Ansuvimab, sold under the brand name Ebanga, is a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

medication for the treatment of ''Zaire ebolavirus'' (Ebolavirus) infection. The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Ansuvimab was approved for medical use in the United States in December 2020.

Chemistry

The drug is composed of a single

(mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of

Ebola virus disease Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after becom ...

Kikwit Kikwit is the largest city of Kwilu Province, lying on the Kwilu River in the southwestern part of the Democratic Republic of the Congo. Kikwit is also known in the region under the nickname "The Mother". The population is approximately 458,000 ( ...

Democratic Republic of Congo The Democratic Republic of the Congo (french: République démocratique du Congo (RDC), colloquially "La RDC" ), informally Congo-Kinshasa, DR Congo, the DRC, the DROC, or the Congo, and formerly and also colloquially Zaire, is a country in ...

. In work supported by the United States

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of

Medimmune MedImmune, LLC was a wholly owned subsidiary of AstraZeneca before February 14, 2019, when it was announced that the MedImmune name and branding would be discontinued in favor of AstraZeneca. MedImmune was founded in 1988 as Molecular Vaccines, ...

Mechanism of action

Neutralization

Ansuvimab is a

monoclonal antibody therapy Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those ...

that is infused

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

into patients with

. Ansuvimab is a

neutralizing antibody A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibod ...

, meaning it binds to a protein on the surface of ''

Ebola virus ''Zaire ebolavirus'', more commonly known as Ebola virus (; EBOV), is one of six known species within the genus ''Ebolavirus''. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and ot ...

'' that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with virus's cell

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

protein, Niemann-Pick C1 (NPC1). This "competition" by ansuvimab prevents Ebola virus from binding to NPC1 and "neutralizes" the virus's ability to infect the targeted cell.

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to "kill" virus particles directly and/or kill infected cells using antibody-mediated "effector functions" such as opsonization,

complement-dependent cytotoxicity Complement-dependent cytotoxicity (CDC) is an effector function of IgG and IgM antibodies. When they are bound to surface antigen on target cell (e.g. bacterial or viral infected cell), the classical complement pathway is triggered by bonding protei ...

antibody-dependent cell-mediated cytotoxicity Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose ...

and antibody-dependent

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of

complement A complement is something that completes something else. Complement may refer specifically to: The arts * Complement (music), an interval that, when added to another, spans an octave ** Aggregate complementation, the separation of pitch-class ...

proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity. Other functional killing tests have not been performed.

History

Ansuvimab is a

that is being evaluated as a treatment for

. Its discovery was led by the laboratory of Nancy Sullivan at the United States

Vaccine Research Center The Vaccine Research Center (VRC), is an intramural division of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), US Department of Health and Human Services (HHS). The mission of ...

and J. J. Muyembe-Tamfum from the

Institut National pour la Recherche Biomedicale The Institut National de la Recherche Biomédicale (INRB) is the national medical research organization of the Democratic Republic of the Congo. The responsible ministry is the Ministry of Scientific Research and Technology. The National Biomedic ...

(INRB) in the

, working in collaboration with the Institute for Biomedical Research (Bellinzona, Switzerland) and the

United States Army Medical Research Institute of Infectious Diseases The United States Army Medical Research Institute of Infectious Diseases (USAMRIID; pronounced: you-SAM-rid) is the U.S Army's main institution and facility for defensive research into countermeasures against biological warfare. It is located ...

. Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of

roughly ten years later. In 2018, a

Phase 1 clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

of ansuvimab was conducted by Martin Gaudinski within the

br>Clinical Trials Program
that is led by Julie E. Ledgerwood. Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak. Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside toltivimab/maftivimab/odesivimab, a similar

Regeneron Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to i ...

-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved ansuvimab based primarily on evidence from a clinical trial (Trial 1/ NCT NCT03719586) of 342 participants with ''Zaire ebolavirus'' infection. The trial enrolled newborn, pediatric and adult participants (including pregnant women) with ''Zaire ebolavirus'' infection. All participants received standard, supportive care for the disease. In addition to the standard care, participants were randomly assigned to receive either a one-time dose of ansuvimab or one of the three other types of experimental treatments (including one as the control group). The participants and the health care providers knew which treatment was being given. The trial was conducted at four sites in the Democratic Republic of Congo during an outbreak that began in August 2018.

Discovery

A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts led by Dr. Nancy Sullivan at the United States

and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the

. This collaborative effort also involved researchers from Institute of Biomedical Research and the

. A survivor from the 1995 outbreak of

donated blood to the project that began roughly ten years after they had recovered.

Memory B cell In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...

s isolated from the survivor's blood were immortalized, cultured and screened for their ability to produce

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

that reacted with the glycoprotein of

. Ansuvimab was identified from one of these cultures and the

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

heavy and light chain gene sequences were sequenced from the cells. These sequences were then cloned into

recombinant DNA Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be foun ...

plasmids and purified antibody protein for initial studies was produced in cells derived from

HEK 293 cells Human embryonic kidney 293 cells, also often referred to as HEK 293, HEK-293, 293 cells, or less precisely as HEK cells, are a specific immortalised cell line derived from a spontaneously miscarried or aborted fetus or human embryonic kidney cells ...

Ansuvimab and mAb100 combination

In an experiment described in the 2016 paper,

rhesus macaque The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...

s were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.

Ansuvimab monotherapy

In a second experiment described in the 2016 paper,

s were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived. Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.

Development

Ansuvimab was developed by the

with support of the United States

and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans.

Human safety testing

In early 2018, a Phase 1 clinical trial of ansuvimab's safety, tolerability and

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

was conducted by Dr. Martin Gaudinski within the

br>Clinical Trials Program
that is led by Dr. Julie E. Ledgerwood. The study was performed in the United States at the

NIH Clinical Center The NIH Clinical Center is a hospital solely dedicated to Medical research, clinical research at the National Institutes of Health campus in Bethesda, Maryland. The Clinical Center, known as Building 10, consists of the original part of the hospi ...

and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

of 24 days.

Ridgeback Biotherapeutics Ridgeback Biotherapeutics is a Miami based biotechnology company, primarily known for their involvement in developing a successful COVID-19 medication. Ridgeback is privately owned by hedge fund manager and physician, Wayne Holman (formerly of S.A ...

A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the

National Institute of Allergy and Infectious Diseases The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...

. Ansuvimab was given

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status in May 2019 and March 2020.

Experimental use in the Democratic Republic of Congo

During the

2018 Équateur province Ebola outbreak The 2018 Équateur province Ebola outbreak occurred in the north-west of the Democratic Republic of the Congo (DRC) from May to July 2018. It was contained entirely within Équateur province, and was the first time that vaccination with the rVSV ...

, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for

compassionate use Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life ...

by the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites. However, the outbreak came to a conclusion before any therapeutic agents were given to patients. Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in

Kivu Kivu was the name for a large "region" in the Democratic Republic of the Congo under the rule of Mobutu Sese Seko that bordered Lake Kivu. It included three "Sub-Regions" ("Sous-Régions" in French): Nord-Kivu, Sud-Kivu and Maniema, correspondin ...

in the DRC ( 2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols. In November 2018, the Pamoja Tulinde Maisha (PALM ogether save lives open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab,

atoltivimab/maftivimab/odesivimab Atoltivimab/maftivimab/odesivimab, sold under the brand name Inmazeb, is a fixed-dose combination of three monoclonal antibodies for the treatment of ''Zaire ebolavirus'' (Ebola virus). It contains atoltivimab, maftivimab, and odesivimab-ebg ...

(REGN-EB3) and

remdesivir Remdesivir, sold under the brand name Veklury, Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. is a broad-spectrum antiviral medication developed by the ...

ZMapp ZMapp is an experimental biopharmaceutical drug comprising three chimeric monoclonal antibodies under development as a treatment for Ebola virus disease. Two of the three components were originally developed at the Public Health Agency of Canada ...

. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator

. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3. In October 2020, the U.S.

(FDA) approved

(Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by ''Zaire ebolavirus''.

References

External links

* * {{Portal bar , Medicine , Viruses Ebola Monoclonal antibodies Orphan drugs