Eftilagimod alpha (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
; development code IMP321 or efti) is a
large-molecule cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
drug being developed by the clinical-stage biotechnology company
Immutep
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 ...
. Efti is a soluble version of the
immune checkpoint
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 stimula ...
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:
* as adjuvant to
cancer vaccines (in a low, effective dose of ~250 µg)
* as
first-line 'chemo-immunotherapy,' that is, combined with standard
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
(e.g.
paclitaxel
Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical canc ...
)
* in combination immunotherapy with PD-1 treatments (e.g.
pembrolizumab
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast canc ...
)
Eftilagimod alpha is in Phase II clinical testing. Currently, the main indications for the drug are
metastatic breast cancer
Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary l ...
,
non-small cell lung cancer
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
(NSCLC), and
head and neck squamous cell carcinoma
Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms ...
(HNSCC).
Background
Eftilagimod alpha ("efti" in short) is a soluble LAG-3 fusion protein that activates
antigen-presenting cells. It is a 160
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
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
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
(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 cell
Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.
Function
Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...
s, 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
Frédéric Triebel (born 20 November 1954) 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 Sero ...
, who discovered LAG-3 in 1990, worked through the 1990s at his laboratory at the
Institut Gustave Roussy
Gustave Roussy is the first leader cancer-research hospital in Europe and ranked among the top 3 best specialized hospitals in the world . It is a centre for high quality patient care, research and teaching. It is highly-known for the treatment of ...
, in collaboration with
INSERM and
Merck Serono
Merck Serono (EMD Serono in the United States and Canada) is a pharmaceutical company headquartered in Darmstadt, Germany, and a brand and division of Merck focused on biopharmaceuticals.
In September 2006, Merck KGaA announced its intent to p ...
, 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
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast canc ...
in three distinct and independent cancer indications (following a basket trial design):
# First-line metastatic NSCLC
# Second-line metastatic NSCLC in patients refractory to PD-L1 or PD-1 therapies such as pembrolizumab, nivolumab, avelumab)
# Second-line HNSCC
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
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast canc ...
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
Washington University School of Medicine (WUSM) is the medical school of Washington University in St. Louis in St. Louis, Missouri. Founded in 1891, the School of Medicine has 1,260 students, 604 of which are pursuing a medical degree with ...
in
St. Louis, Missouri
St. Louis () is the second-largest city in Missouri, United States. It sits near the confluence of the Mississippi and the Missouri Rivers. In 2020, the city proper had a population of 301,578, while the bi-state metropolitan area, which e ...
. This 18-patient study evaluated for safety the combination of efti with
gemcitabine
Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by ...
, 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
Saint-Cloud () is a commune in the western suburbs of Paris, France, from the centre of Paris. Like other communes of Hauts-de-Seine such as Marnes-la-Coquette, Neuilly-sur-Seine and Vaucresson, Saint-Cloud is one of France's wealthiest tow ...
near
Paris
Paris () is the Capital city, capital and List of communes in France with over 20,000 inhabitants, most populous city of France, with an estimated population of 2,165,423 residents in 2019 in an area of more than 105 km² (41 sq mi), ma ...
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:
*
Response rate. At the six-month endpoint, 90% of patients had experienced a clinical benefit. The overall response rate was 50% based on RECIST criteria, which compared favorably with the 25% response rate observed in patients on paclitaxel monotherapy in the ECOG2100 study. The lead investigators of the chemo-immunotherapy combination trial also noted relevant differences in the two studies' patient groups: the ECOG2100 patients were on average younger than in the chemo-immunotherapy study, and a significantly lower percentage had disease in three or more sites upon entry into the trial.
* Increase in relevant cell numbers. There was a sustained increase in the number of
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s,
NK cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
, and activated
CD8+ T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
in the patients' blood samples when compared with baseline data, with the increase at the six-month mark having a 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 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
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
. 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:
* Activated T cells. The eight patients experienced sustained CD8+ T-cell activation (as measured by percentage of CD8+ T cells expressing
CD69
CD69 (Cluster of Differentiation 69) is a human transmembrane C-Type lectin protein encoded by the gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is ...
,
CD38,
HLA-DR
HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen – DR isotype) and peptide, generally between 9 and 30 amino acids in ...
) that was
statistically significant compared to the lower doses (p=0.016). There was a greater percentage of effector-memory CD8+ T cells (CD45RO
hi, CD45RA- and CD62L-), again, statistically significant compared to the lower doses (p=0.008). And there was an increase in the expression of co-stimulatory molecules
CD27
CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.
Expression
During mous ...
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 doses. This results had statistical significance (p=0.015).
The results were published in ''
Clinical Cancer Research
''Clinical Cancer Research'' is a peer-reviewed medical journal on oncology, including the cellular and molecular characterization, prevention, diagnosis, and therapy of human cancer, medical and hematological oncology, radiation therapy, pediatric ...
'' 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:
* A March 2007 paper published in the ''Journal of Immune Based Therapies and Vaccines'' showed that efti could increase T-cell response potentiation in healthy subjects being administered the hepatitis B surface antigen
HBsAg
HBsAg (also known as the Australia antigen) is the surface antigen of the hepatitis B virus (HBV). Its presence in blood indicates current hepatitis B infection.
Structure and function
The viral envelope of an enveloped virus has different sur ...
. This randomized and controlled study, conducted in Paris in 2005 saw 40 healthy subjects immunized with 10 µg of HBsAg, and then given either saline (8 subjects) or ascending doses of efti up to 100 µg (32 subjects). An additional 8 subjects received a conventional Hepatitis B vaccine, the Engerix-B product of
GlaxoSmithKline. Subjects administered efti had higher levels of HBsAg antibody in their blood as well as higher levels of antigen-specific T cells.
* An April 2007 online paper in ''Vaccine'' showed a similar T cell response potentiation, this time with 60 healthy subjects being administered Novartis' Agrippal influenza vaccine. This study, initiated in 2005 and completed in mid-2006, compared the influenza vaccine with the vaccine plus efti at doses up to 100 µg. For subjects that received efti there were higher levels of Th1-type CD4+ T cells in PBMC.
Pre-clinical work, 2000-2008
The years 2000 to 2008 saw a number of demonstrations of efti's effectiveness ''in vitro'' and ''in vivo'':
* A June 2000 paper in the ''
Journal of Immunology
The ''Journal of Immunology'' is a biweekly peer-reviewed medical journal that publishes basic and clinical studies in all aspects of immunology. Established in 1916, it changed its name to ''Journal of Immunology, Virus Research and Experimental C ...
'' showed that efti (LAG-3Ig) could function as a vaccine adjuvant when immunizing mice with hepatitis B surface antigen and soluble
ovalbumin
Ovalbumin (abbreviated OVA) is the main protein found in egg white, making up approximately 55% of the total protein. Ovalbumin displays sequence and three-dimensional homology to the serpin superfamily, but unlike most serpins it is not a serin ...
.
* An April 2002 paper in the ''Journal of Immunology'' showed the mechanism of action of efti in inducing maturation and activation of human monocyte-derived dendritic cells, whereby efti binds to MHC class II molecules expressed in plasma membrane
lipid raft
The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial ...
s on immature dendritic cells 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
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
.
* A February 2003 paper in ''Vaccine'' showed that, in human immature monocyte-derived dendritic cells, efti could induce the production of chemokines that would direct the migration of maturing dendritic cells to lymph nodes. Notably, LAG-3-matured dendritic cells were upregulated for
CCR7. Later, the same authors showed that soluble LAG-3 could reduce the differentiation of macrophages and dendritic cells from monocytes, suggesting that the positive effect of LAG-3 as a dendritic cell-activator applied to pre-existing dendritic cells.
* A March 2003 paper in ''
Cancer Research
Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure.
Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and ...
'' from scientists at the University of Turin, which included Triebel as a co-author, showed that, in mice, efti could potentiate a DNA vaccine targeting HER2 in a spontaneous breast cancer model.
* A March 2006 online paper in ''Vaccine'' showed, in animal models, that efti could immuno-potentiate
therapeutic vaccines A therapeutic vaccine is a vaccine which is administered after a disease or infection has already occurred. A therapeutic vaccine works by activating the immune system of a patient to fight an infection. A therapeutic vaccine differs from a prophyla ...
by inducing dendritic cell maturation.
* An April 2006 paper in ''Cancer Research'' showed, ''in vitro'', showed that efti could induce an antigen-specific CD8+ T-cell response in human PBMCs – evidenced by the upregulation of T cells that displayed cytotoxic activity and produced Tc1 cytokines. The investigators for this work used influenza matrix protein antigen and the tumor antigens
Melan-A
Protein melan-A also known as melanoma antigen recognized by T cells 1 or MART-1 is a protein that in humans is encoded by the ''MLANA'' or "MALENA" gene. A fragment of the protein, usually consisting of the nine amino acids 27 to 35, is bound by ...
/MART-1 and
survivin to verify this CD8+ T cell response. They found that a LAG-3-related adjuvant effect depended on direct activation of antigen-presenting cells. For this paper Triebel collaborated with scientists at the Instituto Nazionale dei Tumori in
Milan, Italy
Milan ( , , Lombard: ; it, Milano ) is a city in northern Italy, capital of Lombardy, and the second-most populous city proper in Italy after Rome. The city proper has a population of about 1.4 million, while its metropolitan city ...
.
* A September 2007 paper in the ''Journal of Immunology'', showed that efti could induce 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 naïve or
central memory T cells, were induced by efti to a full Tc1 response. In their ''in vitro'' work with human blood samples the investigators found that efti bound all the circulating dendritic cells and a fraction of MHC class II+ monocytes. Significantly, 92% of samples responded at clinically meaningful levels to a first, short exposure of efti. The investigators contrasted the potency of efti with TLR1-9 agonists which, while inducing IL-10, are unable to induce a Tc1 IFN-γ response.
* A March 2008 paper in the ''Journal of Immunology'', again in collaboration with the Instituto Nazionale dei Tumori, showed ''in vitro'' that efti could induce the maturation of monocyte-derived dendritic cells to produce chemokines and TNF-α, and that, when given with CD40/CD40L, it could induce full functional activation of dendritic cells so that they could produce heightened levels of IL-12. IL-12 is required for the induction of IFN-γ, which in turn is critical for the induction of Th1 cells.
* A June 2008 paper in ''
Clinical Cancer Research
''Clinical Cancer Research'' is a peer-reviewed medical journal on oncology, including the cellular and molecular characterization, prevention, diagnosis, and therapy of human cancer, medical and hematological oncology, radiation therapy, pediatric ...
'' demonstrated that efti 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. Cell Genesys' lead product,
GVAX, consisted of whole tumor cells genetically modified to secrete GM-CSF. When mice that had been inoculated with the B16 mouse melanoma cell line received both GVAX and 0.1 µg of soluble LAG-3, the result was a 7-day median survival advantage (47 to 54 days) over the mice which received only GVAX at day 3. Correlated with this survival data, 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.
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
is a national university in Yamaguchi Prefecture, Japan. It has campuses at the cities of Yamaguchi and Ube.
History
The root of the university was , a private school founded by Ueda Hōyō (, 1769–1853) in 1815. In 1863 the school became a ...
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
Hong Kong ( (US) or (UK); , ), officially the Hong Kong Special Administrative Region of the People's Republic of China (abbr. Hong Kong SAR or HKSAR), is a city and special administrative region of China on the eastern Pearl River Delta i ...
,
Macao
Macau or Macao (; ; ; ), officially the Macao Special Administrative Region of the People's Republic of China (MSAR), is a city and special administrative region of China in the western Pearl River Delta by the South China Sea. With a po ...
and
Taiwan
Taiwan, officially the Republic of China (ROC), is a country in East Asia, at the junction of the East and South China Seas in the northwestern Pacific Ocean, with the People's Republic of China (PRC) to the northwest, Japan to the nort ...
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
WuXi AppTec (WuXi pronounced ''Wu-shee'') is a global pharmaceutical, biopharmaceutical, and medical device company.
The company covers the development cycle through five core operations, including small molecule R&D and manufacturing, biologics ...
, 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.
References
{{Reflist, 2
Experimental cancer drugs
Biotechnology