as higher levels of antigen-specific T cells[19]
  • An April 2007 online paper, in Vaccine, showed a similar T cell response potentiation, this time with subjects being administered Novartis' Agrippal influenza vaccine. This study compared the influenza vaccine with the vaccine plus IMP321 at doses up to 100μg. For subjects that received IMP321 there were higher levels of Th1-type CD4 T cells in PBMC.[20]

Phase Ib study in renal cell carcinoma, 2009[edit]

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 (ClinicalTrials.gov identifier NCT00351949). These patients were known to be immunocompromised. The study, which initiated in late 2005[21] saw patients administered ascending doses of IMP321 up to 30 mg per injection fortnightly for six injections. The drug appeared to work at the two highest doses of 6 mg and 30 mg, with two notable outcomes for the eight patients who received these doses:

  • Activated T cells. The 8 patients experienced a sustained CD8+ T-cell activation (as measured by percentage of CD8+ cells expressing CD69, CD38 and HLA-DR) that was statistically significant compared to the lower doses (p=0.016). There was a greater percentage of effector-memory CD8 T cells (CD45ROhi,CD45RA- and CD62L-), again, statistically significant compared to the lower doses (p=0.008). And there was an increase in the costimulation molecules CD27 and CD28 (CD27+CD28+, p=0.016; and CD27-CD28+, p=0.014).
  • Stable disease. 7 of the 8 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.[22]

Phase IIa study in metastatic breast cancer, 2006-2010[edit]

A 30-patient Phase IIa open label study in HER2-negative metastatic breast cancer (ClinicalTrials.gov identifier NCT00349934) has suggested that IMP321 works as a chemo-immunotherapeutic in breast cancer, where chemotherapy creates tumor debris, and IMP321 increases activation of APCs as they take up that debris. This trial arose in part from the findings of a June 2005 online paper in the journal Cancer Letters by two researchers at the Centre René Huguenin in Saint-Cloud near Paris who had collaborated with Frédéric Triebel. That paper demonstrated that soluble LAG3 correlated with improved survival in breast cancer patients whose tumors were estrogen or progesterone receptor positive.[23] The Phase IIa study which partly confirmed this finding was initiated by Immutep around August 2006[24] and was conducted at the René Huguenin as well as two other Paris hospitals - the Hôpital Européen Georges-Pompidou (15th arrondissement) and the Hôpital Tenon (20th arrondissement). In the study, patients on paclitaxel were administered ascending doses of IMP321 on days 2 and 16 of a 28-day cycle of paclitaxel over six cycles. The maximum IMP321 dose was 6.25 mg. Paclitaxel was given on days 1, 8 and 15, meaning patients got IMP321 the day after paclitaxel had created tumor debris. There were two notable outcomes to this study:

  • Response rate. At the six-month measurement point the response rate according to the RECIST criteria was 50%. The study investigators argued that this compared favorably with a 25% rate registered for paclitaxel in another study called ECOG2100, which had the same dosing regiment for paclitaxel but where the response rate for patients with measurable disease at inclusion was only 25%.[25] Some 90% of patients experienced clinical benefit because at the six-month endpoint only 3 patients had progressive disease. The investigators also noted that the patients in their trial were older and there were a significantly greater percentage of patients that had disease in three or more sites than was the case in the ECOG2100 study.
  • Increase in relevant cell numbers. There was a sustained increase in the number of monocytes, NK cells and activated CD8+ T cells in the patient's blood samples, compared to baseline, with the increase at the six-month mark having statistical significance in each case. Also, the percentage of PBMCs represented by dendritic cells and terminally differentiated effector memory T cells increased, again with statistical significance.

The results of this study were published in July 2010 in the Journal of Translational Medicine[26] [27]

Phase I study in pancreatic cancer, 2009-2012[edit]

In April 2009 Immutep announced its involvement in a Phase I study in pancreatic cancer conducted at Washington University School of Medicine in St. Louis.[28] This 18-patient study evaluated for safety thwe combination of IMP321 with gemcitabine at doses up to 2 mg. The combination was found to be safe however no significant differences were observed when comparing pre- and post-treatment levels of monocytes, dendritic cells to T cells, probably due to sub-optimal dosing. The results of the study were reported online in the journal Investigational New Drugs in August 2012.[29]

Phase I study in metastatic melanoma, 2007-2014[edit]

In August 2007 Immutep announced its involvement in a Phase I study being conducted at the University Hospital of Lausanne in Switzerland where a group was working on adoptive T cell transfer after transient lymphodepletion associated with peptide vaccination.[30] With this approach, the patient's lymphocytes were depleted using chemotherapy, after which patients were given their own peripheral mononuclear cells, enriched with tumour-specific CD8 T cells. During the immune reconstitution period the patients were given a cancer vaccine containing a peptide melanoma antigen called MART1, adjuvanted with incomplete Freund’s adjuvant and, in half the patients, IMP321. While there was no confirmed responses as per the RECIST criteria for the 12 patients recruited, the investigators noted a significant expansion of MART-1-specific CD8 T cells in the IMP321 group, where there was also a higher proportions of effector cells and a significantly reduced expansion of regulatory T cells. These results were published in the Journal of Translational Medicine in April 2014[31]

Planned clinical studies[edit]

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.[32]

Licensing in China[edit]

Immutep granted the rights to IMP321 in mainland China, Hong Kong, Macao and Taiwan in October 2013 to Eddingpharm, a privately-held Chinese pharmaceutical company.[33]

Mechanism of action[edit]

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[edit]

IMP321 is manufactured in CHO cells. Prima BioMed's contract manufacturer is the Shanghai-based WuXi PharmaTech.[34]

References[edit]

  1. ↑ 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.CS1 maint: Multiple names: authors list (link)
  2. ↑ 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 
  3. ↑ Huard B, Prigent P, Pagès F, Bruniquel D, Triebel F (May 1, 1996). "T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding". Eur J Immunol. 26 (5): 1180–6. PMID 8647185.CS1 maint: Multiple names: authors list (link)
  4. ↑ Subramanyam M, Wands G, Nabioullin R, Tepper MA. (May 1, 1998). "Soluble human lymphocyte activation gene-3 modulates allospecific T cell responses". Int Immunol. 10 (5): 679–89. PMID 9645616.CS1 maint: Multiple names: authors list (link)
  5. ↑ 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.CS1 maint: Multiple names: authors list (link)
  6. ↑ "Key Publications". www.immutep.org. Immutep.
  7. ↑ El Mir S1, Triebel F (June 1, 2000). "MA soluble lymphocyte activation gene-3 molecule used as a vaccine adjuvant elicits greater humoral and cellular immune responses to both particulate and soluble antigens". J Immunol. 164 (11): 5583–9. PMID 10820232.
  8. ↑ Andreae S, Piras F, Burdin N, Triebel F (April 15, 2002). "Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223)". J Immunol. 168 (8): 3874–80. PMID 11937541.CS1 maint: Multiple names: authors list (link)
  9. ↑ Buisson S, Triebel F. (February 14, 2003). "MHC class II engagement by its ligand LAG-3 (CD223) leads to a distinct pattern of chemokine and chemokine receptor expression by human dendritic cells". Vaccine. 21 (9): :862–8. PMID 12547595.
  10. ↑ Buisson S, Triebel F. (March 1, 2005). "LAG-3 (CD223) reduces macrophage and dendritic cell differentiation from monocyte precursors". Immunology. 114 (3): :369–74. PMID 15720438.
  11. ↑ Cappello P, Triebel F, Iezzi M, Caorsi C, Quaglino E, Lollini PL, Amici A, Di Carlo E, Musiani P, Giovarelli M, Forni G (May 15, 2003). "LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice". Cancer Res. 63 (10): 2518–25. PMID 12750275.CS1 maint: Multiple names: authors list (link)
  12. ↑ 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.CS1 maint: Multiple names: authors list (link)
  13. ↑ Casati C, Camisaschi C, Rini F, Arienti F, Rivoltini L, Triebel F, Parmiani G, Castelli C. (April 15, 2006). "Soluble Human LAG-3 Molecule Amplifies the In vitro Generation of Type 1 Tumor-Specific Immunity". Cancer Res. 66 (8): 4450–60. PMID 16618772.CS1 maint: Multiple names: authors list (link)
  14. ↑ 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.CS1 maint: Multiple names: authors list (link)
  15. ↑ Casati C, Camisaschi C, Novellino L, Mazzocchi A, Triebel F, Rivoltini L, Parmiani G, Castelli C (March 15, 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. PMID 18322184.CS1 maint: Multiple names: authors list (link)
  16. ↑ Hege KM, Jooss K, Pardoll D (September 2006). "GM-CSF gene-modifed cancer cell immunotherapies: of mice and men". Int Rev Immunol. 25 (5–6): 321–352. PMID 17169779.CS1 maint: Multiple names: authors list (link)
  17. ↑ 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.CS1 maint: Multiple names: authors list (link)
  18. ↑ WO application 2009032256, Karin Jooss, "APC activators in combination with a cytokine-secreting cell and methods of use thereof", published 2009-05-07, assigned to Cell Genesys 
  19. ↑ 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. PMC 1852106.CS1 maint: Multiple names: authors list (link)
  20. ↑ 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.CS1 maint: Multiple names: authors list (link)
  21. ↑ "Immutep initiates Phase I clinical trial in renal cell cancer" (PDF) (Press release). November 22, 2005.
  22. ↑ 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.CS1 maint: Multiple names: authors list (link)
  23. ↑ Triebel F, Hacene K, Pichon MF (April 8, 2006). "A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors". Cancer Lett. 235 (1): 147–53. PMID 15946792.CS1 maint: Multiple names: authors list (link)
  24. ↑ "Immutep Announces That ImmuFact IMP321 Has Entered A Phase I Chemoimmunotherapy Trial In Breast Cancer" (PDF) (Press release). August 3, 2006.
  25. ↑ Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. (December 27, 2007). "Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer". N Engl J Med. 357 (26): 2666–76. PMID 18160686.CS1 maint: Multiple names: authors list (link)
  26. ↑ 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.CS1 maint: Multiple names: authors list (link)
  27. ↑ WO application 2009044273, Frédéric Triebel, "Use of recombinant LAG-3 or the derivatives thereof for eliciting monocyte immune response", published 2009-04-09, assigned to Immutep 
  28. ↑ "Immutep Announces Start of Clinical Trial in Pancreatic Cancer" (PDF). Immutep.
  29. ↑ Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, Simon PO, Mitchem JB, Hornick JR, Sorscher S, Picus J, Suresh R, Lockhart AC, Tan B, Hawkins WG (June 1, 2013). "A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma". Invest New Drugs. 31 (3): 707–13. doi:10.1007/s10637-012-9866-y. PMID 22864469.CS1 maint: Multiple names: authors list (link)
  30. ↑ "Immutep Announces That ImmuFact IMP321 Has Entered a Phase I Lymphodepletion Therapeutic Vaccine Trial in Metastatic Melanoma" (PDF). Immutep. August 28, 2007.
  31. ↑ Romano E, Michielin O, Voelter V, Laurent J, Bichat H, Stravodimou A, Romero P, Speiser DE, Triebel F, Leyvraz S1, Harari A (April 12, 2014). "MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial". J Transl Med. 12 (97). doi:10.1186/1479-5876-12-97. PMID 24726012.CS1 maint: Multiple names: authors list (link)
  32. ↑ "Prima BioMed Detailed Presentation" (PDF). Prima BioMed. Prima BioMed. 27 February 2015.
  33. ↑ "Immutep and Eddingpharm sign agreement for development of ImmuFact IMP321 in China" (PDF) (Press release). October 8, 2013.
  34. ↑ "Immutep and Eddingpharm start production of ImmuFact IMP321 at WuXi AppTec in China" (PDF) (Press release). April 8, 2014.


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