IMP321 is a large molecule cancer drug being developed by the clinical stage biotechnology company Prima BioMed (Nasdaq: IMMP). The drug is Prima's lead compound. IMP321 (INN name: eftilagimod alpha) is soluble version of the immune checkpoint molecule LAG3, used to increase an immune response to tumours. The drug is administered by subcutaneous injection. IMP321 has two intended clinical settings, 'low dose' (for example 250 µg) as adjuvant to cancer vaccines and 'high dose' (such as 12 injections of 6 mg each) as first-line 'chemo-immunotherapy', that is, combined with standard chemotherapy. IMP321 has been in Phase II clinical testing. The product has been shown to be non-immunogenic, that is, no anti-IMP321 antibodies have been detected in clinical trials. Currently the main indication for the drug is metastatic breast cancer.
IMP321 is a 200 kDA soluble dimeric recombinant fusion protein of the extracellular portion of LAG3 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 to cytotoxic CD8+ T cells 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.
Soluble LAG3 was first established as a dendritic cell activator in the late 1990s. Frédéric Triebel, who discovered LAG3 in 1990, 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 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, and that it inhibited the alloresponses of naive peripheral blood lymphocytes. 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. 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. Immutep called its product 'ImmuFact IMP321', the 'act' part of ImmuFact referring to the products immune activating properties. By 2010 there was a large body of evidence of the efficacy of IMP321 in cancer. Immutep was acquired by Prima BioMed in 2014 and as a result IMP321 became Prima BioMed's lead compound.
The years 2000 to 2008 saw a number of demonstrations of IMP321's effectiveness in vitro and in vivo.
Immutep conducted two Phase I studies with IMP321 designed to evaluate the safety as well as immune response profile of IMP321 in humans
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, Immutep code name P003). These patients were known to be immunocompromised. The study, which initiated in late 2005 saw patients administered ascending doses of IMP321 up to 30 mg per injection fortnightly for six injections subcutaneously. 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:
The results were published online in the journal Clinical Cancer Research in September 2009.
A 30-patient Phase IIa open label study in HER2-negative metastatic breast cancer (ClinicalTrials.gov identifier NCT00349934, Immutep code name P005) 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. The Phase IIa study which partly confirmed this finding was initiated by Immutep around August 2006 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 subcutaneous 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:
The results of this study were reported in January 2010, and following an oral presentation at the ASCO Annual Meeting in June 2010 the results were published in July 2010 in the Journal of Translational Medicine. The study provided the basis of a new patent filing for IMP321 .
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. This 18-patient study (ClinicalTrials.gov identifier NCT00732082, Immutep code name P008) evaluated for safety the 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.
In September 2006 Immutep announced its involvement in a Phase I study being conducted at the Cancer Centre at the St Luc University Clinic in Brussels. This 20-patient study (ClinicalTrials.gov identifier NCT00365937, Immutep code name P006) was a randomised open-label four-arm trial comparing a selected set of 8 HLA-A2 melanoma peptide antigens with or without IMP321 and/or Montanide ISA 51, a vaccine adjuvant composed of a light mineral oil and a surfactant system designed to make a water-in-oil emulsion. In this study all patients randomized in the peptides-alone arm relapsed during the first year whereas a majority of patients in the three other groups were still disease-free at follow-up, when the median disease-free survival follow-up was 33 months. The results of this study were presented to the 25th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer in Washington, DC in October 2010.
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. This study recruited 12 patients (ClinicalTrials.gov identifier NCT00324623, Immutep code name P007) where 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.
A third melanoma trial, also at the University Hospital of Lausanne (ClinicalTrials.gov identifier NCT01308294, Immutep code name P009) was designed to assess the effectiveness of IMP321 when combined with the melanoma peptides NA-17, MAGE-3.A2, NY-ESO-1, Melan-A and MAGE-A3-DP4. This study has been terminated due to a low enrollment rate and has not reported any data.
In 2010 scientists at the Istituto Nazionale dei Tumori initiated a 20-patient open label study in prostate cancer patients that combined peptides from survivin with IMP321 (EudraCT Number 2009-017798-39, Immutep code name P010). The peptides, restricted for different HLA-I alleles, are emulsified in Montanide ISA 51. This study has yet to report any data.
As of October 2017 two clinical studies are ongoing.
In the AIPAC study  IMP321 is administered in combination with Paclitaxel to woman with HER2-negative metastatic breast cancer who progressed after endocrine therapy. This Phase IIb trial is a randomized, double-blind placebo-controlled study aiming to enroll 241 patients.
The TACTImel Phase I study  is investigating safety and possible synergies with the anti-programmed cell death antibody pembrolizumab in unresectable or metastatic melanoma.
The INSIGHT Phase I study  is investigating feasibility and safety of different routes of drug application (e.g. intra tumoral, intra peritoneal and sub cutaneous).
Prima announced in late May 2015 that it had filed a provisional patent application over the use of IMP321 in combination with immune checkpoint inhibitors, following on from pre-clinical work showing higher response rates from the combinations.
In May 2015 Prima announced a collaboration with NEC Corporation and Yamaguchi University in Japan in which Yamaguchi researchers will be combining IMP321 with a peptide vaccine they have developed as a potential therapeutic for hepatocellular carcinoma.
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.
IMP321 is manufactured in CHO cells. Immutep worked with Lonza in 2012 on cell line selection, master cell banking and process development for IMP321 after which the Shanghai-based WuXi PharmaTech was retained as contract manufacture.