Status: being added to U.S. biodefense stockpile; BLA filing expected

Organizations involved:

Elusys Therapeutics Inc. – R&D; Tech.; World mark.

Lonza Biologics plc – Manuf.; Tech.

University of Texas – R&D; Tech.

University of Virginia –R&D; Tech.

University of Glasgow – Tech.

Centers for Disease Control and Prevention (CDC) – USA mark.

U.S.Army Medical Research Institute of Infectious Diseases (USAMRIID) – R&D.

Alusuise-Lonza Group – Parent

Cross ref.: See also the other anthrax monoclonal antibody entry (Anthrax Mab/HGSI).

Description: Anthin is a humanized heterpolymer (bi-specific), recombinant monoclonal antibody (Mab) composed of an antibody portion that binds Bacillus anthracis protective antigen (A) and another portion that binds to the CR1 receptors on human erythrocytes (red blood cells), with the antibody portions cross-linked by a polyethylene glycol (PEG) linker.

Anthim is being developed for pre-exposure and post-exposure prophylaxis of inhalational anthrax disease, as well as active treatment of disease, both as a stand-alone therapy and in conjunction with antibiotics, with delivery by a single intramuscular or intravenous dose. Anthim is being developed for intramuscular delivery using pre-filled syringes or auto-injectors. Anthim’s low effective dose should allow for rapid intramuscular delivery to both military and civilian personnel in emergency situations. Although an IV dosage form is available, IM delivery is considered an essential method of drug delivery to treat large numbers of civilians in an emergency situation.

Anthim (and other Elusys Mabs) incorporate the company's Heteropolymer (HP) Antibody technology to enhance the effectiveness of the body’s natural defense mechanisms that remove and destroy pathogens. An HP Antibody consists of a monoclonal antibody specific to a red blood cell receptor (CR1) that is chemically linked to a second antibody that binds a particular pathogen, e.g,., B. anthracis protective antigen (PA). After administration, the HP drug rapidly binds target pathogens to red blood cells and facilitates their clearance and destruction via liver macrophages. HP drugs have advantages for the treatment of immunocompromised patients, such as AIDS and cancer patients, who typically have low levels of neutrophils and complement, important factors for fighting infection. In vivo studies demonstrate that in addition to treating an infection, HP Mabs also provide active immunity against secondary infections from the same pathogen. This suggests that an HP Mab may be useful as a therapeutic vaccine to provide long term protection from infection.

Nomenclature: Anthrax Mab, rDNA/Elusys [BIO]; Anthim [TR]; Bacillus anthracis (anthrax) Protective Antigen (PA) monoclonal antibody, recombinant [SY]; ETI-204 [SY]

Biological.: See the Anthrax Mab/HGSI entry for information about anthrax monoclonal antibody activity and effects.

Heteropolymer (HP) Antibody technology is based on the RBC receptor (CR1), known to be specific for certain activated complement proteins (C3b, C3bi and C4b). CR1 has an important role in primate defense against microorganism infection by facilitating the neutralization and clearance of certain pathogens. The binding of these immune complexes to RBC's at the CR1 site provides a vehicle for rapid clearance of potentially pathogenic immune complexes from circulation. RBC binding and clearance capacity is confined to immune complexes recognized by the CR1 receptor, that is the immune complexes must contain large amounts of at least one of the activated Complement proteins C3b, C3bi, or C4b. Thus, primates have no normal capacity to take advantage of the clearance system provided by the RBC binding ability to remove antigens not complexed with the identified activated complement proteins. HP antibody technology augments the natural capacity of the mammalian circulatory system to clear antigens through RBC binding ability to include the ability to bind immune complexes (antigen/antibody complexes) via CR1 to RBC's in the absence of activated complement proteins. Specific monoclonal antibody heteropolymers are prepared from Mabs specific to the CR1 RBC receptor and Mabs to at least one other antigen, e.g., PA, and are then heteropolymerized using established techniques. This heteropolymer binds readily to RBC's in whole blood. The RBC's, if franked in vivo with the heteropolymer, will then bind the antigen for which the remaining Mab is specific. These RBC's can act therapeutically by facilitating the neutralization and clearance from the circulation of the bound antigen.

Anthim is highly effective because it completely neutralizes anthrax toxin before the toxin interacts with target cells. The high potency of Anthim is due in part to the “affinity-enhancement” process carried out by the laboratories of Drs. G. Georgiou and B. Iverson at the University of Texas (Austin, TX).

Anthim has been extensively studied in multiple models of anthrax infection and has consistently prevented death in 70 – 100% of animals treated with a single dose. In animal studies, Anthim has demonstrated complete protection against an anthrax spore challenge with a single prophylactic dose and has shown significant protection when administered up to two days after a lethal challenge. A single pre-exposure dose can provide complete protection. A single intramuscular (IM) or intravenous (IV) dose with or without antibiotic, administered 6-12 hours post-exposure, was 100% protective in rabbits as a stand alone therapy, while survival with antibiotics alone was only 33%. A single IV dose demonstrated significant protection up to 48 hours after a lethal anthrax spore challenge. Alluding to ABtrhax (Anthrax Mab/HGSI), Elusys has reported, "Compared with other antibodies in development, Anthim has shown greater efficacy at a significantly lower dose when given either before or after anthrax exposure."

Animal efficacy studies have shown that Anthim prevents the spread of bacteria to the blood and to other organs and reduces the bacterial load in the lungs and lung associated lymph nodes.

Companies.: Anthim was developed by Elusys Therapeutics Inc. The company has been receiving federal funds related to development of Anthim since 2005.

The U.S.Army Medical Research Institute of Infectious Diseases (USAMRIID) collaborated in the development of Anthim through a Collaborative R&D Agreement (CRADA) with Elusys, starting in 2000.

In June 2009, Elusys signed an agreement with Lonza for process development and contract manufacture of Anthim at one of its facilities in the US.., including use of the GS Gene Expression System (see the Tech. transfer section).

In Dec. 2009, BARDA/NIH/DHHS granted Elusys a 5-year contract potentially worth $143 million for further development and supply of Anthim for the national biodefense stockpile. In 2009, Elusys was awarded a contract totaling up to $143 million from the Biomedical Advanced Research and Development Authority (BARDA) within the U.S. Department of Health and Human Services to complete the final development, commercial manufacturing and licensure of Anthim. This contract represented one of the largest awarded by BARDA for advanced product development. The first-year, initial payment was $16.8 million to support manufacturing scale-up and clinical trials. The contract, one of the largest awarded by BARDA for advanced product development, will support the company’s clinical and commercial strategy, including scaling up manufacturing, expanded human safety trials and pivotal, non-clinical effectiveness studies in animals, through FDA licensure. Prior to this contract, Elusys had received a total of $34 million in government funding for advanced development of Anthim from HHS, BARDA, NIAID and the Department of Defense.

Elusys, has received some funding from MedImmune Ventures. Other venture capital investors include include Essex Woodlands Health Ventures LLC, Invesco Private Capital, and Crescendo Ventures.

In Sept. 2012, Elusys was awarded additional funding from the U.S. Government, valued at $14.5 million, to support expanded human safety studies of ETI-204 (Anthim), FDA class: Biologics BLA

Status: FDA has granted Anthim fast-track status and orphan drug designation for treatment of inhalational anthrax. Anthim is being developed under the FDA Animal Rule, a regulatory process specifically designed for the development of medical countermeasures to bioterror threats, e.g., where human trials are unethical or impossible.

An IND was filed on Feb. 24, 2005. An Emergency Use Authorization application was filed on Oct. 5, 2005, and supplemental information was submitted in Aug. 2006.

Tech. transfer: Heteropolymer (HP) Antibody technology was licensed from the University of Virginia. Patents assigned to University of Virginia include U.S. 5,487,890, " Mammalian primate erythrocyte bound heteropolymerized monoclonal antibodies and methods of use thereof." Mammalian, e.g,., human, red blood cells (RBCs) are used to safely and rapidly neutralize and/or clear antigens or immunogens from the circulatory system by binding to the RBCs a monoclonal antibody specific for a receptor (CR1) on the RBC, with this monoclonal antibody chemically bound to a second Mab specific for the antigen to be cleared from the circulatory system.

Patent applications assigned to Elusys include US2006153839, , "Production of bispecific molecules using polyethylene glycol linkers," with Mabs cross-linked using a polyethylene glycol (PEG) linker with one or more second recognition binding moieties that bind another Mab. Elusysis is also the assignee for US2006263792, "Use of CR1-binding molecules in clearance and induction of immune responses," claiming therapeutic and prophylactic uses.

The glutamine synthetase (GS) gene amplification/expression system was used to select and amplify transformed host cells for expression. The GS System is based patents issued to Celltech Biologics plc, now assigned to Lonza Group plc, subsidiary of Alusuise-Lonza Group. Related patents include U.S. 5,846,534; 5,770,359; and 5,747,308 (coassigned to the University of Glasgow). These patents describe dominant selectable markers for use in co-amplification of non-selected genes and transformation of host cell lines to glutamine independence. The GS gene is used in recombinant vectors as a selectable marker along with (an)other gene(s) for expression in cells deficient in GS, e.g., NS0 cells. Only successfully transformed cells are capable of producing their own GS enzyme and surviving in glutamine-deficient culture media, with this allowing easy, reliable selection and amplification of transformed cells. Over 40 companies have licensed GS System technology for various uses.

Trials: In two dose-escalating human clinical safety studies, results showed Anthim to be safe and well-tolerated at doses at or above the anticipated efficacious dose in humans.

Medical: Anthim is generally administered by intramuscular (IM) injection. Anthim's effective low dose allows for single dose IM delivery.

Market: Distribution, if needed, will be handled in the U.S. by the Centers for Disease Control and Prevention (CDC).

Competition: The primary competition for Anthim is ABThrax (see the Anthrax Mab/HGSI entry).