Intended for US audiences only.

Patient’s Guide to IgRT Replacement Therapy for Primary Immunodeficiency

What Are Immunoglobulins?

An immunoglobulin (abbreviated Ig) or antibody is a large, Y-shaped protein produced by the immune system to fight the germs that make us sick. Our white blood cells make 5 different classes of antibodies that help our immune system fight invaders: IgA, IgD, IgE, IgG, and IgM.1

Some people are born with an immune system that doesn’t work correctly, so they get sick more often and for longer than healthy people.1,2 This type of inherited immune deficiency is called primary immunodeficiency (abbreviated PI or PID).2,3 Because people with PI can’t produce the antibodies needed to fight infection, their repeated and serious illnesses can cause damage to their organs and put their lives at risk.4 Over 400 types of PI diseases (or PIDs) have been discovered to-date. Some of these are common while others are more rare. Fortunately, with proper medical diagnosis and treatment, many people with PI can live full, healthy, and independent lives.

The ABC’s of Immunoglobulin Replacement Therapy

A quick reference for commonly used acronyms
PI or PID Primary Immunodeficiency (Disease)
IgG Purified Immunoglobulin Type G
IgRT Immunoglobulin Replacement Therapy
IMIg Intramuscular Immunoglobulin Therapy
IVIg Intravenous Immunoglobulin Therapy
SCIg Subcutaneous Immunoglobulin Therapy

What Is Immunoglobulin Replacement Therapy (IgRT)?

Therapeutic Ig products are purified from the plasma of human donors. Treatments like these are referred to as biologics (or biologic drugs). Immunoglobulin replacement therapy (abbreviated IgRT) is when Ig products are given to patients with weakened immune systems, like those with PI, to help them prevent and fight infections.

Terminology Tips

Quick definitions of terms used in this article
Adverse event Unwanted harmful side effect
Aggregates Clumps of antibodies
Antibody An infection-fighting protein, or immunoglobulin, in blood plasma
Biologic(s) A medical product that is manufactured in, extracted from, or semi-synthesized from living materials including human, animal, plant, fungal, or microbial.
Fractionation Purification process for commercial IgRT products
Plasmapheresis The separation and removal of plasma from the blood cells
Pool Mixture of plasma from multiple donors

How is Immunoglobulin Replacement Therapy (IgRT) Made?

The antibodies used to make Ig biologics are taken from the blood plasma of thousands of healthy human donors.5,6,7 These donors are specially tested to make sure they do not have any serious infections, like hepatitis or HIV.7 If any plasma sample is even suspected of having one of these viruses, the sample is discarded immediately. The donors also are screened for travel or behavior that might increase their risk of contracting an infectious disease.8 The US Food and Drug Administration (FDA) is very strict about who can become a blood or plasma donor.9 All Ig therapies licensed in the US are made from plasma collected in the US.6

The first step in the production of IgRT involves a process known as plasmapheresis. During plasmapheresis blood is continuously being removed and reinfused back into the body. As it is removed the plasma and the components suspended in it, including antibodies, are retained while the red and white blood cells are reinfused back into the body. This process usually takes place at specialized plasma centers designated for this purpose.10 Once the plasma is collected, it is stored at -25°C (-13°F) for several months.7

While stored, the donations are screened for virus infections and prepared for the next phase of production. Once screened and prepared, the fresh frozen plasma is ready to undergo a complicated series of chemical processing steps called fractionation.7,10 Fractionation is the primary purification process for commercial IgRT products.7 The aim is to produce a biologic drug that can save and improve the quality of life of patients with a variety of PIDs and other conditions that respond to immunoglobulin therapy.7

Most IgRT products contain IgG and only trace amounts of IgA, IgM, and other plasma proteins.7 Along with the trace amounts of IgA and other plasma proteins, most Ig products also contain sugars or amino acids, which stabilize the antibodies and keep them from clumping together and forming aggregates.11 If aggregates form in the IgRT, they can cause unwanted harmful side effects (adverse events).7,11,12 Even though these additives are harmless to most people, they can cause problems for others. This is why it is important to work with your healthcare provider to determine which IgRT product is best for you.

How Does Immunoglobulin Replacement Therapy (IgRT) work?

IgRT is a biologic drug that is given to people whose immune systems don’t work correctly because of a PID. The biologic replaces the immunoglobulins that their body can’t make and helps strengthen their immune system so they can fight the germs that make them sick.

During the preparation of IgRT, any germs found in the donated plasma are inactivated and removed.7 The plasma fractionation process ensures that the final Ig product is safe to use and is free of diseases like HIV and hepatitis. Because the final product is made from the plasma of thousands of donors, it contains a mixture or pool of antibodies.6 This mix of antibodies helps the white blood cells destroy the many different types of bacteria, viruses, and other germs that might be hiding in a patient’s tissues or blood.

Although IgRT can help patients fight infections, the treatment can’t make their immune systems work properly. So, by week three or four, about half of the infused antibodies will be used up and the treatment will need to be repeated—otherwise, the patient can get sick again. For this reason, people who start IgRT treatments should be committed to the therapy. Patients should not “skip” infusions nor change their infusion schedule without first talking to their healthcare prescriber or healthcare provider.

The History of Immunoglobulin Therapy

The use of antibodies to prevent infection dates back to the late 1800s when tetanus and diphtheria toxins were first discovered.13 Scientists found that specific antibodies could neutralize the toxins and that the antitoxins these antibodies produced could make people immune to the diseases.13,14 This discovery led to the development of the tetanus antiserum, which saved many lives during the First and Second World Wars.14,15

The success of the tetanus vaccine led to the discovery that antibodies could be removed from blood plasma and used to protect against other contagious diseases. In the early 1940s, scientists used fractionation to purify immunoglobulins to safely inject into patients.13 They successfully demonstrated that fractionated immunoglobulins could prevent measles or weaken the infection in children who were exposed to the virus during the epidemics of 1942 and 1943.13

Initial IgRT with Intramuscular Delivery

The advent of fractionation led to the development of IgRT for people with PI. Early IgRT products were administered intramuscularly. Intramuscular delivery could not give these patients enough antibodies to keep them healthy for long – they needed to be injected once a week.11 Although IMIg was painful, not well tolerated, and not nearly as safe or effective as the Ig therapies available today, it helped patients live healthier, longer lives than before.11,12 Despite being the standard of care for patients with PI in the U.S. for several decades, the treatment was not ideal. In addition to its painful administration and accommodation of only small, frequent dosing levels, if the product accidentally got into a vein, the patient could have an allergic reaction or other serious adverse event.7,11,12 Doctors knew there had to be a better way.

Early IgRT Exploration with SCIg Therapy

In 1952, a U.S. pediatric immunologist, named Dr. Ogden Bruton, was credited with the first successful use of SCIg immunotherapy.16 However, SCIg was not widely used in the U.S., primarily because of the formulation of those early Ig products. As with IMIg, these early SCIg formulations could potentially be dangerous if they were accidentally injected into a vein.11 Because of those early safety concerns, IMIg remained the standard of care for PI patients in the U.S. until the early 1980s.7,11

New Ig Formulations; IVIg Administration

Fortunately, as science advanced, researchers discovered new and better ways not only to make immunoglobulin products, but also to administer them. They found that by adding sugars and later amino acids, they could stabilize the serum, preventing aggregation of the IgG molecules. The stabilized serum allowed doctors to administer the medication in larger doses, with higher levels of IgG, and with fewer harmful side effects than with IMIg— significantly improving the lives of patients with PI.11 By the early 1980s, the first IVIg products were introduced to the U.S. market and12 and have been the most widely used route of Ig administration since.

Because the new IVIg products contained higher levels of stable IgG, they could be administered every 4 weeks instead of weekly. They were also more effective than IMIg in preventing severe bacterial infections, reducing severe illness and death, and improving the quality of life for their patients.11 Furthermore, doctors found that the new IVIg preparations could be used for other medical conditions, including inflammatory and autoimmune disorders.5,17

The Rise of SCIg7,11,12

Soon after Ogden’s initial success in the 1950s, SCIg became widely used throughout Sweden and Norway as a convenient means of conducting Ig replacement therapy18 and the use of SCIg expanded throughout much of Europe. Over the next decade, American and European researchers would conduct many more studies on the safety and/or efficacy (effectiveness) of SCIg therapy.11 In parallel with the development of better Ig formulations, many of these studies found that SCIg was as safe and effective as IVIg for patients with PI. In 2006 the FDA approved the first SCIg preparation for use in the U.S.12 Thanks in part to newer injection pumps and technological advances in product preparation that make for more convenient and comfortable administration, SCIg has gained popularity as a treatment choice for many PI patients in the U.S.

A Wealth of Therapeutic Options

Fortunately, today there are many IgRT options available to PI patients. Your healthcare provider is your best source of information about which IgRT option is best for you.

Immunoglobulin Replacement Therapy Timeline

Immunoglobulin Replacement Therapy Timeline

The page contains general medical information that cannot safely be applied to any individual case. Medical knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical advice.

References:

1. Justiz Vaillant AA, Ramphul K. Immunoglobulin.[Updated 202 Mar 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from https://www.ncbi.nlm.nih.gov/books/NBK513460/

2. McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61-71.

3. Perez EE. Immunoglobulin use in immune deficiency and autoimmune disease states. Am J Manag Care. 2019 Jun;25(6 Suppl):S92-S97.

4. Chapel H, Prevot J, Gaspar HB, et al. Primary immune deficiencies – principles of care. Front Immunol. 2014;5(627):1-12.

5. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017;139(3):S1-S46.

6. Ness S. Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin. Am J Care. 2019;25:S98-S104.

7. Barahona Afonso AF, Pires Joao, CM. The production process and biological effects of intravenous immunoglobulin. Biomolecules. 2016;15(6):1-20.

8. American Association of Blood Banks. Blood Donor Screening and Testing. AABB.org. http://www.aabb.org/advocacy/regulatorygovernment/donoreligibility/Pages/default.aspx. Accessed April 30, 2020.

9. US Food and Drug Administration. Blood & Blood Products. FDA.gov. https://www.fda.gov/vaccines-blood-biologics/blood-blood-products. Accessed March 29, 2020.

10. El-Ghariani K, Unsworth DJ. Therapeutic apheresis – plasmapheresis. Clin Med. 2006;6:343.

11. Skoda-Smith, Torgerson, Ochs. Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease. Ther Clin Risk Manag. 2010;6:1-10

12. Kobrynski L. Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases. Biologics. 2012;6:277-287.

13. Hooper J. The history and evolution of immunoglobulin products and their clinical indications. J LymphoSign. 2015;2(4):181-194.

14. Aubert et al. History, extensive characterization and challenge of anti-tetanus serum from World War I: exciting remnants and deceived hopes : Centenarian IgGs lost their neutralization capacity. Immunol Res. Published online. 06 March 2020.

15. Hall WW. The US Navy’s war record with tetanus toxoid. Ann Intern Med. 1948;28(2):298-308.

16. Bruton, OC. Agammaglobulinemia. Pediatrics. 1952;9(6)722-728.

17. Novaretti MC, Dinardo CL. Immunoglobulin: production, mechanisms of action and formulations. Rev Bras Hematol Hemoter. 2011:33(5):377-382.

18. Jolles, S. et al., New Frontiers in Subcutaneous Immunoglobulin Treatment. Biologics in Therapy. 2011: 1-15.

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