Botulism Immune Globulin Intravenous (Equine); Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine); Heptavalent Botulism Antitoxin; NP-018; botulism immune globulin intravenous; BIG-IV; Clostridium botulinum toxin types A, B, C, D, E, F and G immune globulin F(ab’)2 fragments, equine; Botulism Antitoxin (BAT)
Status: added to U.S. biodefense stockpile; BLA approved in March 2013
Organizations involved:
Cangene Corp. – Manuf.; R&D; Tech.
Centers for Disease Control and Prevention (CDC) – USA mark.
New York Blood Center – Tech.
Cross ref.: Particularly, see also the entry below for an earlier Botulism antitoxin (#912) or equine (horse)-derived botulinum toxin immune globulin. See the entry for Immune Globulin Products (#743), Botulinum Toxin Products (#600) and Botulism Immune Globulin Intravenous (Human) (BabyBIG; #747), a human immune globulin product.
Description: Heptavalent Botulism Antitoxin is a lyophilized (freeze-dried) formulation of “despeciated” equine immune globulin enzymatically (pepsin)-derived F(ab’))2 [and some F(ab) fragments] derived from the pooled plasma of horses immunized with seven botulinum toxoids (i.e., vaccine containing inactivated botulinum toxin from Clostridium botulinum types A, B, C, D, E, F or G; see the Botulinum Toxoids entry, #413), followed by the equivalent toxins, after the horses’ type-specific antibodies are at a protective level. manufacture includes viral inactivation/removal by the solvent-detergent process and nanofiltration. Heptavalent Botulism Antitoxin contains polyclonal IgG F(ab’))2 fragments representative of those of the immunized donor horses having contributed to the plasma pool from which the product is derived. See the manufacture section below for further information.
Biological.: The major drawback to using equine plasma is the need to de-speciate (despeciate) the antitoxin using pepsin to remove the antigenic Fc (constant or framework) section of the equine IgG molecule. This reduces the likelihood of serum sickness and increases tolerability. The de-speciation, however, reduces the circulating half-life of the product, compared to intact IgG.
Nomenclature: Botulinum immune globulin/Cangene [BIO]; Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine) [FDA upon approval]; Botulism Immune Globulin Intravenous (Human) [FDA former]; Heptavalent Botulism Antitoxin [FDA former]; botulinum toxin human immune globulin [SY]; BIG-IV [SY]; Clostridium botulinum toxin immune globulin, equine [SY]; botulism immune globulin intravenous [SY]; Heptavalent Botulism Antitoxin [SY]; Botulism Antitoxin [SY]; BAT [SY]; NP-018 [SY]
Manufacture: The overall manufacturing scheme is immunization of horses; collection and pooling of plasma; solvent-detergent viral inactivation of plasma; diafiltration and depth filtration; cation exchange chromatography; pepsin digestion; filtration/concentration diafiltration; anion exchange chromatography; viral nanofiltration; and diafiltration, formulation, final filtration, and packaging. Manufacturing is performed at the 200 L scale.
Heptavalent Botulism Antitoxin is prepared from plasma obtained from horses that have been immunized with a specific subtype of botulinum toxoid. Plasma from horses immunized with the same toxin type is pooled and immune globulin manufactured by conventional purification and chromatography methods. Each individual horse is immunized against a single botulinum toxin subtype, i.e,. receives a specific C. botulinum toxoid (inactivated toxin; vaccine) - A, B, C, D, E, F or G; and plasma is pooled from horses that have been immunized with the same botulinum toxin subtype. For each antitoxin serotype (A-G), a despeciated product is manufactured by pepsin digestion of the IgG monomer in the pooled equine plasma, yielding predominantly F(ab’))2 fragments. Pepsin digestion at pH = 3.5 cleaves the antigenic Fc (constant or framework) portion from the IgG monomer, leaving F(ab’))2 and Fab fragments. Pepsin also digests unwanted plasma protein contaminants, which are then removed, with the pepsin, by diafiltration and anion exchange chromatography. After viral (nano)filtration, the F(ab’))2\Fab is diafiltered, formulated, and bulk filtered. Later the bulks of the seven botulinum serotypes are blended and filled. The end product is a highly purified liquid F(ab’))2\Fab blend with ≤2% monomeric IgG fraction, which may be safely administered to humans.
Methods used to decrease the chance of equine/animal virus contamination include proper herd management, with plasma, like human immune globulin products, obtained under GMP conditions from carefully screened animals. There is a complete health record for each horse that includes regular physical examination, daily observation and a written procedure for follow-up of unexpected death. After a 21-day quarantine period, each horse undergoes 9 CFR Adventitious testing before joining the herd (tested for equine infectious anemia, piroplasmosis, glanders, dourine, and brucelosis). The horse are washed down with a disinfectant and are kept in a pre-collection area prior to plasmapheresis. The collection area is segregated and is operated similar to a human plasmapheresis center. Autopheresis units are used to collect 20 L of plasma per donation. The plasma pool obtained from various equine plasma donations is tested to detect adventitious agents included: rabies, reovirus (REO-3), bovine viral diarrhea virus (BVDV), equine herpes virus (EHV-1), equine arteritis virus (EAV-1), West Nile Virus (WNV) and Eastern Equine Encephalitis virus (EEEV).
The pooled plasma is subjected to solvent-detergent (SD) viral inactivation (see entry #799). The SD agent [generally, tri-n-butyl phosphate (TNBP), and octoxynol or polysorbate 80 (Tween 80)] are added to plasma that has been filtered to 1.0 to ensure the removal of particles that could harbor viruses. The plasma with the SD chemicals is incubated >4 hours at room temperature. The second viral reduction step is virus (nano)filtration of the purified product, employing Millipore’s NFP (normal flow parvovirus) filter. The virus filtration is performed from one manufacturing area through the wall into a “virus safe” area to prevent re-contamination. The SD process primarily inactivated viruses with lipid envelopes, while virus filtration step does not distinguish between lipid or non-lipid enveloped viruses, but removes viruses based on their size. Both virus clearance steps have been validated by scale-down studies using a panel of model viruses selected to represent viruses that are potential contaminants of equine plasma, and to represent a wide range of physical and chemical properties in order to ensure clearance of new and emerging viruses.
Virus inactivation/reduction processing by nanofiltration results in reduction of porcine parvovirus, 4.5-6.0 log; xenotropic murine leukemia virus, ≥2.3 log; West Nile virus, ≥2.1 log; bovine diarrehea (BBDV), ≥4.5 log; parainfluenza III virus, N.A. (not tested); pseudorabies virus, N.A.; adenovirus (Ad2), ≥4/7 log; and encephalomyocarditis virus (EMC), ≥4.5 log. Virus inactivation/reduction by solvent-detergent inactivation results in reduction of porcine parvovirus, N.A.; xenotropic murine leukemia virus, ≥4.7 log; West Nile virus, ≥5.3 log; bovine diarrehea (BBDV), N.A.; parainfluenza III virus, ≥5.6; pseudorabies virus, ≥5.4; adenovirus (Ad2), N.A.; and encephalomyocarditis virus (EMC), N.A.
Companies.: Heptavalent Botulism Antitoxin is being developed and manufactued by Cangene Corp. under federal government contract for inclusion in the U.S. civilian biodefense stockpile.
In May 2006, the Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, granted Cangene a five-year, $362,641,105, sole-source contract for development, manufacture and delivery of 200,000 doses of Heptavalent Botulism Antitoxin) for addition to the U.S. civilian biodefense stockpile, to be available to treat individuals exposed to the bacteria and/or the toxin that cause botulism. This works out to about $1,813/dose. The contract requires that Cangene receive FDA approval for use of this product. The price per dose is a discounted fixed price, and Cangene receives payments after deliveries of quantities of “usable product” to the U.S. Strategic National Stockpile. Once FDA licensure is received, Cangene may receive a supplemental payment. In addition to this base contract, there is a possibility that optional task orders worth up to $234 million may be awarded at the government’s discretion. These tasks include ongoing testing to support long-term product shelf life, maintaining product manufacturing, and additional clinical testing in special populations. Cangene manufactures the product at its Winnipeg, Canada, facility but uses its U.S. subsidiaries and other U.S. companies for all key subcontracting activities.
Cangene had earlier conducted research and development with this product through a much smaller CDC grant, and Cangene has experience in the final manufacture of BabyBIG (see entry above), the human botulinum toxin immune globulin approved in the the U.S. for pediatric use.
FDA class: Biologics BLA
CBER class: Antitoxins, Antivenins, Enzymes and Venoms
Status: Cangene expects to begin deliveries of the 200,000 doses ordered by CDC in mid-late 2007. Cangene plans to apply a BLA for accelerated approval with Fast Track review with FDA.
Although primarily intended for biodefense uses, e.g., in case of attack using botulinum toxin or toxin-expressing bacteria, Heptavalent Botulism Antitoxin will also presumably be available for treatment of isolated natural and other cases of botulism (C. botulinum toxin poisoning).
Market: See the Market section of the Botulism antitoxin/A,B,E entry below for information about CDC distribution of the product.
Originally developed and manufactured for the U.S. civilian biodefense stockpile, as with most other biodefense products developed for and acquired by the U.S. government, Cangene will likely seek to market this product to other countries and their militaries.
Companies involvement:
Full monograph
911 Botulism antitoxin/A-G
Nomenclature:
Botulism antitoxin/A-G [BIO]
Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine) [FDA upon approval]
Botulism Immune Globulin Intravenous (Equine) [FDA former]
Heptavalent Botulism Antitoxin [FDA former]
BAT [SY]
BIG-IV [SY]
botulinum toxin equine immune globulin [SY]
botulism immune globulin intravenous [SY]
Clostridium botulinum toxin immune globulin F(ab')2 fragments, equine [SY]
heptavalent equine-derived botulinum antitoxin [SY]
NP-018 [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = 2013
Date of 1st FDA approval = 20130323
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
antithrombin III deficiency
biopharmaceutical products
blood products
equine immune globulins <!-- immunoglobulins -->
equine materials used
immune globulins, Fab fragments <!-- immunoglobulins -->
botulinum toxins
Clostridium botulinum
equine plasma/serum
Namalva cells
octoxynol (Triton X-100)
pepsin digestion
polysorbate 80 (Tween 80)
tri-n-butyl phosphate (TNBP)
viral inactivation, solvent detergent
apheresis (hemapheresis)
BHK-21 (C-13)
conjugates
North American coral snake
octoxynol (Triton X-100)
EU000 Not yet/Never filed with EU
UM100 Controlled/Gov't Distribution in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
Copyright© 2020, Biotechnology Information Institute