DiversitAb™ Immunotherapy Platform
Frequently Asked Questions
Why polyclonal antibodies?
Polyclonal antibodies are the natural way that our bodies fight disease. These antibodies are produced and bind to multiple locations (epitopes) on a disease antigen. This is important to reduce the risk of developing escape mutants if only a single location on the disease antigen is targeted, as is the case when using a monoclonal antibody.
This same principle can make polyclonal antibody therapeutics an excellent choice to prevent and treat antiviral and antibiotic resistance. In addition, polyclonal antibodies are polyclonal on the Fc receptor end, and therefore elicit a full range of effector cell functionality to produce a robust immune response to disease.
The use of polyclonal antibodies is not new, in fact it is a very old idea, but was previously limited by the lack of a source other than humans or animal antibodies, which each have limitations. The Tc bovine system is a new source of fully human polyclonal antibodies, which can be targeted to produce high titer, high affinity and high avidity antibodies.
Are there other polyclonal antibody products approved by FDA and on the market?
Yes. In fact, there are over 35 approved polyclonal antibody products on the market in the US. These include products such as human intravenous immunoglobulin (IVIG), human derived anti-anthrax antibody, human derived anti-vaccinia (small pox) antibodies, human derived anti-hepatitis B antibodies, horse derived anti-botulinum antibodies, rabbit and horse derived anti-thymocyte globulin, snake anti-venoms, spider anti-venoms, and scorpion anti-venoms.
How does FDA regulate polyclonal antibodies?
The FDA regulates plasma derived polyclonal antibodies through the Center for Biologics Evaluation and Research (CBER) Office of Tissue and Advance Therapeutics (OTAT) Division of Plasma Derived Therapeutics (DPDT).
This regulation is different from cell culture derived monoclonal antibodies, which are regulated by the Center for Drug Evaluation and Research (CDER). The regulation of polyclonal antibodies is not new for FDA CBER and, in fact, the Tc bovine derived antibodies will be regulated exactly the same as other plasma derived immunoglobulins. The regulatory system for our products already exists and SAB has had multiple interactions with FDA CBER regarding the regulation of these products with no indication that pathway will be any longer than any other antibody products.
How do you dose a polyclonal antibody?
SAB will dose our polyclonal antibody products in the same way as other polyclonal products already approved by FDA. These products are dosed based upon lot-to-lot activity, and doses are typically expressed in units/kg (i.e. 1000 units/kg) of patient body weight. In addition, there is a range specification of total protein that can be administered.
For example, if the total protein specification is 40-60 mg/kg and if the dose were 1000 units per kg and the potency test of lot #1 showed the neutralization units per mg of total protein was 20 units/mg, then the total protein dose would be 50 mg/kg from this lot.
If lot #2 shows the neutralization units per mg of total protein was 24 units/mg, then the total protein dose would be 41.7 mg/kg). These lots would be considered to be “consistent”.
Don’t you require much higher doses of antibody than monoclonal antibodies?
No. An argument can be made that if a monoclonal antibody product binds 100% to a single epitope of a target antigen, and a polyclonal antibody mixture bind 5% to the target antigen, then you will need 20 times more polyclonal antibody to get the same effect. Our studies have shown that this hypothesis is false. In fact, because of the polyclonality of our antibodies, where the antibodies bind to multiple locations (epitopes) on the antigen, both high (-13kEV) affinity and low affinity binding antibodies and polyclonal Fc receptor binding, doses are similar to monoclonal products to similar targets. This makes Tc bovine derived human polyclonal antibodies dose competitive with monoclonal antibody products.
What about off target antibodies, do they cause problems?
No. Off target antibodies are a natural component of all polyclonal antibody therapeutics. The FDA requires human tissue cross reactivity studies to ensure that off target antibodies are not binding to human tissues and organs. Off target antibodies may be beneficial, as polyclonal antibodies have antibodies against other infectious diseases. Polyclonal antibodies are also known to have anti-inflammation and even anti-metastasis properties. Off target antibodies have not been a problem in other approved polyclonal antibody products and we have no reason to believe they would be in Tc bovine derived human antibodies. While antigen affinity chromatography columns could be used to extract the antigen specific antibodies from the polyclonal mixture, the significant risk would be the loss of high affinity binding antibodies that could not be eluted from the antigen column.
How can you ensure lot-to-lot consistency with a polyclonal antibody?
If the total protein specification of polyclonal antibodies is 40-60 mg/kg and if the dose were 1000 units per kg and the potency test of lot #1 showed the neutralization units per mg of total protein was 20 units/mg, then the total protein dose would be 50 mg/kg from this lot. A lot #2 shows the neutralization units per mg of total protein was 24 units/mg, then the total protein dose would be 41.7 mg/kg. These lots would be considered to be “consistent” because they are within the specifications. Additionally, all lots are manufactured by the same downstream purification process and must meet QC test specifications of impurities and parameters.
The motivation behind the Transchromosomal (Tc) bovine platform is to produce large amounts of targeted, fully human polyclonal antibodies (aka immunoglobulin) with high titers or neutralizing activity to treat human disease. Cattle are large animals, which produce meat, and milk that is ubiquitously consumed safely by humans. The technology has also existed for nearly two decades to perform the required genetic engineering to turn off the endogenous bovine antibody genes, replace them with the entire germ line repertoire of the human antibody genes in a human artificial chromosome (HAC) vector in bovine fibroblast cells (skin cells), and then produce animals through somatic cell nuclear transfer (cloning).
What about bovine spongiform encephalitis (BSE, aka “Mad Cow Disease”)?
Prion diseases such as BSE (cattle), Scrapie (Sheep), Creutzfeldt Jacob Disease (Human) and Kuru (Human) and other transmissible spongiform encephalitis diseases are a concern for any mammalian donor system, such as blood transfusions, plasma donors and production of polyclonal immunoglobulins.
The greatest risk of these diseases in ruminants, i.e. cattle, sheep, and goats, is when they are fed by-products from other ruminants. Animal feed caused the major outbreak of BSE in Europe in the 1990’s and a ban of feeding ruminant material to ruminants was initiated in 1997 in the US and around the world. This has resulted in no new cases in the US in almost a decade.
Prion disease risk in plasma products is known to be low. In addition, regulatory agencies, such as FDA, require prion removal validation in downstream purification methods. In discussions with FDA, SAB has learned that the agency has no more concern with cattle donors than with humans. SAB has performed validation studies of TSE (transmissible spongiform encephalopathy) clearance on our purification methods, which have met the requirements (>5 log10 reduction) of regulatory authorities.In addition, SAB maintains a rigorous risk mitigation strategy to ensure that all inputs into Tc bovine do not contain ruminant material.
Have you completed human clinical trials on any Tc bovine antibodies? Is it safe?
Yes. SAB is currently conducting two Phase 1 clinical studies and has completed all necessary pre-clinical studies in animals to show that our products are safe. Although the clinical studies are not yet complete, there have been no reports of any serious adverse events in the studies up to doses as high as 100 mg/kg. Safety studies will continue as more products move into clinical studies and SAB will continue to work closely with the FDA as products move through the clinic.
Are transgenic animals like Tc bovine regulated?
Transgenic animals that produce therapeutic human proteins are regulated by the FDA Center for Veterinary Medicine (CVM). There are approved transgenic animals that are producing human therapeutic proteins, including goats, chickens and rabbits. SAB works closely with the CVM and have CVM regulatory filings that coincide with the development of our products. In addition, CVM and CBER work closely together on the regulation of both the animal platform as well as the antibody products themselves.
Is this platform sustainable? How do you scale up and maintain a herd of production animals?
SAB Biotherapeutics’ Tc animals are produced by cloning. SAB maintains master and working cell banks of Tc bovine fibroblast cells, which are frozen and are thawed to produce more animals. SAB currently has around 40-50 Tc bovine for our current stage of development, but we have the capability to quickly ramp up to produce several hundred Tc bovine per year. It takes about 15 months from the time the process begins to produce animals to the time the animals are ready to enter production (i.e. 9 month gestation of the Tc bovine until birth and 6 months of growth prior to entering production). SAB has enough cells in our cell banks to clone Tc bovines for several decades if not centuries.
What is the purification method and is it scalable?
The purification method consists of a plasma fractionation, followed by multiple chromatography steps, nano-filtration, and final fill. This purification method is not novel and has been used by manufacturers of approved products for many years. Our purification process is scalable (we currently run 30L plasma batches) and we have suggested multiple lines of 500L plasma batches. Each Tc bovine can produce up to 30-60L of plasma per month and these animals are producing between 10 and 20 grams of human antibody per liter of plasma.
How do the Cost of Goods and Services (COGS) compare to monoclonal antibodies?
The cost of goods and services of our antibodies are lower than monoclonal antibodies. While the downstream purification costs are similar to monoclonals, the upstream production of antibodies in the Tc bovine is lower than mammalian cell-based production of monoclonals.
What experience does your team have with developing and manufacturing therapeutic antibody products?
Our team has many years of experience working for biopharmaceutical companies developing both monoclonal and polyclonal antibody therapeutics; and developed our regulatory strategy and quality systems. We have also consulted with a former FDA reviewer within the same office that regulates our product and have direct consultations with the FDA on an ongoing basis.