Eftilagimod alpha
Eftilagimod alpha (INN; development code IMP321 or efti) 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: Eftilagimod alpha is in Phase II clinical testing. Currently, the main indications for the drug are metastatic breast cancer, non-small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC). Background. Eftilagimod alpha ("efti" in short ) is a soluble LAG-3 fusion protein that activates antigen-presenting cells. It is a 160 kDa protein consisting of the four extracellular domains of LAG-3 fused to the Fc region of an IgG1(LAG-3Ig). Efti binds preferentially to a subset of MHC class II molecules that are enriched in lipid rafts and/or composed of stable peptide-MHC II (pMHCII) complexes. On T cells, membrane-anchored LAG-3 is an inhibitory receptor downregulating T-cell receptor (TCR) signaling. Efti – as a soluble LAG-3 protein – is an MHC class II agonist and therefore a dendritic-cell activator, causing increased antigen presentation to cytotoxic (CD8 +) T cells. In the absence of antigen presentation via MHC class II molecules, efti reactivates dormant antigen-experienced memory T cells, allowing them to recognize their antigen targets at the tumor site. History. Soluble LAG-3 was first established as a dendritic-cell activator in the late 1990s. Frédéric Triebel, who discovered LAG-3 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 adaptive immune system. Triebel et al. had successfully produced a soluble LAG-3Ig fusion protein by 1995 and subsequently discovered  its anti-cancer properties "in vivo" in different mouse tumor models in 1990. Shortly thereafter in 2001, Triebel formed a biotechnology company called Immutep SA in order to develop the therapeutic potential of LAG-3. Immutep was acquired by Prima BioMed in 2014 and as a result Eftilagimod alpha became Prima BioMed's lead compound. In 2017, Prima BioMed changed its name to Immutep to reflect its developmental focus on LAG-3 therapeutics. Clinical Trials. Ongoing Clinical Studies. As of February 2020, three clinical studies are ongoing: Metastatic breast carcinoma (HER2 HR). In the AIPAC study efti is administered in combination with  paclitaxel to women with HER2 metastatic breast cancer whose disease progressed after endocrine therapy. This Phase IIb trial is a randomized, double-blind, placebo-controlled study aiming to enroll 241 patients. It had an open run-in phase with 15 patients being treated and the results were published at the 2018 ASCO annual meeting. The study is ongoing and is expected to show results in the first half of 2020. Solid Tumors. The INSIGHT Phase I study is investigating the feasibility and safety of different routes of drug delivery (e.g. intra-tumoral, intra-peritoneal, and subcutaneous). Non-small Cell Lung  Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC). In the TACTI-002 Phase II study, efti is administered in combination with pembrolizumab in three distinct and independent cancer indications (following a basket trial design): In each of the three indications, a first cohort of patients is treated and only if a certain pre-determined number of tumor responses is reached may a second cohort of patients be enrolled. This follows the Simons two-stage design. At the 2019 SITC meeting, Immutep released interim results from their first-line metastatic NSCLC trial before announcing that stage 2 of the trial  had officially commenced. In early 2020, Immutep also announced in a press release the continuation of their stage 2 trial in HNSCC. Completed Clinical Trials. Phase I study in melanoma, 2016-2019. The TACTI-mel Phase I study investigated the safety and potential synergies of efti in combination with the programmed cell death (PD-1) antibody pembrolizumab in unresectable or metastatic melanoma. The trial is noted as complete on clinicaltrials.gov; final results were published at the 2019 World Immunotherapy Congress in Basel, Switzerland. No major safety concerns and preliminary safety results were reported. Phase I study in pancreatic cancer, 2009-2012 . 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, Missouri. This 18-patient study evaluated for safety the combination of efti with gemcitabine, a chemotherapy drug, 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, and T cells, likely due to sub-optimal dosing. The results of the study were reported online in "Investigational New Drugs" in August 2012. Phase IIa study in  metastatic breast cancer, 2006-2010. A 30-patient Phase IIa open-label study in HER2-negative metastatic breast cancer has suggested that efti works as a chemo-immunotherapeutic in breast cancer, whereby chemotherapy creates tumor debris (circulating tumor antigen), and efti increases activation of antigen-presenting cells (APCs) as they take up that debris. This trial arose in part from the findings of a June 2005 online paper in "Cancer Letters" by two researchers at the Centre René Huguenin in Saint-Cloud near Paris who had collaborated with Frédéric Triebel. This paper demonstrated that the level of serum soluble LAG-3  correlated with improved survival in breast cancer patients whose tumors were estrogen or progesterone receptor-positive. In the study, patients on weekly low-dose paclitaxel (chemotherapy) were administered ascending subcutaneous doses of efti on days 2 and 16 of a 28-day cycle of paclitaxel over six cycles. The maximum efti dose was 6.25 mg. Paclitaxel was given on days 1, 8, and 15, meaning that patients were administered efti the day after paclitaxel had killed some tumor cells leading to antigenic tumor debris to be processed by dendritic cells for antigen presentation to CD8+ T cells. 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 Eftilagimod alpha. Phase Ib study in renal cell carcinoma, 2005-2009. Immutep's first Phase I study of efti in cancer patients was an open-label study in 21 metastatic renal cell carcinoma patients, with the drug being used as a monotherapy. These patients were known to  be immunocompromised. The study, which began in late 2005, saw the patients administered ascending doses of efti (up to 30 mg per subcutaneous injection) fortnightly for six injections. The drug appeared to work at the two highest doses of 6 mg and 30 mg, with the primary outcomes among the eight patients who received these doses: The results were published in "Clinical Cancer Research" in September 2009. Early proof-of-concept studies, 2005-2007. Immutep conducted two Phase I studies designed to evaluate the safety as well as immune response profile of efti in humans: Pre-clinical work, 2000-2008 . The years 2000 to 2008 saw a number of demonstrations of efti's effectiveness "in vitro" and "in vivo": Potential use in a liver cancer vaccine. In May 2015, Immutep (Prima Biomed at the time) announced a collaboration with NEC Corporation and Yamaguchi University in Japan in which Yamaguchi researchers would be combining efti with a peptide vaccine they had developed as a potential therapeutic for hepatocellular carcinoma. Licensing in China. Immutep granted the rights to efti in mainland China, Hong Kong, Macao and Taiwan in October 2013 to Eddingpharm, a privately held Chinese pharmaceutical company. Manufacture. Efti is manufactured  in CHO cells. Immutep worked with Henogen as the contracted manufacturing organization to provide efti for all trials until 2014. Immutep changed their contracted manufacturer to the Shangai-based WuXi PharmaTech, who began producing efti for all trials starting from 2016 onwards. 200-liter batches of efti are accepted for clinical trial use by multiple national agencies including FDA, PEI and MHRA. Recently, it was reported that upscaling to 2000-liter batches has initiated.